A Phase II Randomized Study of Durvalumab and Tremelimumab and Best Supportive Care vs Best Supportive Care Alone in Patients With Advanced Colorectal Adenocarcinoma Refractory to Standard Therapies
Phase: PHASE2
Conditions: Colorectal Cancer
Sponsor: Canadian Cancer Trials Group

 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: CO.26 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION 
 
ADMINISTRATIVE UPDATE #1: 2018-JAN-24 
 
 
ADMINISTRATIVE UPDATE #2: 2018-JAN-31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE II RANDOMIZED STUDY OF DURVALUMAB AND TREMELIMUMAB AND BEST 
SUPPORTIVE CARE VS BEST SUPPORTIVE CARE ALONE IN PATIENTS WITH ADVANCED 
COLORECTAL ADENOCARCINOMA REFRACTORY TO STANDARD THERAPIES 
 
CCTG Protocol Number: CO.26 
 
 
 
STUDY CHAIR: 
Eric Chen 
 
 
TRIAL COMMITTEE: 
Derek Jonker 
 
 
Hagen Kennecke 
 
 
Sheryl Koski 
 
 
SENIOR INVESTIGATOR: 
Chris O’Callaghan  
 
 
BIOSTATISTICIAN: 
Dongsheng Tu 
 
 
QUALITY OF LIFE COORDINATOR: 
Alice Wei 
 
 
STUDY COORDINATOR: 
Nadine Magoski 
 
 
REGULATORY SPONSOR: 
CCTG 
 
 
SUPPORTED BY: 
AstraZeneca 
 
 
(For contact information of study personnel see Final Page.) 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .................................................................................. 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 2 
 
1.0 
OBJECTIVES ......................................................................................................................................... 3 
1.1 
Primary Objective ................................................................................................................................... 3 
1.2 
Secondary Objectives .............................................................................................................................. 3 
1.3 
Tertiary Objectives .................................................................................................................................. 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 4 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION.......................................................................... 10 
3.1 
Durvalumab ........................................................................................................................................... 10 
3.2 
Tremelimumab ...................................................................................................................................... 11 
3.3 
Fixed Dosing in Durvalumab and Tremelimumab ................................................................................ 13 
 
4.0 
STUDY POPULATION ....................................................................................................................... 14 
4.1 
Eligibility Criteria ................................................................................................................................. 14 
4.2 
Ineligibility Criteria ............................................................................................................................... 18 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT....................................................................................................................................... 20 
5.1 
Patient Evaluation Flowsheet: Pre-study (Baseline) and Post-randomization Follow-up ..................... 20 
5.2 
Patient Evaluation Flowsheet: Pre-Treatment, On-Study, and after Protocol Treatment ...................... 22 
5.3 
Follow-up for Ineligible Patients ........................................................................................................... 24 
 
6.0 
ENTRY/RANDOMIZATION PROCEDURES .................................................................................... 25 
6.1 
Entry Procedures ................................................................................................................................... 25 
6.2 
Stratification .......................................................................................................................................... 25 
6.3 
Randomization ...................................................................................................................................... 26 
 
7.0 
TREATMENT PLAN ........................................................................................................................... 27 
7.1 
Protocol Treatment Plan ........................................................................................................................ 27 
7.2 
Concomitant Therapy ............................................................................................................................ 31 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 33 
8.1 
Definitions ............................................................................................................................................. 33 
8.2 
Response and Evaluation Endpoints ..................................................................................................... 33 
8.3 
Response Duration ................................................................................................................................ 38 
8.4 
Stable Disease Duration ........................................................................................................................ 38 
8.5 
Methods of Measurement ...................................................................................................................... 38 
 
9.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 40 
9.1 
Definition of a Reportable Serious Adverse Event (Durvalumab +/- Tremelimumab Arm) ................ 40 
9.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 42 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting............................ 43 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 44 
9.5 
CCTG Reporting Responsibility to AstraZeneca .................................................................................. 44 
9.6 
AstraZeneca Reporting Responsibilities ............................................................................................... 44 
9.7 
Reporting Safety Reports to Investigators ............................................................................................. 44 
 
 

 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 46 
10.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 46 
10.2 
Duration of Protocol Treatment ............................................................................................................ 46 
10.3 
Therapy After Protocol Treatment is Stopped ...................................................................................... 46 
 
11.0 
CENTRAL REVIEW PROCEDURES ................................................................................................. 47 
11.1 
Central Radiology Review .................................................................................................................... 47 
11.2 
Central Pathology Review ..................................................................................................................... 47 
12.0 
CORRELATIVE STUDIES .................................................................................................................. 48 
12.1 
Protocol-Mandated Correlative Studies ................................................................................................ 48 
12.2 
Optional Banking of Samples ............................................................................................................... 50 
 
13.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 51 
13.1 
Objectives and Design ........................................................................................................................... 51 
13.2 
Study Endpoints and Analysis ............................................................................................................... 51 
13.3 
Sample Size and Duration of Study ...................................................................................................... 52 
13.4 
Safety Monitoring ................................................................................................................................. 52 
13.5 
Interim Analysis .................................................................................................................................... 52 
 
14.0 
PUBLICATION POLICY ..................................................................................................................... 53 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. ..................................................................................... 53 
14.2 
Responsibility for Publication ............................................................................................................... 53 
14.3 
Submission of Material for Presentation or Publication ........................................................................ 53 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 54 
15.1 
Regulatory Considerations .................................................................................................................... 54 
15.2 
Inclusivity in Research .......................................................................................................................... 54 
15.3 
Obtaining Informed Consent ................................................................................................................. 55 
15.4 
Discontinuation of the Trial .................................................................................................................. 56 
15.5 
Retention of Patient Records and Study Files ....................................................................................... 56 
15.6 
Centre Performance Monitoring ............................................................................................................ 56 
15.7 
On-Site Monitoring/Auditing ................................................................................................................ 57 
15.8 
Case Report Forms ................................................................................................................................ 57 
 
16.0 
REFERENCES ...................................................................................................................................... 58 
 
APPENDIX I -  
PERFORMANCE STATUS SCALES/SCORES .............................................................. 61 
APPENDIX II -  
DRUG DISTRIBUTION, SUPPLY AND CONTROL...................................................... 62 
APPENDIX III -  
DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED 
REACTIONS...................................................................................................................... 63 
APPENDIX IV -  
DOCUMENTATION FOR STUDY .................................................................................. 63 
APPENDIX V -  
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .................... 88 
APPENDIX VI -  
QUALITY OF LIFE ASSESSMENT ................................................................................ 89 
 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 

 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG and 
AstraZeneca. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG and CCTG and 
AstraZeneca to study personnel under my supervision. I will discuss this material with them to ensure that 
they are fully informed about the investigational product and the study. 
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of AstraZeneca and CCTG. The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, I will give prompt notice to AstraZeneca 
and CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG or AstraZeneca with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
AstraZeneca and CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG CO.26  
 
CENTRE: ___________________________________________ 

 
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TREATMENT SCHEMA 
 
This is a multi-centre, phase II study of doublet immunotherapy (durvalumab + tremelimumab) and best 
supportive care versus best supportive care only in patients with advanced colorectal cancer who are 
refractory to all available therapy, conducted by the Canadian Cancer Trials Group with the support of 
AstraZeneca. 
 
Patients with advanced CRC, 
refractory to all available therapy 
 Randomize 
1:2 
 
ARM 1: 
Best Supportive Care 
N=60 
 
 
 ARM 2: 
Durvalumab + Tremelimumab* 
and Best Supportive Care 
N=120 
Sample Size: 180 
Primary Endpoint: Overall Survival 
 
* Tremelimumab and Durvalumab every 4 weeks for 4 cycles (1 cycle = 4 weeks (28 days), followed by 
Durvalumab monotherapy to objective disease progression. See Section 7 for details.  
 
Patients will be stratified by: 
• 
ECOG Performance Status: 0 vs 1 
• 
Site of tumour:  
− 
right colon (caecum, ascending colon, hepatic flexure) vs  
− 
transverse colon vs  
− 
left colon (within the splenic flexure, descending colon, sigmoid colon, or rectosigmoid junction) 
vs  
− 
rectum vs  
− 
unknown  

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
The primary objective is to determine the effect on overall survival (OS) of the combination of 
durvalumab and tremelimumab and best supportive care versus best supportive care only in patients 
with refractory, advanced colorectal cancer. 
 
1.2 
Secondary Objectives 
• 
To determine the effect on progression-free survival (PFS) of the combination of durvalumab 
and tremelimumab and best supportive care versus best supportive care only in patients with 
refractory, advanced colorectal cancer. 
• 
To assess the toxicity and safety of the combination of durvalumab and tremelimumab and best 
supportive care in patients with refractory, advanced colorectal cancer. 
• 
To determine the effect on objective response rate (ORR) of the combination of durvalumab 
and tremelimumab and best supportive care versus best supportive care only in patients with 
refractory, advanced colorectal cancer. 
 
1.3 
Tertiary Objectives 
• 
To determine the effect on quality of life (QoL) of the combination of durvalumab and 
tremelimumab and best supportive care versus best supportive care only in patients with 
refractory, advanced colorectal cancer. 
• 
To determine the effect of tumour PD-L1 expression assessed by IHC on efficacy of the 
combination of durvalumab and tremelimumab and best supportive care versus best supportive 
care only in patients with refractory, advanced colorectal cancer. 
• 
To explore association between putative biomarkers in archival tumour specimens and the 
potential for clinical benefit between the combination of durvalumab and tremelimumab and 
best supportive care versus best supportive care only in patients with refractory, advanced 
colorectal cancer. 
• 
To explore association with baseline values and changes in putative biomarkers in blood, serum 
and plasma and the potential for clinical benefit between the combination of durvalumab and 
tremelimumab and best supportive care versus best supportive care only in patients with 
refractory, advanced colorectal cancer. 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Colorectal Cancer 
 
Cancer of the colon and rectum is the 2nd leading cause of cancer death in Canada [Canadian Cancer 
Society Statistics 2015]. Each year, there are 25,100 new cases and 9100 deaths from colorectal cancer. 
For patients with advanced colorectal cancer, the overall survival is approximately 8-10 months 
without treatment. Over the last 10-15 years, there have been unprecedented improvements in the 
overall survivals of patients with advanced colorectal cancer, with median survivals of approaching 
30 months [Venook 2014]. These improvements in survival are a result of increased availability of 
drugs, including cytotoxic chemotherapeutic agents (5-FU, irinotecan, oxaliplatin, TAS-102), those 
targeting the VEGF pathway (bevacizumab, aflibercept, ramucirumab, and regorafenib) and those 
targeting the EGFR pathway (cetuximab and panitumumab). 
 
Unfortunately, the majority of patients with advanced colorectal cancer will succumb to their 
disease, with 5-year survival being only approximately 5%. Once they progress on standard 
therapies, the estimated overall survival for patients with advanced colorectal cancer is 5-6 months 
with best supportive care [Grothey 2013; Mayer 2015]. In this patient population, treatment with 
regorafenib or TAS-102 leads to improvement in the median overall survival of only 2.5 months 
or 1.8 months respectively. Therefore, new treatment options/strategies are urgently needed in 
patients with advanced colorectal cancer who progressed on standard therapies. 
 
Immunotherapy & Immune Checkpoint Inhibitors 
 
Immune responses directed against tumours are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from constant 
immune attacks, cancers develop strategies to evade the immune system allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory 
signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such protein, and it is 
upregulated in a broad range of cancers with a high frequency, with up to 88% expression in some 
tumour types. In a number of these cancers, including lung [Mu 2011], renal [Thompson 2005; Thompson 
2006; Krambeck 2007], pancreatic [Nomi 2007; Loos 2008; Wang 2010], ovarian cancer [Hamanishi 2007], and 
hematologic malignancies [Andorsky 2011; Brusa 2013], tumour cell expression of PD-L1 is associated 
with reduced survival and an unfavorable prognosis. 
 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation. It acts at multiple sites in the body to help regulate normal immune responses and is 
utilized by tumours to help evade detection and elimination by the host immune system. In the 
lymph nodes, PD-L1 on antigen-presenting cells binds to PD-1 or CD80 on activated T cells and 
delivers an inhibitory signal to the T cell [Keir 2008; Park 2010]. This results in reduced T-cell 
activation and fewer activated T cells in circulation. In the tumour microenvironment, PD-L1 
expressed on tumour cells binds to PD-1 and CD80 on activated T cells reaching the tumour. This 
delivers an inhibitory signal to those T cells, preventing them from killing target cancer cells and 
protecting the tumour from immune elimination [Zou 2008]. 

 
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Blockade of PD-1 engagement with its ligand PD-L1 induces immune responses in vitro and has 
been shown to mediate anticancer activity preclinically [Fife 2009]. Clinically, blockade of the PD-
1 inhibitory checkpoint pathway by inhibiting PD-L1/ PD-1 engagement has been shown to induce 
tumour regression across many cancer types, including melanoma and renal cell, colon and lung 
cancers [Pardoll 2012; Brahmer 2012]. Single agent immunotherapy with anti-PD-1 or anti-PDL-1 
antibodies across many tumour types has been generally well tolerated, with common drug related 
adverse events mainly limited to grade 1 or 2 fatigue, diarrhea, rash, pruritus, nausea and decreased 
appetite. Immune-related adverse events are uncommon (< 2%), and include pneumonitis, vitiligo, 
colitis, hepatitis and hypophysitis and thyroiditis [Antonia 2014b]. 
 
CTLA-4 is another co-inhibitory receptor expressed on activated T cells and regulates early stage 
T cell activation, reducing the amplitude of T-cell activation. Inhibition of CTLA-4 signaling is a 
validated approach to cancer therapy, as shown by the approval in 2011 of ipilimumab for the 
treatment of metastatic melanoma based on statistically significant and clinically meaningful 
improvement in overall survivals of patients with advanced melanoma [Hodi 2010; Robert 2011]. 
 
