A Phase II Study of Durvalumab and Tremelimumab in Patients With Advanced Rare Tumours
Phase: PHASE2
Conditions: Advanced Rare Tumours
Sponsor: Canadian Cancer Trials Group

Title: Protocol (including statistical design) of  A Phase II Study of Durvalumab and Tremelimumab 
in Patients With Advanced Rare Tumours
NCT number: NCT02879162
Document date: 2022-Jan-26

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HEALTH CANADA SUBMISSION: 2016-JUL-18 
AMENDMENT #1: 2017-MAY-17 
ADMINISTRATIVE UPDATE #1: 2018-JAN-04 
AMENDMENT #2: 2019-JAN-25 
ADMINISTRATIVE UPDATE #2: 2019-NOV-14 
ADMINISTRATIVE UPDATE #3: 2020-SEP-23 
ADMINISTRATIVE UPDATE #4: 2020-DEC-04 
CANADIAN CANCER TRIALS GROUP (CCTG) 
A PHASE II STUDY OF DURVALUMAB AND TREMELIMUMAB 
IN PATIENTS WITH ADVANCED RARE TUMOURS 
CCTG Protocol Number: IND.228 
STUDY CHAIR: 
Abha Gupta 
PATHOLOGY CO-CHAIR: 
Torsten Nielsen 
GENOMICS CO-CHAIR: 
Ming Tsao 
SENIOR INVESTIGATOR: 
Janet Dancey 
BIOSTATISTICIAN: 
Dongsheng Tu 
STUDY COORDINATOR: 
Joana Sederias 
REGULATORY SPONSOR: 
CCTG 
SUPPORTED BY: 
AstraZeneca 
(For contact information of study personnel see Final Page.) 

 
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CONFIDENTIALITY STATEMENT 
 
This protocol contains information that is confidential and proprietary. The contents of this protocol, its 
amendments and any information that may be added to this document or provided as a part of the conduct 
of this trial may not be used for any other purpose and may not be disclosed to any other person or entity 
without the prior written permission of CCTG (and other applicable parties as designated by CCTG).  
 
 

 
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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 
Exploratory Objectives .................................................................................................................... 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ............................................................... 4 
2.1. 
Immunotherapy & Immune Checkpoint Inhibitors .......................................................................... 5 
2.2. 
Rationale for the Combination of Durvalumab and Tremelimumab ............................................... 6 
2.3 
Rationale for Rare Cancer Cohorts .................................................................................................. 7 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION .................................................................... 9 
3.1 
Durvalumab ...................................................................................................................................... 9 
3.2 
Tremelimumab ............................................................................................................................... 10 
3.3 
Fixed Dosing in Durvalumab and Tremelimumab ........................................................................ 12 
 
4.0 
STUDY POPULATION ................................................................................................................ 13 
4.1 
Eligibility Criteria .......................................................................................................................... 13 
4.2 
Ineligibility Criteria ....................................................................................................................... 16 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT ............................................................................................................................... 18 
5.1 
Follow-up for Ineligible or Patients That Go Off Study Prior to Starting Protocol Therapy......... 19 
 
6.0 
ENTRY/REGISTRATION PROCEDURES ................................................................................. 20 
6.1 
Entry Procedures ............................................................................................................................ 20 
6.2 
Registration .................................................................................................................................... 20 
 
7.0 
TREATMENT PLAN .................................................................................................................... 21 
7.1 
Durvalumab and Tremelimumab Treatment Plan .......................................................................... 21 
7.2 
Duration of Therapy ....................................................................................................................... 23 
7.3 
Patient Compliance ........................................................................................................................ 23 
7.4 
Concomitant Therapy..................................................................................................................... 23 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ................................................. 25 
8.1 
Definitions ..................................................................................................................................... 25 
8.2 
Response and Evaluation Endpoints .............................................................................................. 25 
8.3 
Immune-Related Response Assessment......................................................................................... 28 
8.4 
Response Duration (RECIST 1.1 and iRECIST) ........................................................................... 30 
8.5 
Stable Disease Duration ................................................................................................................. 30 
8.6 
Methods of Measurement .............................................................................................................. 30 
 