In general, tumour response rates to anti-CTLA-4 therapy are low (~10%). However, in patients 
who respond, the responses are generally durable, lasting several months even in patients with 
aggressive tumours such as refractory metastatic melanoma. Because these agents work through 
activation of the immune system and not by directly targeting the tumour, responses can occur late 
and some patients may have perceived progression of their disease in advance of developing disease 
stabilization or a tumour response. In some cases, early growth of pre-existing lesions or the 
appearance of new lesions may have been due to immune-cell infiltration into the tumour and not 
due to proliferation and extension of neoplastic cells, per se [Wolchok 2009]. Overall, although the 
impact on conventionally-defined PFS can be small, durable response or stable disease seen in a 
proportion of patients can lead to significant prolongation of OS. The melanoma data with 
ipilimumab clearly demonstrate that a small proportion of patients with an objective response had 
significant prolongation of OS, supporting the development of this class of agents in other tumours. 
Although Phase 2 and Phase 3 studies of tremelimumab in metastatic melanoma did not meet the 
primary endpoints of response rate and OS respectively, the data suggest activity of tremelimumab 
in melanoma [Kirkwood 2010; Ribas 2013]. In a large Phase 3 randomized study comparing 
tremelimumab with dacarbazine (DTIC)/temozolomide in patients with advanced melanoma, the 
reported median OS in the final analysis was 12.6 months for tremelimumab versus 10.7 months 
for DTIC/temozolomide (HR = 1.14; p=0.13) [Ribas 2013]. 
 
Tremelimumab  
 
Tremelimumab is a human IgG2 monoclonal antibody directed against the T-cell receptor protein 
cytotoxic T-lymphocyte-associated protein 4 (CTLA4) [Tarhini 2013]. Tremelimumab binds to 
CTLA4 and blocks the binding of the antigen-presenting cell ligands B7-1 and B7-2 to CTLA4, 
resulting in inhibition of B7-CTLA4-mediated downregulation of T-cell activation. In addition, 
blockade of CTLA-4 binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced T-
cell activation and anti-tumour activity in animal models, including killing of established murine 
solid tumours and induction of protective anti-tumour immunity. Therefore, it is expected that 
treatment with an anti-CTLA-4 antibody, such as tremelimumab, will lead to increased activation 
of the human immune system, increasing anti-tumour activity in patients with solid tumours.  

 
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An extensive program of non-clinical and clinical studies has been conducted for tremelimumab 
both as monotherapy and combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules. As of the data cut-off date of 
12 November 2014 (for all studies except D4190C00006, which has a cut-off date of 
4 December 2014), 973 patients have received tremelimumab monotherapy (not including 497 
patients who have been treated in the blinded phase IIb study, D4880C00003) and 208 patients 
have received tremelimumab in combination with other agents. 
 
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days. 
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.  
 
Durvalumab 
 
Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa (IgG1κ) 
subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], 
cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). 
Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall 
molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein 
C1q and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect 
of PD-L1 on primary human T cells, resulting in their restored proliferation and release of interferon 
gamma (IFN-γ). Additionally, durvalumab demonstrated a lack of antibody-dependent cell-
mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based 
functional assays. In vivo studies show that durvalumab inhibits tumour growth in a xenograft 
model via a T lymphocyte (T-cell) dependent mechanism. Moreover, an anti-mouse PD-L1 
antibody demonstrated improved survival in a syngeneic tumour model when given as 
monotherapy and resulted in complete tumour regression in > 50% of treated mice when given in 
combination with chemotherapy. 
 
Combination of Durvalumab and Tremelimumab 
 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity because the 
mechanisms of action of CTLA-4 and PD-1 are non-redundant [Pardoll 2014]. In fact, combining 
immunotherapy agents has been shown to result in improved response rates (RRs) relative to 
monotherapy. For example, the concurrent administration of nivolumab and ipilimumab to patients 
with advanced melanoma induced higher objective response rates (ORRs) than those obtained with 
single-agent therapy [Larkin 2015]. Importantly, responses appeared to be deep and durable [Wolchok 
2014]. Similar results have been observed in an ongoing study of durvalumab + tremelimumab in 
NSCLC [Antonia 2014a]. 
 
 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
Study D4190C00006 is a phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumour activity of durvalumab + tremelimumab combination therapy in patients 
with advanced NSCLC. The dosing schedule utilized is durvalumab every 2 weeks (q2w) or every 
4 weeks (q4w) up to Week 50 and 48 (12 months), combined with tremelimumab q4w up to Week 
24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months. Objectives of this 
study include evaluating the safety profiles of the combination of durvalumab and tremelimumab, 
collecting preliminary evidence of anti-tumour effects and selecting an optimal combination dose 
of durvalumab and tremelimumab that would yield sustained target suppression (sPD-L1). The 
study is ongoing and continues to accrue.  
 
As of 24 October 2016, a total of 835 patients provided evaluable samples for ADA analysis. 
Overall, 26 of 835 patients (3.1%) tested positive for treatment-emergent ADAs in the ADA 
evaluable population. Three patients (0.4%, in 3/835 patients) were neutralizing ADA (nAb) 
positive. Based on population PK covariate analysis, ADA positive status was not associated with 
a clinically relevant reduction of exposure to durvalumab. At the 10 mg/kg Q2W dose, sPD-L1 
suppression in ADA positive patients was similar to that observed in ADA negative patients. 
 
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were 
narrowed to 15 and 20 mg/kg durvalumab q4w. PK simulations from the durvalumab monotherapy 
data indicated that a similar area under the plasma drug concentration-time curve at steady state 
(AUCss; 4 weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w durvalumab. 
The observed durvalumab PK data from the D4190C00006 study were well in line with the 
predicted monotherapy PK data developed preclinically. This demonstrates similar exposure of 
durvalumab 20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when durvalumab and 
tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together. While the median Cmax at 
steady state (Cmax,ss) is expected to be higher with 20 mg/kg q4w (approximately 1.5 fold) and 
median trough concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg 
q2w (approximately 1.25 fold), this is not expected to impact the overall safety and efficacy profile, 
based on existing preclinical and clinical data. 
 
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab relative 
to the activity observed in patients treated with durvalumab monotherapy. There was evidence of 
augmented PDx activity relative to durvalumab monotherapy with combination doses containing 1 
mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus 1 mg/kg 
tremelimumab combinations. 
 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 
10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the q2w schedule, the number of patients reporting any AE, Grade 
3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar 
pattern was noted in the q4w regimens, suggesting that, as the dose of tremelimumab increased 
above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, the SAEs 
frequently attributed to immunotherapy, pneumonitis and colitis, were more commonly seen in 
cohorts using either 3 or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts. 
Together, these data suggest that a combination using a tremelimumab dose of 1 mg/kg appeared 
to minimize the rate of toxicity when combined with durvalumab. As a result, all combination doses 
utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final dose selection.  
 
 

 
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In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab 
may not impact the safety of the combination as much as the tremelimumab dose. Further, safety 
data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in safety events 
with increasing dose of durvalumab. 
 
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥ 3 AEs, SAEs, and 
treatment discontinuations due to AEs, but still showed strong evidence of clinical activity. This 
cohort had a lower number of treatment-related Grade ≥ 3 AEs or treatment-related SAEs. No dose-
limiting toxicities were reported.  
 
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15 and 20 mg/kg durvalumab q4w cohorts 
demonstrated objective responses at all doses of tremelimumab, and increasing doses of 
tremelimumab did not provide deeper or more rapid responses. 
 
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort may 
demonstrate equivalent clinical activity to other dose combinations. A total of 5 of 11 patients in 
the 20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for efficacy with at least 
8 weeks of follow-up. Of these, there were 2 patients (40%) with partial response (PR), 1 patient 
(20%) with stable disease (SD), and 1 patient (20%) with progressive disease (PD). (The fifth 
patient had only a single scan, which was conducted outside the window for these evaluations.) 
 
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort had 
the fewest AEs, Grade ≥ 3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed 
some evidence of clinical activity. Altogether, the data suggested that a 20 mg/kg durvalumab + 
1 mg/kg tremelimumab dose combination should be selected for further development. 
 
In summary, combinations of durvalumab and tremelimumab appear tolerable at doses of 
durvalumab 20 mg/kg q4w and tremelimumab 1 mg/kg q4w. Higher doses did not result in greater 
antitumour activity but were generally associated with higher rates of AEs. Related Grade 3/4 
events were reported in 4/18 (22%) patients, while the most frequently reported events were 
diarrhea, pruritus, rash, and elevated AST/ALTs (11% for each AE). Only one patient discontinued 
study therapy due to drug-related AEs [Antonia 2015]. 
 
Immune Therapy in Advanced Colorectal Cancer 
 
The role of immune therapy in CRC has recently been reported. PD-1 positive lymphocytes are 
present in 47% of CRC [Gatalica 2014]. Overexpression of PD-L1 in CRC is associated with poor 
prognosis [Song 2013]. Chemotherapy induced PD-1 expression has been associated with improved 
PFS in CRC suggesting an indirect chemotherapy induced antitumour immune response [Formica 
2013]. Microsatellite instability (MSI-H), a feature of a subset of CRC, is also associated with 
enhanced CLTA-4 and PD1 expression [Llosa 2015]. 
 
A recent publication in the New England Journal of Medicine (NEJM) [Le 2015] demonstrated that 
the anti PD-1 antibody pembrolizumab has significant activity in MSI-H CRC, which makes up 
less that 5% of patients with advanced refractory disease. In this trial, 78% of MSI-H patients had 
disease control, There was superior OS (HR 0.22) and PFS (HR 0.10) in the MSI-H vs MSI-S 
patients (see Figures A & B below). 
 
 

 
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Figure 1: Biochemical (A) and Radiographic (B) responses in patients with colorectal cancer treated with the anti-PD-1 
antibody pembrolizumab [Le 2015]. 
 
Further exploration of the value of immune therapy in CRC is desirable, given the large unmet 
need. 
 
Despite the exciting results of pembrolizumab in patients with advanced MSI-H colorectal cancer, 
inhibiting PD-1/PD-L1 interaction alone is likely of limited therapeutic value in colorectal cancer 
since only 5% patients with advanced colorectal cancer harboring MSI-H. Targeting both PD-1/PD-
L1 and CTLA-4 pathways may have additive or synergistic activity because the mechanisms of 
action of CTLA-4 and PD-1/PD-L1 inhibition are non-redundant. This study is designed to evaluate 
whether combining PD-1/PD-L1 and CTLA-4 inhibition will lead to improved patient survivals 
compared to best supportive care in advanced colorectal cancer, regardless of MSI status. 

 
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ADMIN UPDATE #1: 2018-JAN-24 
3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Durvalumab 
 
3.1.1 
Name and Chemical Information 
 
Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1κ) subclass 
that inhibits binding of programmed cell death ligand (PD-L1) (B7 homolog 1[B7-H1], cluster of 
differentiation [CD]274 to programed cell death 1 (PD-1; CD279) and CD80 (B7). 
See the current durvalumab Investigator Brochure for additional details and the most up to date 
information. 
 
3.1.2 
Chemical Structure 
 
Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall 
molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein 
C1q and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
 
3.1.3 
Mechanism of Action 
 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect 
of PD-L1 on primary human T cells, resulting in their restored proliferation and release of interferon 
gamma (IFN-γ). 
 
3.1.4 
Experimental Antitumour Activity 
• 
In a xenograft model durvalumab inhibited human tumour growth via a T-cell-dependent 
mechanism. 
• 
An anti-mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumour model 
when given as monotherapy and resulted in complete tumour regression in > 50% of treated 
mice when given in combination with chemotherapy. 
• 
Combination therapy (dual targeting of PD-L1 and CTLA-4) resulted in tumour regression in 
a mouse model of colorectal cancer.  
• 
Dual targeting of PD-1 and PD-L1 in a syngeneic model of sarcoma in mice demonstrated 
statistically significant mean tumour growth delay relative to the control group. 
 
3.1.5 
Animal Toxicology 
 
In general, treatment of cynomolgus monkeys with durvalumab was not associated with any 
durvalumab-related adverse effects that were considered to be of relevance to humans. 
 
Data from the pivotal 3-month GLP toxicity study with durvalumab in cynomolgus monkeys 
showed that subchronic dosing of durvalumab was not associated with any adverse effects. 
Therefore, the NOAEL of durvalumab in all the general toxicity studies was considered to be 100 
mg/kg, the highest dose tested in these studies. In addition to the in vivo toxicology data, no 
unexpected membrane binding of durvalumab to human or cynomolgus monkey tissues was 
observed in GLP tissue cross-reactivity studies using normal human and cynomolgus monkey 
tissues. 

 
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3.1.6 
Clinical Trials 
 
As of the most recent Investigator’s Brochure, over 5000 subjects have been enrolled and treated 
in ongoing durvalumab clinical studies No studies have been completed or terminated prematurely 
due to toxicity. 
 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
appears consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumour types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include pneumonitis, hepatitis, diarrhea/colitis and intestinal perforation, 
endocrinopathies 
(hypo- 
and 
hyperthyroidism, 
adrenal 
insufficiency, 
hypophysitis 
/ 
hypopituitarism diabetes insipidus and Type 1 diabetes mellitus), nephritis, rash/dermatitis, 
pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent irAEs including 
neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. Other 
inflammatory responses that are rare with a potential immune-mediated etiology include, but are 
not limited to, pericarditis, sarcoidosis, uveitis and other events involving the eye, skin, 
haematological and rheumatological events. It is possible that events with an inflammatory or 
immune-mediated mechanism could occur in nearly all organs. Please refer to the most recent 
version of the Investigator Brochure for incidence. 
 
3.1.7 
Pharmaceutical Data - Durvalumab 
 
Supplied: 
Supplied as a vialed liquid solution containing 500 mg (nominal) durvalumab. The solution 
contains 50 mg/mL durvalumab, 26 mM histidine/histidine-HCI, 275 mM trehalose dihydrate, 
0.02% (w/v) polysorbate 80, at pH 6.0. 
 
Storage: 
Durvalumab must be stored at 2°C to 8°C. 
 
Route of Administration: 
Intravenous. 
 
Please refer to the CO.26 Pharmacy Manual for additional details. 
 
3.2 
Tremelimumab 
 
3.2.1 
Name and Chemical Information  
 
Tremelimumab is a human monoclonal antibody of the immunoglobulin G2 (IgG2) subclass that 
inhibits binding of B7 ligands (B7.1 (CD80) or B7.2 (CD86)) to cytotoxic T lymphocyte- 
associated antigen 4 (CTLA-4; cluster of differentiation [CD]152). 
 
See the current tremelimumab Investigator Brochure for additional details and the most up to date 
information. 
 
3.2.2 
Chemical Structure 
 
Tremelimumab has an overall molecular weight of approximately 149 kDa including 
oligosaccharides. 

 
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3.2.3 
Mechanism of Action 
 
Tremelimumab binds with high affinity and specificity to human CTLA-4, a cell surface receptor 
expressed primarily on activated T cells. Binding of CTLA-4 to its target ligands (B7.1 and B7.2) 
on antigen-presenting cells, provides a negative regulatory signal, which limits T-cell activation. 
Tremelimumab blocks this interaction of B7 ligands with CTLA-4, thus leading to prolongation 
and enhancement of T-cell activation and expansion. This mechanism is supported by in vitro 
studies where tremelimumab antagonizes binding of CTLA-4 to B7 ligands and enhances human 
T-cell activation as demonstrated by increased cytokine (IL-2, IFN-γ) production. 
 
3.2.4 
Experimental Antitumour Activity 
 
In a mouse model of fibrosarcoma, an anti-mouse CTLA-4 antibody demonstrated dose-dependent 
antitumour activity and, at the maximum dose tested, resulted in complete tumour regression in 4 
of 5 treated animals. Also these animals were resistant to tumour rechallenge, demonstrating a 
durable antitumour immunity. Finding was corroborated in other mouse models of cancer. 
 
In a mouse model of colon cancer, the combination of anti-mouse PD-L1 and anti-mouse CTLA-4 
resulted in greatly increased activity with tumour regression observed in all mice treated relative to 
control. 
 
3.2.5 
Clinical Trials 
 
To date, 34 clinical studies have been conducted in over 1500 patients in both monotherapy and 
combination therapy clinical trials. Full details are described in the current tremelimumab 
Investigator Brochure. 
 
To date, no tumour type or stage appears to be associated with unique AEs (except for vitiligo that 
appears to be confined to subjects with melanoma). Treatment-related AEs were reported at similar 
rates in the 10 and 15 mg/kg groups, and were mostly Grade 1 or 2 in severity. The most frequent 
(in > 5% of subjects) treatment-related AEs (all grades) in patients with tremelimumab 
monotherapy were diarrhea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, headache, 
pyrexia, abdominal pain, and colitis. Please refer to the most recent version of the Investigator 
Brochure for incidence. 
 
Across clinical trials, a pattern of efficacy has emerged that is similar to the anti-CTLA-4 antibody, 
ipilimumab, which appears to be consistent across tumour types. Response rates to anti-CTLA-4 
antibodies are generally low, approximately 10%. However, in subjects who respond, the responses 
are generally durable, lasting several months even in subjects with aggressive tumours such as 
refractory metastatic melanoma. 
 
3.2.6 
Pharmaceutical Data - Tremelimumab 
 
Supplied: 
Supplied as a vialed solution containing 400 mg (nominal) tremelimumab. The solution contains 
20 mg/mL tremelimumab, 20 mM histidine/histidine-HCI, 222 mM trehalose dihydrate, 0.02% 
(w/v) polysorbate 80, 0.27 mM disodium edetate dehydrate (EDTA), pH 5.5. 
 
Storage: 
Tremelimumab must be stored at 2°C to 8°C and must not be frozen. The product should be 
protected from light when not in use. 

 
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Route of Administration: 
Intravenous. 
 
Please refer to the CO.26 Pharmacy Manual for additional details. 
 
3.3 
Fixed Dosing in Durvalumab and Tremelimumab 
 
A population PK model was developed for durvalumab using monotherapy data from a phase I 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumours). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected 
to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were 
simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body WT-
based and fixed dosing regimens yield similar median steady state PK concentrations with slightly 
less overall between-subject variability with fixed dosing regimen.  
 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [Wang 
et al. 2014]. Population PK model indicated minor impact of body WT on PK of tremelimumab 
(coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on 
median body WT of ~75 kg) regimens were compared using predicted PK concentrations (5th, 
median and 95th percentiles) using population PK model in a simulated population of 1000 patients 
with body weight distribution of 40 to 120 kg. Similar to durvalumab, simulations indicated that 
both body WT-based and fixed dosing regimens of tremelimumab yield similar median steady state 
PK concentrations with slightly less between-subject variability with fixed dosing regimen. 
 
Similar findings have been reported by others [Ng 2006, Wang 2009, Zhang 2012, Narwal 2013]. Wang and 
colleagues investigated 12 monoclonal antibodies and found that fixed and body size-based dosing 
perform similarly, with fixed dosing being better for 7 of 12 antibodies. In addition, they 
investigated 18 therapeutic proteins and peptides and showed that fixed dosing performed better 
for 12 of 18 in terms of reducing the between-subject variability in pharmacokinetic / 
pharmacodynamics parameters [Zhang 2012]. 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W and 75 mg 
tremelimumab (equivalent to 1 mg/kg) is planned. 
 
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30 kg 
body weight due to endotoxin exposure. Patients with a body weight less than or equal to 30 kg 
should be dosed using a weight-based dosing schedule. This is not expected to be applicable to this 
trial in an adult patient population. 

 
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4.0 
STUDY POPULATION 
 
The trial population will consist of patients with advanced (metastatic or locally advanced) 
histologically confirmed colorectal cancer that is unresectable and who have exhausted standard 
treatment options. Patients will have progressed with or after standard chemotherapy based 
regimens containing a fluoropyrimidine, irinotecan and oxaliplatin, or are deemed unsuitable for 
such regimens by their treating physicians. Subjects with RAS wild type tumours must have 
previously received cetuximab or panitumumab. Subjects treated previously with the following 
agents will be eligible, though previous treatment with these agents is not a requirement for 
enrolment: 
• 
anti-VEGF therapy, such as bevacizumab and/or aflibercept and/or regorafenib 
• 
TAS-102 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects in these patient populations. 
 
4.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed prior to calling for randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfil all of the following criteria to be eligible for admission to the study: 
 
4.1.1 
Must have histologically or pathologically confirmed advanced (metastatic or locally advanced) 
colorectal cancer that is unresectable. 
 
4.1.2  Received a prior thymidylate synthase inhibitor (e.g. 5-fluorouracil (5-FU), capecitabine, 
raltitrexed, UFT) for metastatic disease or as adjuvant therapy. A thymidylate synthase inhibitor 
may have been given in combination with oxaliplatin or irinotecan. 
 
The intention of this criterion is to ensure that it is the conclusion of the investigator that this patient 
would not benefit from further therapy with a thymidylate synthase inhibitor and is therefore an 
appropriate candidate for treatment with best supportive care only. 
 
4.1.3 
Received and failed an irinotecan -containing regimen (i.e. single-agent or in combination) for 
treatment of metastatic disease, OR relapsed within 6 months of completion of an irinotecan-
containing adjuvant therapy, OR have documented unsuitability for an irinotecan-containing 
regimen. 
 
Failure is defined as either progression of disease (clinical or radiologic) or intolerance to the 
irinotecan-containing regimen, where intolerance is defined as discontinuation due to any of the 
following: severe allergic reaction or delayed recovery from toxicity preventing retreatment. 

 
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Documented unsuitability for irinotecan includes (but is not confined to) known hypersensitivity 
to irinotecan, abnormal glucuronidation of bilirubin, Gilbert’s syndrome or previous 
pelvic/abdominal irradiation. 
 
The intention of this criterion is to ensure that it is the conclusion of the investigator that this patient 
would not benefit from further therapy with irinotecan and is therefore an appropriate candidate for 
treatment with best supportive care measures only. 
 
4.1.4 
Received and failed an oxaliplatin-containing regimen (i.e. single-agent or in combination) for 
treatment of metastatic disease, OR relapsed within 6 months of completion of an oxaliplatin-
containing adjuvant therapy OR have documented unsuitability for an oxaliplatin-containing 
regimen. 
 
Failure is defined as either progression of disease (clinical or radiological) or intolerance to the 
oxaliplatin-containing regimen, where intolerance is defined as discontinuation due to any of the 
following: severe allergic reaction, persistent severe neurotoxicity or delayed recovery from 
toxicity preventing retreatment. 
 
Documented unsuitability for oxaliplatin includes (but is not confined to) known hypersensitivity 
to oxaliplatin or other platinum compounds, pre-existing renal impairment, or Grade 2 or greater 
neurosensory neuropathy. 
 
The intention of this criterion is to ensure that it is the conclusion of the investigator that this patient 
would not benefit from further therapy with oxaliplatin and is therefore an appropriate candidate 
for treatment with best supportive care measures only. 
 
4.1.5 
For patients with colorectal cancer that is RAS-wild type:  
Received and failed a cetuximab or panitumumab-containing regimen (i.e. single-agent or in 
combination) for treatment of metastatic disease OR have documented unsuitability for a cetuximab 
or panitumumab-containing regimen 
 
Failure is defined as either progression of disease (clinical or radiological) or intolerance to the 
cetuximab- or panitumumab-containing regimen, where intolerance is defined as discontinuation 
due to any of the following: severe infusion reaction, persistent severe skin toxicity or delayed 
recovery from toxicity preventing retreatment. 
 
Documented unsuitability for cetuximab includes (but is not confined to) known hypersensitivity 
to cetuximab or the presence of tumours with an activating RAS or RAF mutation. 
 
Documented unsuitability for panitumumab includes (but is not confined to) known 
hypersensitivity to panitumumab or the presence of tumours with an activating RAS mutation. 
 
The intention of this criterion is to ensure that it is the conclusion of the investigator that this patient 
would not benefit from further therapy with either cetuximab or panitumumab and is therefore an 
appropriate candidate for treatment with best supportive care measures only. 
 
4.1.6 
Patient prior treatment with VEGF targeting therapy, such as bevacizumab, aflibercept, 
ramucirumab, or regorafenib, is permitted but not mandatory. Reasons not used are to be 
documented. 

 
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4.1.7 
Patient prior treatment with TAS-102 (an agent composed of a combination of trifluorothymidine 
(FTD) and tipiracil hydrochloride (TPI)), is permitted but not mandatory. Reasons not used are to 
be documented. 
 
4.1.8 
The only remaining standard available therapy as recommended by the Investigator, in consultation 
with the patient, is best supportive care. 
 
4.1.9 
Must have presence of measurable or evaluable disease as defined by Response Evaluation Criteria 
in Solid Tumours (RECIST 1.1). 
 
4.1.10 Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as necessary to 
document all sites of disease done within 28 days prior to randomization. 
 
4.1.11 Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 
4.1.12 Life expectancy of ≥ 12 weeks at the time of study entry. 
 
4.1.13 Must be ≥ 18 years of age. (Note that the lower age limit at each centre will be determined by that 
centre’s policy regarding the age at which an individual may sign their own consent.)  
 
4.1.14 Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method. A woman is considered to be of "childbearing potential" if she has had menses at any time 
in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or 
with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
Female patients of childbearing potential who are sexually active with a non-sterilized male partner 
must use at least one highly effective method of contraception while on study and for 6 months 
after the last dose of durvalumab and tremelimumab or for 3 months after the last dose of 
durvalumab alone. Male partners of a female subject and non-sterilized male patients who are 
sexually active with a female partner of childbearing potential must use male condom plus 
spermicide while on study and for 6 months after the last dose of durvalumab and tremelimumab 
or for 3 months after the last dose of durvalumab alone. Female partners of a male subject must use 
a highly effective method of contraception throughout this period. Cessation of birth control after 
this point should be discussed with a responsible physician. See Section 9.3.1 for additional details. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Sections 5.1 and 5.2); this may include an ultrasound to rule-out 
pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin 
is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen 
with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
Male patients should also refrain from donating sperm during the study and for 6 months after the 
last dose of durvalumab and tremelimumab or for 3 months after the last dose of durvalumab alone. 
 
 
 

 
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4.1.15 Patient must consent to provision of, and investigator(s) must confirm adequacy of tissue, and 
confirm access to and agree to submit within 4 weeks of randomization to the CCTG Central 
Tumour Bank, a representative formalin fixed paraffin block of tumour tissue in order that the 
specific correlative marker assays proscribed in Section 12 (Correlative Studies) may be conducted. 
Where adequate amount and quality of tissue exists but local centre regulations prohibit submission 
of blocks of tumour tissue, the approval of the CCTG must be sought prior to randomization of the 
first patient to allow cores (two 2 mm cores of tumour from the block) and a predetermined number 
of slides of representative tumour tissue to be substituted. Failure to submit any tissue samples on 
request will result in the patient being considered ineligible. Where no previously resected or 
biopsied tumour tissue exists or is found to be of inadequate amount or quality, additional biopsy 
of the primary or metastatic tumour will be required for the patient to be considered eligible for the 
study and will be required to be done prior to randomization. Please refer to the CO.26 Correlative 
Studies Manual for details concerning adequacy of amount and quality of tumour tissue. 
 
4.1.16 Patient must consent to provision of samples of blood in order that the specific correlative marker 
assays proscribed in Section 12 (Correlative Studies) may be conducted. 
 
4.1.17 Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in 
either English or French. The baseline assessment must be completed within 14 days prior to 
randomization. Inability (lack of comprehension in English or French, or other equivalent reason 
such as cognitive issues or lack of competency) to complete the questionnaires will not make the 
patient ineligible for the study. However, ability but unwillingness to complete the questionnaires 
will make the patient ineligible. 
 
4.1.18 Patients must be accessible for treatment and follow-up. Investigators must assure themselves the 
patients randomized on this trial will be available for complete documentation of the treatment, 
adverse events, and follow-up. 
 
4.1.19 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization. 
 
4.1.20 The patient is not receiving therapy in a concurrent clinical study and the patient agrees not to 
participate in other clinical studies during their participation in this trial while on study treatment. 
 