9.0 
SERIOUS ADVERSE EVENT REPORTING .............................................................................. 32 
9.1 
Definition of a Reportable Serious Adverse Event ........................................................................ 32 
9.2 
Serious Adverse Event Reporting Instructions .............................................................................. 33 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting .................... 33 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .......................... 35 
9.5 
CCTG Reporting Responsibility to AstraZeneca ........................................................................... 35 
 
 

 
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9.6 
CCTG and AstraZeneca Reporting Responsibilities ..................................................................... 35 
9.7 
Reporting Safety Reports to Investigators ..................................................................................... 35 
 
10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ..... 36 
10.1 
Criteria for Discontinuing Protocol Treatment .............................................................................. 36 
10.2 
Duration of Protocol Treatment ..................................................................................................... 36 
10.3 
Therapy After Protocol Treatment is Stopped ............................................................................... 36 
10.4 
Follow-up Off Protocol Treatment ................................................................................................ 37 
 
11.0 
CENTRAL REVIEW PROCEDURES .......................................................................................... 38 
11.1 
Central Radiology Review ............................................................................................................. 38 
11.2 
Central Pathology Review ............................................................................................................. 38 
 
12.0 
CORRELATIVE STUDIES .......................................................................................................... 39 
12.1 
Protocol-Mandated Correlative Studies ......................................................................................... 39 
12.2 
PD-L1 and TILs Pre-Screening - Tumour Tissue .......................................................................... 40 
12.3 
Blood Collection ............................................................................................................................ 40 
12.4 
Genomic Analyses ......................................................................................................................... 40 
12.5 
Statistical Analysis ......................................................................................................................... 40 
 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 41 
13.1 
Objectives and Design ................................................................................................................... 41 
13.2 
Primary Endpoints and Analysis .................................................................................................... 41 
13.3 
Analysis of Secondary Endpoints: Efficacy Outcomes ................................................................. 42 
13.4 
Analysis of Secondary Endpoints: Translational Research ........................................................... 42 
13.5 
Safety Monitoring .......................................................................................................................... 43 
 
14.0 
PUBLICATION POLICY ............................................................................................................. 44 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. .............................................................................. 44 
14.2 
Responsibility for Publication ........................................................................................................ 44 
14.3 
Submission of Material for Presentation or Publication ................................................................ 44 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES .............................................. 45 
15.1 
Regulatory Considerations ............................................................................................................. 45 
15.2 
Inclusivity in Research ................................................................................................................... 45 
15.3 
Obtaining Informed Consent .......................................................................................................... 46 
15.4 
Discontinuation of the Trial ........................................................................................................... 47 
15.5 
Retention of Patient Records and Study Files ................................................................................ 47 
15.6 
Centre Performance Monitoring .................................................................................................... 47 
15.7 
On-Site Monitoring/Auditing ......................................................................................................... 47 
15.8 
Case Report Forms ......................................................................................................................... 48 
 
16.0 
REFERENCES .............................................................................................................................. 49 
APPENDIX I - PERFORMANCE STATUS SCALES/SCORES .............................................................. 52 
APPENDIX II - DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED REACTIONS .... 53 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL .................................................. 54 
APPENDIX IV - DOCUMENTATION FOR STUDY .............................................................................. 56 
APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ................. 57 
APPENDIX VI - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS .................................. 58 
APPENDIX VII - EMERGENCY SITUATIONS AND COMPLIANCE ................................................. 59 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 

 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol and any supplementary information that may be added to this document, 
contains information that is confidential and proprietary and must be kept in confidence. 
 
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, in accordance with any modifications that may 
occur over the duration of the study, 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 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 enrollment 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. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG IND.228 
 
CENTRE: ___________________________________________ 
 
 

 
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TREATMENT SCHEMA 
 
This is a multi-centre, non-blinded, open-label single arm phase II study of durvalumab in combination 
with tremelimumab in patients with rare tumours. A minimum of 80, and a maximum of 160 patients will 
be enrolled.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients with either: 
1. Salivary carcinoma 
(excluding adenoid cystic 
carcinoma histology)  
2. Carcinoma of unknown 
primary with tumour 
infiltrating lymphocytes 
(TILs) and/or expressing 
PD-L1 
3. Mucosal melanoma 
4. Acral melanoma 
5. Osteosarcoma 
6. Undifferentiated 
pleomorphic sarcoma  
7. Clear cell carcinoma of the 
ovary 
8. Squamous cell carcinoma 
of the anal canal (SCCA)  
TILs present 
and/or positive 
expression of 
PD-L1 
for cohort 2 
ONLY  
Registration 
2-stage design 
each cohort 
(see section 13) 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate the objective response rate of the combination of durvalumab and tremelimumab given 
by IV every 4 weeks for 4 cycles, followed by durvalumab alone in patients with rare tumours.  
 