 
 

 
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4.1.21 Adequate normal organ and marrow function as defined below (must be done within 14 days prior 
to randomization): 
 
Hematology 
Absolute neutrophils 
> 1.5 x 109/L 
Platelets 
> 100 x 109/L 
Hemoglobin 
> 90 g/L 
Lymphocytes 
Note: no range is specified for eligibility 
Chemistry 
Bilirubin 
< 1.5 x ULN (upper limit of normal)* 
AST and ALT ** 
< 2.5 x ULN 
Serum creatinine 
or: 
Creatinine clearance*** 
< 1.25 x ULN 
 
> 40 mL/min 
* 
If confirmed Gilbert’s, eligible providing ≤ 3 x ULN. 
** < 3 x UNL in presence of liver metastases 
*** Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft and 
Gault equation below: 
Females: GFR  = 1.04 x (140-age) x weight in kg / serum creatinine in μmol/L 
Males: GFR 
= 1.23 x (140-age) x weight in kg / serum creatinine in μmol/L 
 
4.1.22 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrolment in the trial to document 
their willingness to participate. 
 
4.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
4.2.1 
Patients with a history of other malignancies, except: adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with 
no evidence of disease for ≥ 5 years. 
 
4.2.2 
Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, or an anti-CTLA4, 
including tremelimumab.  
 
4.2.3 
History of primary immunodeficiency, history of organ transplant that requires therapeutic 
immunosuppression or prior history of severe (grade 3 or 4) immune mediated toxicity from other 
immune therapy. 
 
4.2.4 
Current or prior use of immunosuppressive medication within 28 days before the first dose of 
durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, 
or an equivalent corticosteroid. 
 
4.2.5 
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel 
disease (e.g. Crohn’s disease, ulcerative colitis) within the past 2 years NOTE: Subjects with 
vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are 
not excluded. 
 
 
 

 
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4.2.6 
Patients with active or uncontrolled intercurrent illness including, but not limited to: 
• 
cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia) 
• 
active peptic ulcer disease or gastritis, 
• 
active bleeding diatheses  
• 
psychiatric illness/social situations that would limit compliance with study requirements or 
compromise the ability of the subject to give written informed consent 
• 
known history of previous clinical diagnosis of tuberculosis 
• 
known human immunodeficiency virus infection (positive HIV 1/2 antibodies) 
• 
known active hepatitis B infection (positive HBV surface antigen (HBsAg). Patients with a 
past or resolved HBV infection (defined as presence of hepatitis B core antibody (anti-HBc) 
and absence of HBsAg) are eligible. 
• 
known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA. 
 
4.2.7 
History of leptomeningeal carcinomatosis. 
 
4.2.8 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not 
limited to surgery, radiation and/or corticosteroids. 
 
4.2.9 
Receipt of live attenuated vaccination (examples include, but are not limited to, vaccines for 
measles, mumps, and rubella, live attenuated influenza vaccine (nasal), chicken pox vaccine, oral 
polio vaccine, rotavirus vaccine, yellow fever vaccine, BCG vaccine, typhoid vaccine and typhus 
vaccine) within 30 days prior to randomization. 
 
4.2.10 Pregnant or lactating women.  
 
4.2.11 Any active disease condition which would render the protocol treatment dangerous or impair the 
ability of the patient to receive protocol therapy. 
 
4.2.12 Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the 
protocol. 
 
4.2.13 Receipt of anti-cancer chemotherapy or biologic therapy within the lesser of i) 21 days, or ii) the 
usual cycle length of the regimen (e.g. 14 days for FOLFOX), prior to the first planned dose of 
durvalumab or tremelimumab. An exception is made for capecitabine and regorafenib, where a 
minimum of 10 days since last dose must be observed prior to the first planned dose of durvalumab 
or tremelimumab. 
 
4.2.14 Receipt of radiotherapy or investigational agents within four weeks of first planned dose of 
durvalumab or tremelimumab, with the exception of a single dose of radiation up to 8 Gray (equal 
to 800 RAD) with palliative intent for pain control up to 14 days before randomization. 
 
4.2.15 Any unresolved toxicity (CTCAE grade 2) from previous anti-cancer therapy. However, patients 
with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational 
products in the Investigator’s opinion may be included (e.g. hearing loss, peripheral neuropathy). 

 
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20 
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5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT  
 
All patients entered on study must be evaluated according to the schedule outlined below with 
documentation submitted according to the schedule in Appendix IV. 
 
5.1 
Patient Evaluation Flowsheet: Pre-study (Baseline) and Post-randomization Follow-up 
For Patients Randomized to Best Supportive Care (Arm 1) 
 
Required Investigations 
PRE-STUDY 
(≤ 14 days prior 
to randomization, 
unless otherwise 
indicated) 
PRIOR to objective disease progression 
(timing from randomization) 
AFTER objective disease 
progression 
(timing from randomization) 
Every 4 weeks until 
objective disease 
progression 
Every 8 weeks until objective 
disease progression  
(maintain schedule even if clinic  
visits are delayed)3 
Every 12 weeks 
History and Physical Exam 
 
 
 
 
Including: height (baseline only), 
weight, ECOG performance status, 
clinical tumour measurements (if 
applicable) 
X 
X 
 
 
Vital Signs (blood pressure, heart rate, 
temperature) 
X 
X 
 
 
Concomitant Medications 
X 
X 
 
 
Overall Survival 
 
 
 
 
Survival Status Assessment 
 
X 
X 
X1 
Hematology 
 
 
 
 
CBC, differential (including 
lymphocytes), platelets 
X 
X 
 
 
Coagulation 
 
 
 
 
PTT, PT/INR 
X 
X 
 
 
Biochemistry 
 
 
 
 
Serum Creatinine, Chloride, 
Sodium, Potassium, Calcium, 
Magnesium, Bilirubin, ALP, AST 
and ALT, LDH, Albumin, TSH2, 
Amylase, Lipase, Serum CEA 
X 
X 
 
 
Creatinine Clearance (calculated) 
X 
as clinically indicated 
 
 
Glucose 
X 
as clinically indicated 
 
 
Radiology3 
 
 
 
 
Chest/abdomen/pelvis CT or MRI 
scan3  
X 
≤ 28 days 
 
X3 
 
Other scans as necessary to 
document all measurable and non-
measurable disease3 
X 
≤ 28 days 
Other Investigations 
 
 
 
 
Pregnancy Test4 
X 
 
 
 
ECG 
X 
as clinically 
indicated 
 
 
Dipstick Urinalysis (including protein, 
specific gravity, glucose and blood) 
X 
 
 
 
table continued on next page ... 
 
 

 
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Correlative Studies 
 
 
 
 
Archival Tissue Sample5 
(mandatory) 
Availability of 
sufficient tissue 
must be 
confirmed prior 
to randomization 
Submit tissue 
within 4 weeks 
of randomization 
 
 
Whole blood, plasma and serum5,6 
(mandatory) 
X 
To be done at 8 weeks, and at the time of objective disease  
progression7, if not already done 
Adverse Events 
 
 
 
 
Adverse Event Assessment8 
X 
(To document 
residual adverse 
events form 
previous therapy 
and baseline 
symptoms) 
X 
To be evaluated 
continuously for 
adverse events (until 
objective disease 
progression) 
 
 
Quality of Life 
 
 
 
 
EORTC QLQ C309 
X 
At 4, 8, 12, 16 and 24 weeks after 
randomization,  then every 12 weeks thereafter 
(until deterioration to ECOG PS 4 or hospitalization  
for end of life care) 
 
1. In the event that patient is unable to attend clinic, post-progression follow-up may be by means of telephone contact. 
2. If abnormal, T3 and T4 must be measured. 
3. To ensure comparability, scans must identify and report each lesion at baseline and at reassessment. These scans must be performed using 
identical technique (i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, the 
identical contrast agent, and preferably the same scanner). Tumour evaluations must be consistently performed every 8 weeks (i.e. at 8 
weeks, 16 weeks, 24 weeks, 32 weeks etc. from randomization) until objective disease progression is documented (as described in 
Section 8). Sites should adhere to this calendar-based schedule regardless of any delays in clinic visits . If a radiology scan is done off 
schedule, future protocol-required scans should still be performed based on the original schedule, i.e. every 8 weeks counting from 
randomization (not from the date of the off schedule scan). 
4. For women of childbearing potential only. May be urine or serum. Pregnancy test (in women of childbearing potential), as part of Pre-Study 
Evaluation, may include an ultrasound to rule-out pregnancy. 
5. See Section 12.0 and the CO.26 Correlative Studies Laboratory Manual for details. 
6. Details for collection, processing, storing, and shipping these samples will be provided in the CO.26 Correlative Studies Manual 
7. Whole blood, plasma and serum should be obtained as close to the time of objective progression as possible and should be done within 
28 days (e.g. at the next clinic visit). Blood for correlatives done within 28 days PRIOR to date of progression does not need to be repeated. 
8. Adverse Events to be evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0) (see Appendix V). 
9. To be completed by patient in clinic. 
 
 

 
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5.2 
Patient Evaluation Flowsheet: Pre-Treatment, On-Study, and after Protocol Treatment 
For Patients Randomized to Durvalumab and Tremelimumab (Arm 2) 
 
Required Investigations 
PRE-STUDY 
(≤14 days prior to 
randomization, 
unless otherwise 
indicated) 
DURING Protocol 
Treatment 
AFTER Protocol Treatment is Permanently Discontinued1 
PRIOR to objective disease 
progression 
AFTER objective disease 
progression 
Day 1 each cycle, and as 
clinically indicated 
(unless otherwise indicated) 
4 weeks after 
end of last 
cycle date 
Every 4 
weeks 
thereafter 
4 weeks after 
end of last 
cycle date1 
Every 12 weeks 
thereafter 
History and Physical Exam2 
 
 
 
 
 
 
Including: height (baseline 
only), weight, ECOG 
performance status, clinical 
tumour measurements (if 
applicable) 
X 
X 
X 
X 
X 
 
Vital Signs (blood pressure, 
heart rate, temperature) 
X 
X3 
 
 
 
 
Concomitant Medications 
X 
X 
X 
 
X 
 
Overall Survival 
 
 
 
 
 
 
Survival status assessment 
 
X 
X 
X 
X 
X4 
Hematology2,5 
 
 
 
 
 
 
CBC, differential (including 
lymphocytes), platelets 
X 
X2 
X 
X 
X 
X5 
Coagulation2,5 
 
 
 
 
 
 
PTT, PT/INR 
X 
X2 
X 
X 
X 
X5 
Biochemistry2,5 
 
 
 
 
 
 
Serum Creatinine, 
Chloride, Sodium, 
Potassium, Calcium, 
Magnesium, Bilirubin, 
ALP, AST and ALT, LDH, 
Albumin, TSH6, Amylase, 
Lipase, Serum CEA 
X 
X2 
X 
X 
X 
X5 
Creatinine Clearance 
(calculated) 
X 
as clinically indicated 
 
 
 
 
Glucose 
X 
as clinically indicated 
 
 
 
 
Radiology7 
 
 
 
 
 
 
Chest/abdomen/pelvis  
CT or MRI scan  
X 
≤ 28 days 
X7 
Every 8 weeks from randomization until objective 
disease progression 
(maintain schedule even if cycles are delayed) 
 
 
Other scans as necessary to 
document all measurable 
and non-measurable disease 
X 
≤ 28 days 
 
 
Other Investigations 
 
 
 
 
 
 
Pregnancy Test8 
X 
 
 
 
 
 
ECG 
X 
as clinically indicated 
 
 
 
 
Dipstick Urinalysis 
(including protein, specific 
gravity, glucose and blood) 
X 
 
 
 
 
 
table continued on next page ... 
 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
Required Investigations 
PRE-STUDY 
(≤14 days prior to 
randomization, unless 
otherwise indicated) 
DURING Protocol Treatment 
AFTER Protocol Treatment is Permanently Discontinued1 
PRIOR to objective disease progression 
AFTER objective disease progression 
Day 1 each cycle, and as 
clinically indicated (unless 
otherwise indicated) 
4 weeks after end 
of last cycle date 
Every 4 weeks 
thereafter 
4 weeks after end of 
last cycle date1 
Every 12 weeks 
thereafter 
Correlative Studies 
 
 
 
 
 
 
Archival Tissue Sample9 
(mandatory) 
Availability of 
sufficient tissue must 
be confirmed prior 
to randomization 
Submit tissue within  
4 weeks of 
randomization 
 
 
 
 
Whole blood, plasma and 
serum9 
(mandatory) 
After randomization 
but before first dose 
of study treatment 
To be done at 8 weeks and at the time of objective 
disease progression10, if not already done 
 
 
Adverse Events 
 
 
 
 
 
 
Adverse Event 
Assessment11 
X 
(To document 
residual adverse 
events form previous 
therapy and baseline 
symptoms) 
X12 
(To be evaluated 
continuously for adverse 
events) 
X 
X13 
X1 
X13 
Quality of Life 
 
 
 
 
 
 
EORTC QLQ C3014 
X 
At 4, 8, 12, 16 and 24 weeks after randomization, then 
every 12 weeks thereafter (until deterioration to ECOG PS 
4 or hospitalization for end of life care) 
 
 
1. 
All patients will be seen at 4 weeks after the end of the last cycle date. Thereafter, continued follow-up is not required for patients who go off 
protocol treatment with unequivocal progressive disease, except to document ongoing toxicities (until resolved to < grade 2) and late toxicities 
(including second malignancies). For patients who go off protocol treatment with CR, PR, or SD ongoing, follow-up will be required every 12 weeks 
until relapse (see Appendix I for investigations to be performed). Death Report will be required for all patients. Due within 2 weeks of knowledge of 
death (see Appendix IV - Documentation for Study). 
2 
Timing of Day 1 Assessments: Pre-treatment blood draws and physical exams may be done one working day prior to treatment if necessary , and 
when treatment is to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). In order to ensure that nadir 
counts are not missed, every effort should be made to do interim blood draws within 24 hours of the day specified in the protocol. If a patient shows 
an AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x ULN, refer to Appendix III for further instructions on cases of increases in liver 
biochemistry and evaluation of Hy’s Law. These cases should be reported as SAEs if, after evaluation, they meet the criteria for a Hy’s law case or if 
any of the individual liver test parameters fulfill any of the SAE criteria. Note: Labs do not need to be repeated Day 1, Cycle 1. In order to ensure 
that nadir counts are not missed, every effort should be made to do interim blood draws within 24 hours prior to the day specified in the protocol. 
3. 
Vital signs are to be monitored before, during, and after the infusion of tremelimumab and durvalumab with assessment of vital signs to be collected 
≤ 30 minutes prior to start of infusion then every 30 ±5 minutes during infusion and observation periods. A 1-hour observation period is 
recommended after the first infusion of tremelimumab, during which time durvalumab may be administered (see Section 7.1.3). A second 1-hour 
observation period is recommended after the first infusion of durvalumab. If no clinically significant infusion reactions are observed during or after 
the first cycle of tremelimumab and durvalumab, subsequent infusion observation periods can be at the Investigator’s discretion but are 
recommended to be of 30 minutes, i.e., 30 minutes after tremelimumab infusion, during durvalumab infusion, and for 30 minutes after durvalumab 
infusion.  For patients who receive only durvalumab, the recommended observation period is 30 minutes after infusion.  
4. 
In the event that patient is unable to attend clinic, post-progression follow-up may be by means of telephone contact. 
5. 
Hematology, Coagulation and Biochemistry investigation to be done after objective progression ONLY if there are ongoing hematologic AEs that 
are related to protocol treatment. 
6. 
If abnormal, T3 and T4 must be measured. 
7. 
To ensure comparability, scans must identify and report each lesion at baseline and at reassessment during treatment. These scans must be performed 
using identical technique (i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, the identical 
contrast agent, and preferably the same scanner). Tumour evaluations must be consistently performed every 8 weeks (i.e. at 8 weeks, 16 weeks, 24 
weeks, 32 weeks etc. from randomization) until objective disease progression is documented (as described in Section 8). Sites should adhere to this 
calendar-based schedule regardless of any delays in treatment. If a radiology scan is done off schedule, future protocol-required scans should still be 
performed based on the original schedule, i.e. every 8 weeks counting from randomization (not from the date of the off schedule scan). 
8. 
For women of childbearing potential only. May be urine or serum. Pregnancy test (in women of childbearing potential), as part of Pre-Study 
Evaluation, may include an ultrasound to rule-out pregnancy. 
9. 
See Section 12.0 and the CO.26 Correlative Studies Laboratory Manual for details. 
10. Whole blood, plasma and serum should be obtained as close to the time of objective progression as possible and should be done within 28 days (e.g. 
at the next clinic visit). Blood for correlatives done within 28 days PRIOR to date of progression does not need to be repeated. 
11. Adverse Events to be evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0) (see Appendix V). 
12. See Section 7 and Appendix III for additional monitoring of patients with toxicity. 
13. Follow every adverse event felt related to study therapy until resolved to ≤ grade 2 – i.e. follow-up every 12 weeks until deterioration to ECOG PS 4 
and/or end of life care or until all toxicities thought to be possibly-, probably-, or definitely-related to durvalumab or tremelimumab have resolved, 
returned to baseline, or been deemed irreversible, whichever is longer. 
14. To be completed by patient in clinic. 
 
 

 
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5.3 
Follow-up for Ineligible Patients 
 
The follow-up requirements for ineligible patients: 
• 
Randomized to Arm 1 (BSC) include submission of the Baseline Report plus annual follow-
up using the Minimal Follow-up Report. 
• 
Randomized to Arm 2 (tremelimumab and durvalumab) but who have received no protocol 
therapy include submission of the Baseline Report plus annual follow-up using the Minimal 
Follow-up Report. Data submission for ineligible participants who have received at least one 
dose of protocol therapy should be followed according to the protocol to allow for treatment 
and adverse event assessment. 
 
Note: The dates of objective progression and death must be reported for ineligible patients. 

 
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6.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
6.1 
Entry Procedures 
 
All registration/randomizations will be done through the CCTG web-based, password-protected 
Electronic Data Capture (EDC) system. Complete details regarding obtaining a password, 
accessing the system and registering/randomizing patients will be provided at the time of study 
activation and will also be included in the “EDC Data Management Guidebook”, posted on the 
CO.26 trial specific website. If sites experience difficulties accessing the system and/or 
registering/randomizing patients please contact the help desk (link in EDC) or the CO.26 Study 
Coordinator. 
 
All eligible patients enrolled on the study by each participating centre will be assigned a serial 
number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG CO.26) 
• 
investigator CCTG user ID 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
tissue banking consent version date 
• 
confirmation of the requirements listed in Section 4.0, including dates of essential tests and 
actual laboratory values 
• 
stratification factors 
 
6.2 
Stratification 
 
Subjects will be stratified by: 
• 
ECOG Performance Status: 0 vs1 
• 
Site of tumour:  
− 
right colon (caecum, ascending colon, hepatic flexure) vs  
− 
transverse colon vs  
− 
left colon (within the splenic flexure, descending colon, sigmoid colon, or rectosigmoid 
junction) vs  
− 
rectum vs  
− 
unknown  
 
 
 

 
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6.3 
Randomization 
 
Randomization will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the patient withdraws from the trial and requests that data 
collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the treating physician to satisfy himself or herself that the patient is indeed eligible 
before requesting registration/randomization. 
 
All randomized patients are to be followed until death or until sites are informed by CCTG that 
further follow-up is no longer required. The follow-up requirements for ineligible patients are 
outlined in Section 4.2. 

 
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ADMIN UPDATE #1: 2018-JAN-24 
7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Clinical Trials Group acts as the coordinating agency for the trial, 
the responsibility for the treatment of patients rests with each individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization. 
 
7.1 
Protocol Treatment Plan 
 
7.1.1 
Drug Administration 
 
Patients will be randomized at a 2:1 ratio to receive durvalumab plus tremelimumab plus best 
supportive care or best supportive care only to a planned sample size of 180. 
 
Best supportive care is defined as those measures designed to provide palliation of symptoms and 
improve quality of life as much as possible. 
 
When durvalumab is given with tremelimumab, tremelimumab will be administered first. 
Durvalumab will start immediately after the tremelimumab infusion (during the post-
tremelimumab observation period). 
 
One cycle will be defined as 28 days (4 weeks). Study drugs will be started on cycle 1. 
Tremelimumab will only be given for the first 4 cycles. 
 
Arm 
Agent(s) 
Dose 
Route 
Duration* (infusion) 
Schedule 
1 
Best Supportive Care 
NA 
NA 
NA 
NA 
2 
Tremelimumab 
75 mg 
IV 
60 minutes 
Day 1, cycles 1-4 
Durvalumab 
1500 mg 
IV 
60 minutes 
Day 1 every 28 days 
Best Supportive Care  
NA 
NA 
NA 
NA 
* Duration (overall) of durvalumab and tremelimumab is until unequivocal progression or unacceptable toxicity. 
 
 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
Arm 2: DURVALUMAB and TREMELIMUMAB 
 
The major toxic effects of durvalumab or tremelimumab which are anticipated to limit dosing are 
hypersensitivity/ infusion related reactions and possible class related immune related AEs, based 
on the mechanism of action of durvalumab ± tremelimumab leading to T-cell activation and 
proliferation. Potential immune related AEs include pneumonitis, hepatitis, diarrhea/colitis and 
intestinal perforation, endocrinopathies (hypo and hyperthyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism diabetes insipidus and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent irAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. Other 
inflammatory responses that are rare with a potential immune-mediated etiology include, but are 
not limited to, pericarditis, sarcoidosis, uveitis and other events involving the eye, skin, 
hematological and rheumatological events. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs. With anti-PD-L1 and anti-CTLA-4 
combination therapy, the occurrence of overlapping or increasing cumulative toxicities that include 
immune related AEs could potentially occur at higher frequencies than with either durvalumab or 
tremelimumab monotherapy. 
 
7.1.2 
Premedication (Arm 2) 
 
No routine premedication (e.g. for nausea) or prophylaxis for hypersensitivity is required. 
Management of symptoms should take place as necessary. Premedication is not expected to be 
required. See Appendix III with respect to premedication of patients that have had a prior < Grade 2 
infusion-related reaction. Details of any premedication or concomitant medication given to manage 
or prevent adverse events should be recorded on the electronic case report form (eCRF). 
 
7.1.3 
Patient Monitoring (Arm 2) 
 
Patients will be monitored before, during infusion and after the infusion of tremelimumab and 
durvalumab with assessment of vital signs as specified in Section 5.2. A 1-hour observation period 
is recommended after the first infusion of tremelimumab, at which time durvalumab may be 
administered. A second 1-hour observation period is recommended after the first infusion of 
durvalumab. After the first cycle of tremelimumab and durvalumab therapy, subsequent 
observation periods can be at the discretion of the investigator (30 minutes is suggested – i.e. 
30 minutes after tremelimumab infusion, during durvalumab infusion, and for 30 minutes after 
durvalumab infusion). For patients who receive only durvalumab, the recommended observation 
period is 30 minutes after infusion. 
 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
Patients should be monitored for signs and symptoms of immune related AEs. In the absence of an 
alternate etiology (e.g. infection or relapse), signs or symptoms of events with a potential 
inflammatory or immune-mediate mechanism should be considered to be immune- related. 
 
Drug Administration and Patient Monitoring/Vitals for Arm 2 
(Durvalumab + Tremelimumab + BSC) 
 
Drug 
administration 
Infusion 
duration 
Vital signs and Monitoring* 
Tremelimumab 
60 min 
Vital signs 
≤ 30 minutes prior to start of 
infusion then every 30 ±5 
minutes during infusion and 
observation periods 
60 min observation period after 
administration of 1st cycle of 
durvalumab/tremelimumab, for 
subsequent cycles 30 min 
(recommended) 
Durvalumab 
60 min 
* 
Guidelines for management of infusion-related reaction are summarized in 7.1.6 and Appendix III. 
 
Tremelimumab infusion  
Tremelimumab observation* 
 
 
Durvalumab infusion 
Durvalumab observation* 
<------------- 60 minutes -------------> 
<------------- 60 minutes -------------> 
<------------- 60 minutes -------------> 
* 60 minutes observation period (patient monitoring) after administration of 1st cycle of durvalumab/tremelimumab.  
For subsequent cycles 30 minutes (recommended). 
Note: Vital signs ≤ 30 minutes prior to start of each infusion then every 30 ±5 minutes during infusion and 
observation periods. 
 
7.1.4 
Dose Modifications 
 
Guidelines for dose modification and toxicity management of immune related and non-immune 
related adverse events are summarized in Appendix III. 
 
The guidelines outline dose adjustments and recommended interventions for several of these 
immune related adverse events. If a patient experiences several adverse events and there are 
conflicting recommendations, please use the recommended dose adjustment that requires the 
greatest dose hold or discontinuation. Adverse events will be graded using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) (see Appendix V). 
 
Important: If the infusion cannot be administered, it should be omitted until the next planned 
infusion. 
 
Centres must contact CCTG in the event of severe immune related adverse event(s), especially 
when the use of drugs such as infliximab is considered. 
 
 
 

 
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7.1.5 
Management of Toxicity  
 
The following general guidance should be followed for management of toxicities: 
1. Treat each of the toxicities with maximum supportive care (including slowing / interrupting / 
omitting the agent suspected of causing the toxicity where required). 
2. If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same doses of durvalumab and tremelimumab along with appropriate continuing 
supportive care. 
 
In addition to the criteria for permanent discontinuation of study drug/regimen based on CTCAE 
grade/severity (tables below), permanently discontinue study drugs for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤ 10 mg of oral prednisone per day (or equivalent) 
within 12 weeks after last doses of study drug(s). 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE following resumption of 
dosing. 
 
In addition to the dose adjustments shown in Appendix III, the following are recommended: 
• 
Patient evaluation to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature should be 
considered to be immune-related. 
• 
Symptomatic and topical therapy should be considered for low-grade events. 
• 
For persistent (greater than 3 to 5 days) low-grade (Grade 2) or severe (≥ Grade 3) events 
promptly start prednisone PO 1-2 mg/kg/day or IV equivalent. 
• 
If symptoms recur or worsen during corticosteroid tapering (≥ 4 weeks of taper), increase the 
corticosteroid dose (prednisone dose [e.g. up to 2-4 mg/kg/day or IV equivalent]) until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate. 
• 
More potent immunosuppressives (refer to individual sections of Appendix III - immune 
related adverse events for specific type of immunosuppressive) should be considered for events 
not responding to systemic steroids. 
• 
Discontinuation of study drugs is not mandated for Grade 3 / Grade 4 inflammatory reactions 
attributed to local tumour response (e.g. inflammatory reaction at sites of metastatic disease, 
lymph nodes etc.). Continuation of study drugs in this situation should be based upon a 
benefit/risk analysis for that patient and be discussed with CCTG. 
 
7.1.6 
Management of Infusion Reactions 
 
Guidelines for management of infusion-related reaction are summarized in Appendix III. 
 
The standard infusion times for both durvalumab and tremelimumab are 1 hour. However, if there 
are interruptions during infusion, the total allowed time should not exceed 8 hours at room 
temperature. 
 
Study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to appropriate drugs and medical equipment to treat acute anaphylactic reactions, 
emergency resuscitation teams and equipment in addition to the ability to admit patients to an 
intensive care unit if necessary. 
 
 

 
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7.1.7 
Duration of Therapy  
 
In the absence of unequivocal disease progression, as defined in Section 10.2.5, intolerable toxicity 
or withdrawal of consent to further participation, patients may continue to receive study treatment 
of durvalumab and tremelimumab at the discretion of the Investigator. 
 
If, in the opinion of the Investigator, a patient is deriving clinical benefit from study therapy despite 
the documentation of objective disease progression per RECIST 1.1 criteria, then provided the 
patient does not have any significant, unacceptable, or irreversible toxicities that indicate that 
continuing treatment will not further benefit the patient, the patient may remain on study therapy 
pending their next disease assessment. However, appropriate imaging studies must be repeated 
within 4-8 weeks to re-assess treatment response. A patient with objective disease progression 
confirmed on subsequent assessment by either RECIST 1.1 criteria or Immune-Related Response 
criteria (irRC) as appropriate should be discontinued from the study. Patients should also be 
discontinued from the study if objective disease progression occurs in a target lesion that has 
previously shown a confirmed response. 
 
For a complete list of general criteria for stopping study treatment, please see Section 10.0. 
 
7.1.8 
Patient Compliance  
 
Treatment compliance will be monitored by drug accountability, as well as recording drug 
administration in the patient’s medical record and case report form (CRF). 
 
Arm 1: Patients randomized to ARM 1 will receive best supportive care per institutional standards at each 
participating centre. 
 
7.2 
Concomitant Therapy 
 
The Investigator must be informed as soon as possible about any medication taken from the time 
of screening until the end of the clinical phase of the study (final study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study are to be recorded in the eCRF. 
 
7.2.1 
Permitted 
 
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate prophylactic or supportive care except for those medications identified as “not permitted” 
below. In addition, the following medications or treatments are permitted during the study: 
• 
Growth factors may be used according to centre policy to treat life threatening toxicity but 
cannot be used in place of protocol defined dose adjustments. Please consult CCTG in the case 
of patients experiencing multiple delays as exceptions may be made for patients who are 
benefitting from protocol therapy. 
• 
Other best supportive and palliative care (e.g. pain control) as required throughout the study. 
• 
Anti-emetics or anti-diarrheal agents as required. 
 
 
 

 
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7.2.2 
Not Permitted 
• 
Cytokines  
• 
Other anti-cancer treatment (administration of any other anti-cancer therapy is not permitted 
while the patient is receiving protocol therapy. Thereafter, patients may be treated at the 
investigator’s discretion 
• 
Other investigational therapy 
• 
Concurrent radiation treatment; Note: local radiation treatment of isolated lesions for palliative 
intent is acceptable. Protocol therapy should be held prior to and during the radiation (consult 
CCTG in these cases). 
• 
Corticosteroids IV or PO (except for the treatment of ≥ Grade 3 infusion reaction and nausea 
prophylaxis for chemotherapy). Note: Topical applications (e.g. rash), inhaled sprays (e.g. 
obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed, as 
are oral dose of steroids equivalent to 10 mg or less of prednisone. 
• 
Other immunosuppressive medications including methotrexate, azathioprine, and TNF-α 
blockers. Use of immunosuppressive medications for the management of investigational 
product-related AEs is acceptable. 
• 
Live attenuated vaccines (examples include, but are not limited to, vaccines for measles, 
mumps, and rubella, live attenuated influenza vaccine (nasal), chicken pox vaccine, oral polio 
vaccine, rotavirus vaccine, yellow fever vaccine, BCG vaccine, typhoid vaccine and typhus 
vaccine) within 30 days of durvalumab and tremelimumab dosing (i.e., 30 days prior to the first 
dose, during treatment with durvalumab and tremelimumab and for 30 days post 
discontinuation of durvalumab and tremelimumab). Inactivated vaccines, such as the injectable 
influenza vaccine, are permitted. 

 
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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for Adverse Events 
 
All patients will be evaluable for adverse event evaluation from the time of their first treatment. 
 
8.1.2 
Evaluable for Response 
 
All patients who have received at least one cycle of therapy and have their disease re-evaluated will 
be considered evaluable for response (exceptions will be those who exhibit objective disease 
progression prior to the end of cycle 1 who will also be considered evaluable). Patients on therapy 
for at least this period and who meet the other listed criteria will have their response classified 
according to the definitions set out below [Eisenhauer 2009]. 
 
8.1.3 
Evaluable for Quality of Life Assessment 
 
All patients who have completed the quality of life questionnaire are evaluable for quality of life. 
 
8.2 
Response and Evaluation Endpoints 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee as well 
as the Immune-Related Response Criteria (irRECIST). In the event of disease progression using 
the RECIST 1.1 criteria (unconfirmed PD (uPD)), investigators should continue treatment, if the 
patient is clinically stable (i.e. stable performance status and disease related symptoms) until 
disease progression is confirmed at a subsequent scan at least 4 weeks later (unequivocal confirmed 
disease progression (cPD)). This is particularly important for patients in whom pseudoprogression 
may have occurred. Follow up response assessments must be continued until unequivocal disease 
progression has occurred. 
 
8.2.1 
Measurable Disease.  
 
Measurable tumour lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray and as ≥ 10 mm with CT 
scan or clinical examination. Bone lesions are considered measurable only if assessed by CT scan 
and have an identifiable soft tissue component that meets these requirements (soft tissue component 
≥ 10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumour measurements must be 
recorded in millimetres (or decimal fractions of centimetres). Previously irradiated lesions are not 
considered measurable unless progression has been documented in the lesion. 
 
8.2.2 
Non-measurable Disease 
 
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitic involvement of lung or skin and abdominal masses followed by clinical examination 
are all non-measurable. Lesions in previously irradiated areas are non-measurable, unless 
progression has been demonstrated. 

 
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8.2.3 
Target Lesions 
 
When more than one measurable tumour lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis of ≥ 15 mm by 
CT scan and only the short axis of these nodes will contribute to the baseline sum. All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target 
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed (see 8.2.4). At baseline, the sum of the target lesions (longest diameter of 
tumour lesions plus short axis of lymph nodes: overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately measured 
but are deemed to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be used. 
 
8.2.4 
Non-target Lesions 
 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”. 
 
8.2.5 
New Lesions 
 
The transitory appearance of new lesions has been well described for immunotherapies. All new 
lesions must be recorded on the CRF up to a maximum of 5 lesions total (and a maximum of 
2 lesions per organ) representative of all involved organs, using standard RECIST 1.1 criteria for 
nodal and non-nodal disease. Each new lesion should be measured at all subsequent assessments 
but is NOT included in the sum of target lesions for evaluation of response or progression. 
 
8.2.6 
RECIST 1.1 Response 
 
8.2.6.1 RECIST 1.1 - Patients With Measurable Disease 
 
RECIST 1.1 response will be classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and normalization of 
tumour markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: 
continue to record the measurement even if < 10 mm and considered CR). Residual lesions (other 
than nodes < 10 mm) thought to be non-malignant should be further investigated (by cytology 
specialized imaging or other techniques as appropriate for individual cases [Eisenhauer 2009]) before 
CR can be accepted. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumour 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD. 

 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND an 
absolute increase of ≥ 5 mm. Appearance of new lesions will also constitute progressive disease 
(including lesions in previously unassessed areas). In exceptional circumstances, unequivocal 
progression of non-target disease may be accepted as evidence of disease progression, where the 
overall tumour burden has increased sufficiently to merit discontinuation of treatment or where the 
tumour burden appears to have increased by at least 73% in volume. Modest increases in the size 
of one or more non-target lesions are NOT considered unequivocal progression. If the evidence of 
PD is equivocal (target or non-target), treatment may continue until the next assessment, but if 
confirmed, the earlier date must be used. 
 
Table 1: Integration of Target, non-Target and New Lesions into Response Assessment for patients 
with measurable disease: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
Documented at least once ≥ 4 weeks 
from baseline  
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10 mm 
No Target 
Non-CR/non-PD 
No 
Non-
CR/non-
PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 

 
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8.2.6.2 RECIST 1.1 - Patients With Non-Measurable Disease Only 
 
Patients with only non-measurable (but evaluable) disease, may only have an overall RECIST 1.1 
response or SD or PD as follows: 
 
Complete Response (CR): disappearance of non-target lesions. Residual lesions thought to be non-
malignant should be further investigated (by cytology specialized imaging or other techniques as 
appropriate for individual cases [Eisenhauer 2009] before CR can be accepted. 
 
Stable Disease (SD): steady state of disease. No new lesions and not sufficient progression of non-
target lesions to qualify for PD. 
 
Progressive Disease (PD): the appearance of new lesions and/or unequivocal progression of non-
target lesions. 
 
Table 2: Integration of Target, non-Target and New Lesions into Response Assessment for patients 
with only non-measurable, evaluable, lesions: 
 
Non-Measurable Lesions* 
New Lesions 
Overall 
Response 
Best Overall Response for this 
category also requires 
Complete disappearance 
No 
CR 
 
Non-PD 
No 
SD 
Documented at least once > 4 weeks 
from baseline 
PD** 
No 
PD 
No prior SD 
Any 
Yes 
PD 
* 
Note that these lesions should be recorded under the "Non-Target" lesions table on the CRFs. 
** 
Unequivocal progression in non-measurable lesions will be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 

 
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8.2.7 
irRECIST Response 
 
8.2.7.1 irRECIST - Patients With Measurable Disease 
 
Table 3: Immune-Related RECIST Criteria (irRECIST) for patients with measurable disease: 
 
Response 
Description of Response 
Confirmation by 
Complete remission: irCR  
Complete disappearance of all lesions 
(whether measurable or not, and no 
new lesions). Patient may have had 
prior uPD by RECIST 1.1 criteria.  
Repeat, consecutive assessment 
no less than 4 weeks from the 
date first documented 
Partial Remission: irPR 
Decrease in tumour burden > 30% 
relative to baseline. Patient may have 
had prior uPD by RECIST 1.1 criteria. 
Consecutive assessment at least 4 
weeks after first documentation 
Stable Disease: irSD 
Not meeting criteria for irCR or irPR, 
in absence of irPD. Patient may have 
had prior uPD by RECIST 1.1 criteria 
 
Progressive disease: irPD 
Increase in tumour burden ≥ 20% 
relative to nadir (minimum recorded 
tumour burden) 
Confirmation by a repeat, 
consecutive assessment no less 
than 4 weeks from the date first 
documented is required  
New measurable lesions 
(i.e. ≥ 10 mm in long axis) 
Measured but not incorporated into 
overall assessment of target lesions. 
 
New, non-measurable 
lesions 
Recorded 
 
unidimensional measurements will be collected per RECIST 1.1 
 
8.2.7.2 irRECIST - Patients With Non-Measurable Disease Only 
 
Table 4: Immune-Related RECIST Criteria (irRECIST) for patients with only non-measurable, 
evaluable, lesions: 
 
Response 
Description of Response 
Confirmation by 
Complete remission: irCR  
Complete disappearance of all non-
measurable lesions (and no new 
lesions). Patient may have had prior 
uPD by RECIST 1.1 criteria. 
Repeat, consecutive assessment 
no less than 4 weeks from the 
date first documented 
Stable Disease: irSD 
Not meeting criteria for irCR in 
absence of irPD. Patient may have had 
prior uPD by RECIST 1.1 criteria. 
 
Progressive disease: irPD 
Unequivocal increase in tumour 
burden  
Confirmation by a repeat, 
consecutive assessment no less 
than 4 weeks from the date first 
documented is required 
New measurable lesions 
(i.e. ≥ 10 mm in long axis) 
Measured but not incorporated into of 
overall assessment of target lesions. 
 
New, non-measurable 
lesions 
Recorded 
 

 
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8.3 
Response Duration 
 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including baseline). 
 
8.4 
Stable Disease Duration 
 
Stable disease duration will be measured from randomization until the criteria for progression are 
met, taking as reference the smallest sum on study (including baseline). 
 
8.5 
Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
8.5.1 
Clinical Lesions 
 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm as 
assessed using callipers (e.g. skin nodules). For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging 
is preferred. 
 
8.5.2 
Chest X-ray 
 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions > 
20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
 
8.5.3 
CT, MRI 
 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). Other specialized imaging or other 
techniques may also be appropriate for individual case [Eisenhauer 2009]. For example, while PET 
scans are not considered adequate to measure lesions, PET-CT scans may be used providing that 
the measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 

 
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8.5.4 
Ultrasound 
 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
 
8.5.5 
Endoscopy, Laparoscopy 
 
The utilization of these techniques for objective tumour evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response or surgical resection is an endpoint. 
 
8.5.6 
Tumour Markers 
 
Tumour markers alone cannot be used to assess objective tumour response. If markers are initially 
above the upper normal limit, however, they must normalize for a patient to be considered in 
complete response. 
 
8.5.7 
Cytology, Histology 
 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumour types such as germ cell tumours, where known 
residual benign tumours can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when 
the measurable tumour has met criteria for response or stable disease is advised to differentiate 
between response or stable disease and progressive disease. 

 
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ADMIN UPDATE #1: 2018-JAN-24 
9.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG. 
 
9.1 
Definition of a Reportable Serious Adverse Event (Durvalumab +/- Tremelimumab Arm) 
 
• 
For patients randomized to receive best supportive care (BSC), SAE reporting is NOT required. 
• 
All serious adverse events, regardless of whether they are unexpected or related to protocol 
treatment, occurring during the treatment period and within 30 days after the last protocol 
treatment administration, must be reported in an expedited manner. Any late serious adverse 
event occurring after this 30-day period which is related to protocol treatment must also be 
reported in an expedited manner (see Section 9.2 for reporting instructions). 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above.  
 
Important Notes:  
1. Any immune-related adverse event (irAE) requiring high dose steroids is by definition 
medically significant and must be reported as such (i.e., as expedited events using the SAE 
reporting system). 
2. If a patient shows an AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x ULN, refer to 
Appendix III for further instructions on cases of increases in liver biochemistry and evaluation 
of Hy’s Law. These cases should be reported as SAEs if, after evaluation, they meet the criteria 
for a Hy’s law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. 
 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
9.1.1 
Durvalumab +/-  Tremelimumab Adverse Events of Special Interest 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be 
serious or non-serious.  
 
AESIs for durvalumab ± tremelimumab include, but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs may require close monitoring in the treatment arms with durvalumab ± 
tremelimumab. 
 
An immune-mediated adverse event (imAE) is defined as an AESI that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is no 
clear alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an imAE diagnosis. Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  
 
If the Investigator has any questions in regards to an event being an imAE, the Investigator should 
promptly contact the CCTG.  
 
AESIs observed with durvalumab ± tremelimumab include: 
• 
Diarrhea / Colitis, and intestinal perforation; 
• 
Pneumonitis / Interstitial Lung Disease (ILD); 
• 
ALT/AST increases / hepatitis / hepatotoxicity; 
• 
Neuropathy / neuromuscular toxicities (e.g. Guillain-Barré syndrome, and myasthenia gravis); 
• 
Endocrinopathies (i.e. events of hypophysitis, hypopituitarism, adrenal insufficiency, diabetes 
insipidus, hyper- and hypothyroidism and type I diabetes mellitus); 
• 
Rash / Dermatitis; 
• 
Nephritis / Blood creatinine increases; 
• 
Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase); 
• 
Myocarditis; 
• 
Myositis/polymyositis 
• 
Other inflammatory responses that are rare with a potential immune-mediated aetiology 
include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events involving the 
eye, skin, hematological and rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab Investigator’s Brochures. More specific guidelines for their 
evaluation and treatment are described in detail in Appendix III. 
 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
9.1.2 
Events Not to be Treated as SAEs (Durvalumab +/- Tremelimumab Arm) 
 
• 
Serious adverse events which are unequivocally related to the underlying malignancy or disease 
progression do NOT require expedited reporting. These include such adverse events as 
admission for pain control, palliative care or paracentesis of malignant effusions. 
• 
In addition, the following events will NOT be recorded as AEs (or SAEs): 
− 
lack of efficacy /disease progression (will be recorded separately on CRF); 
− 
laboratory abnormalities for protocol specified tests (these are derived electronically from 
actual values supplied and need not be reported separately in adverse event tables on 
CRFs); 
− 
elective hospitalization for medical, radiological or surgical procedures for treatment of 
disease or to simplify treatment for study procedures (will be recorded separately on CRF); 
− 
hospitalization for palliative care or pain control. 
 
9.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the CO.26 section of the CCTG website (www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
CO.26 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application. 
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the CO.26 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application. 
 
 

 
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In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430). 
 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting 
 
9.3.1 
Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 4.1.15. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy. 
 
A highly effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Highly effective methods of 
contraception are described in the table below. Note that some contraception methods are not 
considered highly effective (e.g. male or female condom with or without spermicide; female cap, 
diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; 
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary 
mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and 
triphasic combined oral contraceptive pills). 
 
Highly Effective* Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing 
intrauterine system (e.g. Mirena®)** 
• 
Etonogestrel implants: e.g. Implanon or Norplan 
• 
Intravaginal device: e.g. ethinylestradiol and etonogestrel 
• 
Medroxyprogesterone injection: e.g. Depo-Provera  
• 
Normal and low dose combined oral contraceptive pill 
• 
Norelgestromin/ethinylestradiol transdermal system 
• 
Cerazette (desogestrel) 
* 
Highly effective (i.e. failure rate of <1% per year). 
** This is also considered a hormonal method. 
 
9.3.2 
Pregnancy Reporting 
 
If a patient becomes pregnant during the course of the study, the investigational agent should be 
discontinued immediately. 
 
Pregnancy itself - occurring in female participants, and female partners of male participants - is not 
regarded as an AE unless there is a suspicion that the IP under study may have interfered with the 
effectiveness of a contraceptive medication. The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from the study. 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants, and 
female partners of male participants. Pregnancies occurring up to 6 months after the last dose of 
study treatment must also be reported. 
 
 

 
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The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage. 
 
Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca). 
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which a causal relationship with protocol treatment cannot be ruled out). 
 
9.5 
CCTG Reporting Responsibility to AstraZeneca 
 
AstraZeneca will be notified of all protocol reportable serious adverse events (as defined in 
Section 9.1) within one working day of receipt of report at CCTG. CCTG, as sponsor, will 
determine regulatory reportability in Canada. 
 
AstraZeneca will be notified of all pregnancies and outcomes of pregnancies within 30 days of 
receipt of the report at CCTG. 
 
9.6 
AstraZeneca Reporting Responsibilities 
 
AstraZeneca will report all regulatory reportable serious adverse events from non-CCTG trials 
(Safety Updates) with durvalumab and tremelimumab to CCTG within the timelines outlined in the 
contract. CCTG will review these events to determine which meet the criteria (serious, unexpected, 
drug related) for reporting to CO.26 investigators. AstraZeneca will report these events to Health 
Canada. 
 
9.7 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to the CCTG. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. The reports will be posted to the CCTG 
trial CO.26 web-based safety monitoring utility. 
 
 

 
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Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
CO.26 web-based safety monitoring utility and documentation of REB submission must be retained 
in the study binder on site. The REB submission template provided by CCTG can be used to assist 
with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 
 
 

 
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ADMIN UPDATE #1: 2018-JAN-24 
10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
10.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 7.0 and Appendix III. 
• 
Tumour progression or disease recurrence as defined in Section 8.0. 
• 
Request by the patient. 
 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if 
patients discontinue protocol treatment prematurely and/or no longer attend the participating 
institution. 
 
10.2 
Duration of Protocol Treatment  
 
Investigators are encouraged to continue therapy, as appropriate in the absence of unacceptable 
toxicity, until disease progression has been unequivocally documented. This is particularly 
important for patients in whom pseudoprogression may have occurred. In patients for whom study 
therapy is continued beyond the first documentation of objective disease progression (i.e. per 
RECIST 1.1 criteria) on the basis of clinical benefit, continued follow-up assessments per protocol 
must also be continued until disease progression has been unequivocally confirmed, either through 
RECIST 1.1 or Immune-Related Response Criteria (irRC) [Wolchok 2009] (i.e. treatment failure), at 
which time study therapy should cease. 
 
10.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 

 
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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Central Radiology Review 
 
There will be no central radiology review for this study. 
 
11.2 
Central Pathology Review 
 
There will be no central pathology review for this study. 

 
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12.0 
CORRELATIVE STUDIES 
 
Tissue samples collected on this trial may be used by researchers now or in the future to better 
understand the nature of colorectal cancer and how patients respond to treatment. Samples will be 
used for research purposes only and will not be sold. A scientific review process of any proposals 
to use the tissue will take place and any proposals approved will have undergone ethics approval. 
Patients will not be identified by name. The only identification of tissue will be by a tumour banking 
code assigned at the time of sample receipt. Material issued to researchers will be anonymized and 
only identified by tumour banking coded number. 
 
Specific samples to be collected and priority assays are as follows: 
 
12.1 
Protocol-Mandated Correlative Studies 
 
Archival FFPE Tumour Tissue Submission (Mandatory)  
 
Archival Tumour Block/Slides: 
 
The submission of a representative block of the diagnostic tumour tissue (from primary or 
metastatic tumour) and the adjacent normal tissue (part of the standard resection) is mandatory for 
participation on this trial. Blocks will be carefully stored as part of the CCTG Tumour Tissue Data 
Repository at Queen’s University in Kingston, Ontario, but the only assays done will be as part of 
this study. All patients on whom a diagnostic tumour block is collected will be aware of this 
retrieval and will have given their consent. 
 
Blocks are the preferred material to collect, as it is well known that tissue materials (including 
protein and nucleic acid integrity) on unstained sections deteriorate rapidly within 3-6 months after 
preparation. One of the objectives will be to create tissue micro arrays. These will optimize the 
amount of tissue available to investigators and permit the preservation of the tumour block 
submitted. 
 
If, at any time, the submitting hospital requires the block to be returned for medical or legal 
concerns, it will be returned by courier on request. 
 
Samples will be used for research purposes only and will not be sold. Patients will not be identified 
by name. The only identification of tissue will be by a patient study number assigned at the time of 
registration to the trial, the surgical/ histology number and/or patient initials. Material issued to 
researchers will be anonymized and only identified by a coded number. 
 
Testing specifically for hereditary genetic defects predisposing to malignant disease will not be 
carried out without the expressed consent of the patient. 
 
Where no previously resected or biopsied tumour tissue exists, additional biopsy of the primary or 
metastatic tumour will be required. 
 
Directions: 
 
At the same time that the baseline form is submitted, original tumour block should be sent to the 
CCTG Pathology Coordinator. Centres should contact CCTG if they are unable to submit a tumour 
block, as sufficient tissue is required for the assays described above. 

 
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Within 4 weeks of randomization (note: a request letter will not be sent), complete the EDC 
Archival Tumour Tissue Submission Form. Print a copy of the completed form and ship tumour 
blocks/slides along with a Request for Payment form to: 
 
Shakeel Virk  
Pathology Coordinator, Canadian Cancer Trials Group  
Richardson Labs Bldg, 4th Floor  
88 Stuart St. 
Queen’s University  
Kingston, ON K7L 3N6  
Tel: 613-533-2906  
Fax: 613-548-2486  
Email: virks@queensu.ca 
 
Detailed instructions for FFPE sample acquisition, preparation, and shipping are found in the 
CO.26 Lab Manual. 
 
Planned priority assays on archival tumour tissue include:  
• 
Immunohistochemistry for PD-L1 and CTLA-4 expression; 
• 
Immunohistochemistry for tumour infiltrating lymphocytes (CD8+ T cells); 
• 
Other exploratory analysis by IHC and/or flow cytometry for more detailed characterization of 
immune cell population / additional immune markers (IDO, CD4, CD3, FOXP3); 
• 
Immunohistochemistry for mismatch repair (MMR) proteins; 
• 
Genomic instability measured by MSI assays or using SNP arrays; 
• 
Mutational load measured using targeted next generation sequencing; 
• 
Expression profiling to identify microsatellite instability immune, canonical, metabolic and 
mesenchymal subtypes of tumour. 
 
Blood, Serum and Plasma Collection: 
 
The CCTG is interested in exploring the use of surrogate tissues such as serum and plasma in 
evaluating potential prognostic or predictive biomarkers, or as evidence of pharmacodymanic 
effects. Blood, serum and plasma samples will be collected and banked for planned studies from 
all patients. 
 
Planned priority assays on blood, serum and plasma include:  
• 
Circulating tumour DNA 
 
Detailed instructions for blood, serum and plasma sample acquisition, preparation, and shipping 
are found in the CO.26 Lab Manual. 

 
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12.2 
Optional Banking of Samples 
 
Banking of Tumour Tissue: 
 
Mandatory submission of tumour tissue has been described above. The subsequent banking of 
collected diagnostic tissue is not mandatory for participation in the study, but the participation of 
all centres is strongly encouraged. Blocks and blood will be carefully banked as part of the CCTG 
tissue/tumour bank at Queen’s University in Kingston, Ontario. 
 
After patient consent, collection of paraffin tumour blocks will preferred, as one of the objectives 
will be to create tissue micro arrays. These will optimize the amount of tissue available to 
investigators and permit the preservation of the tumour block submitted. If tumour blocks are 
unavailable, then two x 2 mm cores of tumour from the block and 30 specimen slides are preferred. 
If, at any time, the submitting hospital requires the block to be returned for medical or legal 
concerns, it will be returned by courier on request. 
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 
 
Banking of Blood, Serum, and Plasma: 
 
Mandatory submission of whole blood, serum, and plasma has been described above. The 
subsequent banking of collected samples is not mandatory for participation in the study, but the 
participation of all centres is strongly encouraged. Samples will be carefully banked as part of the 
CCTG tissue/tumour bank at Queen’s University in Kingston, Ontario. 
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 

 
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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
The primary objective of this phase II randomized study is to assess the effect of the combination of 
durvalumab and tremelimumab and best supportive care (BSC) on the Overall Survival of patients with 
refractory, advanced colorectal cancer. Patients will be randomized to receive either combination of 
durvalumab and tremelimumab plus best supportive care, or best supportive care only in a 2:1 ratio after 
stratification by ECOG performance status (0 versus 1). Secondary objectives include comparisons of 
Progression Free Survival, Objective Response Rate, and Adverse Events between the two treatment 
arms. 
 
13.2 
Study Endpoints and Analysis 
 
Overall Survival: 
Overall Survival, the primary endpoint of this study, is defined as the time from randomization to 
death from any cause. Patients who are alive at the time of the final analysis or who have become 
lost to follow-up will be censored at their last date known to be alive. Patients will be analyzed in 
the arm to which they are randomized regardless of the treatment they received (intent-to-treat 
analysis). The survival experience of patients in both treatment groups will be summarized by the 
Kaplan-Meier method and compared primarily by a stratified log-rank test adjusting for the 
stratification variable (ECOG performance status and site of tumour) at randomization. Secondary 
analyses based on stratified Cox proportional hazards model will also be performed. ECOG 
performance status (0 versus 1) and site of tumour (right colon, transverse colon, left colon, rectum, 
unknown) will be the stratification factors to define the stratified Cox proportional hazards model. 
Besides the treatment factor (combination of durvalumab and tremelimumab + BSC versus BSC 
alone), the following factors at patient entry will be included in the stratified Cox proportional 
hazards model:  
• 
Age (< 65 versus ≥ 65) 
• 
Sex (male versus female) 
• 
Number of organ sites involved at baseline (≤ 2 versus > 2) 
• 
Presence of liver metastases (yes versus no) 
 
A formal pre-planned subset analysis for the primary endpoint (OS) will be conducted to address 
the benefit of combination of durvalumab and tremelimumab between the groups defined by the 
above factors and the following: 
• 
ECOG Performance Status (0 versus 1) 
• 
Race (white, black, Asian, other)  
• 
Site of tumour: (right colon, transverse colon, left colon, rectum) 
 
Progression-Free Survival: 
Progression-Free Survival (PFS) is defined as the time from randomization to the first objective 
documentation of disease progression or death due to any cause. If a patient has not progressed or 
died at the time of final analysis, PFS will be censored on the date of the last tumour assessment. 
This includes patients who are lost to follow-up or have withdrawn consent. All analyses for OS 
will also be performed for PFS, using similar methodology. A sensitivity analysis of PFS will also 
be performed where PFS is defined as the time from randomization to the second documentation 
of unequivocal disease progression in those patients who continued study therapy beyond the first 
objective documentation of disease progression and with interim CR, PR or SD documented. 

 
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Objective Response Rate: 
Objective Response Rate (ORR) is defined as the proportion of patients with a documented 
complete response and partial response based on RECIST 1.1. The primary estimate of ORR will 
be based on all patients randomized. A Cochran-Mantel-Haenszel test adjusting for the 
stratification factors (ECOG performance status, site of tumour) at the time of randomization will 
be used to compare the objective response rates between two arms. A sensitivity analysis of ORR 
will also be performed where response is defined as the proportion of patients with a documented 
complete response and partial response based on RECIST 1.1 and/or Immune-Related Response 
Criteria (irRC) [Wolchok 2009]. 
 
Safety Analysis: 
All patients who have received at least one dose of protocol treatment will be included in the safety 
analysis. The incidence of adverse events will be summarized by type of adverse event and severity 
using the NCI Common Terminology Criteria for Adverse Events. A Fisher’s exact test will be 
used to compare adverse events between the two arms if required. 
 
13.3 
Sample Size and Duration of Study 
 
The study is designed to have a power of 80% and a two-sided alpha of 10% to detect a 35% 
reduction in the continuous risk of death (HR 0.65, which corresponds to an increase of median 
survival from 4.5 to 6.9 months). It is estimated that 150 events will be required to detect this 
reduction. The final analysis will be performed when 150 events are observed. Assuming an accrual 
rate of around 10 patients per month, the required number of events would be observed by accruing 
a total of 180 patients and following them for a minimum of 6 months. The total duration of the 
trial would be around 24 months. 
 
13.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators’ meetings. 
 
13.5 
Interim Analysis 
 
No interim analysis will be performed. 

 
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14.0 
PUBLICATION POLICY 
 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
14.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group may be credited as 
authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
 
14.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
14.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following the analysis of study results the 
draft is not substantially complete, the central office reserves the right to make other arrangements 
to ensure timely publication. 
 
14.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by the CCTG 
Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. 
Individual participating centres may not present outcome results from their own centres separately. 
Supporting groups and agencies will be acknowledged. 

 
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15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
15.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
15.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion. 
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs. 
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately. 
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs. 
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable). 
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation. 

 
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15.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in a CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study. 
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrolment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial. 
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject. 
 
15.3.1 Obtaining Consent for Pregnancy 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up consent form will not be required by 
CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” can be found on the trial webpage. The 
appropriate consent form must be used to obtain consent from any non-trial participant (such as the 
pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy. Similarly, male participants will not be 
withdrawn from the main study should their partner refuse/withdraw permission. 

 
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Obtaining Consent for Research on Children  
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian. 
 
15.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why. 
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
15.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP. 
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site. 
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained. 
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access. 
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained. 
 
15.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI).  
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 

 
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15.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
AstraZeneca has reserved the right to audit participating centres. Audits may only be conducted 
after consultation with CCTG. 
 
15.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For 
details of accessing the EDC system and completing the on-line Case Report Forms please refer to 
the “Registration/Randomization and Data Management Guidebook” posted on the CO.26 area of 
the CCTG web-site (www.ctg.queensu.ca). 

 
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16.0 
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Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, et al. Programmed cell death 1 
(PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer 
Epidemiol Biomarkers Prev. 2014 Dec;23(12):2965-70. 
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C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent 
D, CORRECT Study Group: Regorafenib monotherapy for previously treated metastatic colorectal cancer 
(CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 
2013;381(9863): 303. 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell death 1 ligand 
1 and tumour-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Nat Acad 
Sci U S A. 2007;104(9):3360-5. 
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanan JB, et al. Improved survival with 
ipilimumab in patients with metastatic melanoma [published erratum appears in N Engl J Med 
2010;363(13):1290]. N Engl J Med 2010;363(8):711-23. 

 
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Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol. 2008;26:677-704. 
Khleif S, Lutzky J, Segal N et al. MEDI4736, an anti-PD-L1 antibody with modified Fc domain: preclinical 
evaluation and early clinical results from a phase I study in patients with advanced solid tumours. (Abst 802) 
European Cancer Congress 2013, Amsterdam, Netherlands Sept 27-Oct 1, 20 
Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II trial of tremelimumab 
(CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res 2010;16(3):1042-8. 
Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, et al. Meta-analysis of phase II cooperative 
group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for 
future phase II trials. J Clin Oncol 2008;26(4):527-34. 
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin and B7-H1 are 
collaborative predictors of survival and represent potential therapeutic targets for patients with renal cell 
carcinoma. Clin Cancer Res. 2007;13(6):1749-56. 
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with 
Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. 
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Cancer Discov. 2015 Jan;5(1):43-51. 
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance and regulation of the 
costimulatory molecule B7-H1 in pancreatic adenocarcinoma. Cancer Lett. 2008;268(1):98-109. 
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of 
TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-19. 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to 
poor prognosis and tumour cells immune escape through suppressing tumour infiltrating dendritic cells 
maturation. Med Oncol. 2011 Sep;28(3):682-8. 
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Interferonalpha Monoclonal Antibody, in Systemic Lupus Erythematosus. Clin Pharmacokinet 52:1017–1027. 
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based on population pharmacokinetic analysis. Pharm Res. 2006 Jun;23(6):1275-84. 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, 
Nakajima Y. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed 
death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007; 13(7):2151-2157. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64. 
Pardoll D. Immunotherapy: it takes a village. Science. 2014;344(6180):149. 
Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, Yao S, Tsushima F, Narazaki H, 
Anand S, Liu Y, Strome SE, Chen L, Tamada K. B7-H1/CD80 interaction is required for the induction and 
maintenance of peripheral T-cell tolerance. Blood 2010; 116(8):1291-1298. 
Ribas A, Kefford R, Marshall MA, Punt CJA, Haanen JB, Marmol M, et al. Phase III randomized clinical trial 
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Robert C., Thomas L., Bondarenko I., et al. Ipilimumab plus dacarbazine for previously untreated metastatic 
melanoma. N Engl J Med 2011; 364:2517-2526. 
 
 

 
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Song M, Chen D, Lu B, Wang C, Zhang J, Huang L, et al.  PTEN loss increases PD-L1 protein expression and  
affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PLoS One. 2013 
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Tarhini AA. Tremelimumab: a review of development to date in solid tumours. Immunotherapy 2013;5:215-29. 
Thompson RH, Webster WS, Cheville JC, Lohse CM, Dong H, Leibovich BC, Kuntz SM, Sengupta S, Kwon 
ED, Blute ML. B7-H1 glycoprotein blockade: A novel strategy to enhance immunotherapy in patients with renal 
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Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nature Reviews Immunology 
2008; 8.6:467-477. 

 
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APPENDIX I - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 

 
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APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Details of Drug Distribution, Supply and Control/Accountability are provided in the CO.26 Pharmacy 
Information Manual, available on the CO.26 website 
(http://www.ctg.queensu.ca/trials/gi/CO26/CO26.html). 

 
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ADMIN UPDATE #1: 2018-JAN-24 
APPENDIX III - DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED REACTIONS 
(MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or Tremelimumab Monotherapy) 1Nov2017 Version 
 
 
 

 
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APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization and will apply to all eligible patients. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For details of 
accessing the EDC system and completing the on-line Case Report Forms please refer to the “CCTG EDC 
Generic Data Management Guidebook” posted on the CO.26 area of the CCTG web-site 
(www.ctg.queensu.ca). 
 
The electronic CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Timing 
To be completed electronically 
Supporting Documentation Required1 
Eligibility Checklist  
At the time of randomization 
• consent form2 
• relevant pathology report(s) 
• RAS reports 
• relevant operative report(s) 
• relevant radiology reports (including 
CT/MRI abdomen/pelvis, CT/MRI 
chest, chest x-ray) 
• tumour measurement worksheet 
• ECG report 
Baseline Report 
 
Within 2 weeks of randomization  
Correlative Studies 
Report 
(Tumour and 
Blood) 
Continuous running-
log folder 
 
See Section 5.0 
Information pertaining to tumour 
tissue submission must be 
completed as soon as possible after 
randomization, and tissue submitted 
within 4 weeks of randomization. 
• Consent form2 
• Diagnostic pathology report  
(for tumour tissue only)  
Information pertaining to 
baseline/pretreatment blood 
collection for correlative studies 
(i.e. whole blood, plasma, serum) 
must be completed within 2 weeks 
of randomization. 
Information pertaining to post 
randomization blood collection 
samples (i.e. whole blood, plasma, 
serum) for correlative studies and 
banking should be completed within 
2 weeks after collection of blood 
specimens. 
Concomitant 
Medication Report 
Continuous running-
log folder 
 
 
Best Supportive 
Care Report (Arm 1 
only) 
Every 4 weeks (28 
days) until objective 
progression 
Within 2 weeks of the end of each 
reporting period 
• If available/applicable: 
• CT/MRI abdomen/pelvis report 
• CT/MRI chest 
• other radiology reports 
• tumour measurement worksheet 
• ECG report 
Treatment Report 
(Arm 2 only) 
Every 4 weeks  
(28 days) while patient 
is on protocol 
treatment 
Within 2 weeks of the end of each 4 
week reporting period 
If available/applicable: 
• CT/MRI abdomen/pelvis report 
• CT/MRI chest 
• other radiology reports 
• tumour measurement worksheet 
• ECG report 
table continues on next page ... 
 
 

 
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Electronic Folder 
Timing 
To be completed electronically 
Supporting Documentation Required1 
End of Treatment 
Report(Arm 2 only) 
As soon as permanent 
off treatment status is 
confirmed.  
Within 2 weeks of end of treatment 
 
4-Week Post-
Treatment Follow-
Up Report (Arm 2 
only) 
4 weeks from the date 
of last infusion 
Within 2 weeks of the 4-week post 
treatment follow up visit 
• relevant radiology reports 
Follow-up Report3 
(Arm 2 only) 
Every 4 weeks (28 
days) until objective 
progression 
Within 2 weeks of follow-up visit 
If available/applicable: 
• CT/MRI abdomen/pelvis report 
• tumour measurement worksheet 
• CT/MRI chest report 
• other radiology reports 
• ECG report  
Short Follow-up 
Report 
Every 12 weeks after 
objective disease 
progression 
Within 2 weeks of follow-up visit 
 
Relapse/Progression 
Report 
Upon the patient’s 
objective disease 
progression / relapse 
Within 4 weeks of confirmation  
• relevant radiology, operative and 
pathology reports  
Death Report 
Upon patient’s death  
Within 4 weeks of patient death  
• autopsy/post-mortem report, if 
performed  
Serious Adverse 
Event (SAE) 
Report4 
Within 24 hours of 
event 
 
At time of event and 
reported to CCTG 
Within 1 working day4 
 
Minimal Follow-up 
Report5 
Annual  
Within 6 weeks of contact 
If available/applicable: 
• autopsy report 
• CT/MRI report 
1 
Please scan and upload all required source documentation into EDC. Please ensure the patient’s identifiers (e.g. name) are blacked-out on 
all source documentation. 
2 
It is acceptable to submit only the signature page(s) of the main consent and only the check box page(s)/signature page(s) of the optional 
consent provided that the version date of the consent form is indicated. 
3 
The aim of this folder: To collect follow-up information on all patients who have permanently discontinued Durvalumab and 
Tremelimumab. 
4 
See Section 9.0 Serious Adverse Event Reporting for details. 
5 
For ineligible patients who have received no protocol therapy (see Section 5.3 for details). 
 

 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (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 website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 

 
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APPENDIX VI - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or pre-registration (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
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If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to 
treatment. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel 
unwell. In that case, you may express sympathy that things are below par, but state that this 
is exactly the information we require if we are to understand more about how quality of 
life is affected. You may also remind them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
5. What If . . .  
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient.  

 
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Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over 
the phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible.  
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion.  
 
6. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
cannot comprehend either English or French (or other languages that the questionnaire may be available 
in). In other words, if the assistance of a translator is required to comprehend the questions and reply, 
the questionnaires should not be completed. Translation of the questions is not acceptable. Please 
indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 

 
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8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire 
should be read to them and the answers recorded by a health care professional (e.g. preferably the 
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who 
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient 
is completing the questionnaire at home, and a telephone interview by the clinical research associate is 
not possible, then a spouse or friend may read the questions to the patient and record the answers. 
However, this method should be a last resort, and the spouse or friend should be instructed to not coach 
or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 

 
 
Quality of Life Questionnaire – ENGLISH 
 
CCTG Trial: CO.26 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization 
After randomization: 
 4 weeks      8 weeks      12 weeks      16 weeks      24 weeks      _____ weeks 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy           mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
 
 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.26 
Page 1 of 3 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (CO.26) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.26 EORTC QLQ-C30 
Page 2 of 3 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.26 EORTC QLQ-C30 
Page 3 of 3 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
Please check to make sure you have answered all the questions. 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 
 

 
PROTOCOL DATE: 2016-JUL-20 
 
CCTG TRIAL: CO.26 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
ELIGIBILITY CHECKLIST 
Must be completed prior to 
allocation. 
Julia Baran and Vicki Classen 
Clinical Trials Assistants, CCTG 
Email: 
jbaran@ctg.queensu.ca or 
vclassen@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Nadine Magoski 
Study Coordinator, CCTG 
Email: nmagoski@ctg.queensu.ca 
or: 
Dr. Chris O’Callaghan 
Senior Investigator, CCTG 
Email: cocallaghan@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Eric Chen 
Study Chair 
Email: eric.chen@uhn.on.ca 
416-946-2263 
416-946-4467 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for 
details of reportable events. 
Dr. Chris O’Callaghan 
Senior Investigator, CCTG 
or: 
Nadine Magoski 
Study Coordinator, CCTG 
613-533-6430 
613-533-2941 
DRUG ORDERING 
See Appendix II and the CO.26 
pharmacy information manual for 
full details. 
See Appendix III and trial website: 
http://www.ctg.queensu.ca/trials/gi/CO26/CO26.html 
for details and contact information 
ELECTRONIC DATA 
CAPTURE (EDC) AND RIPPLE 
(technical support) 
CCTG Home Page (Toolbox): 
https://scooby.ctg.queensu.ca 
Email Support Staff at: support@ctg.queensu.ca