1.2 
Secondary Objectives 
• 
To evaluate the tolerability and safety of durvalumab and tremelimumab combination.  
• 
To evaluate the effect of durvalumab and tremelimumab combination including time to 
progression, progression free survival and response duration. 
 
1.3 
Exploratory Objectives 
• 
To explore the correlation between anti-tumour activity and PD-L1 expression, presence of 
tumour infiltrating lymphocytes (TILs) and T cell subsets within the tumour. 
• 
To explore the correlation between anti-tumour activity and genomic alterations in tumour. 
• 
To assess the consistency of histopathological diagnosis of rare tumours through central review 
of pathology specimens. 
• 
To explore the correlation between anti-tumour activity and toxicity with blood based 
biomarkers. 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Very rare cancers are poorly understood, misdiagnosed and under researched. As a result, patients 
with very rare cancers usually have few treatment options. The United States Congress Orphan 
Drug Act 1983 defines “rare” as affecting under 200,000 people in the USA, or more than 200,000 
people but no reasonable expectation that the costs of developing a new drug for this condition will 
be recovered from its sales. This definition was created in relation to drug development and is now 
being used by information services, database, and registry organizers. An extension of this 
definition to Canada, with roughly one-tenth the US population, would be < 20,000 people. Cancers 
like leukemia, head and neck cancer fall within this definition. However, considerably greater 
challenges, in terms of research, funding, and available information exist for ‘very rare’ cancers. 
Unlike the latter tumour types, even small phase II clinical trials for patients with very rare tumours 
are difficult to conduct. The ethical, regulatory and resource demands of maintaining a trial at a 
centre that will accrue few or no patients per year are disincentives to mounting multi-centre 
treatment trials. A more relevant definition of rare disease may be that of the European Commission 
on Public Health which defines rare diseases as "life-threatening or chronically debilitating diseases 
which are of such low prevalence that special combined efforts are needed to address them”. 
 
Compelling medical and scientific reasons exist for mounting multicentre treatment clinical trials 
in very rare tumours. Options for patients with such cancers are limited. Due to their infrequency, 
diagnosis may be difficult and delayed, therapeutic studies are most often retrospective case series 
of patients treated over a period of years. In addition to the unmet medical need, there is a 
compelling research need to investigate these tumours. Although basic and translational research 
is limited, some rare tumours appear to be more biologically homogenous and have potentially 
identifiable oncogenic drivers than more common tumours. While the logistics of mounting phase 
II trials in rare tumours seem initially daunting, with relatively few treatment options and few 
competing trials, recruitment to trials may be more easily accomplished than in more common 
disease settings, assuming challenges of running a trial with anticipated limited enrolment at 
individual institutions are addressed. Finally, determining efficient means of conducting trials in 
rare tumours defined histologically may inform the design and conduct of trials of rare tumour 
populations based on molecular profiles required to evaluate personalized medicine approaches and 
facilitate the evaluation of individualized therapies. 
 
To address the challenges of conducting trials of novel therapies for patients with very rare cancers, 
we designed and successfully completed IND.206, a multi-arm, multiphase study of sunitinib and 
temsirolimus in patients with rare cancers (defined as <100 eligible patients/year). There were 10 
histologic or genetic defined rare tumour cohorts and 1 exploratory cohort testing both of the agents 
separately. Over three years, 136 patients were enrolled, and 162 patients were registered (25 
patients were registered and received both agents). Activity was seen in multiple cohorts [Dancey 
2015]. The majority of participating sites were able to enroll multiple patients on the study, 
suggesting that the design is feasible and an acceptable means of testing promising agents in very 
rare cancer settings. 

 
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2.1. 
Immunotherapy & Immune Checkpoint Inhibitors 
 
Programmed death 1 (PD-1) protein is a co-inhibitory receptor known to be expressed on activated 
T cells, which when bound to its ligand PD-L1, limits T cell antitumour activity in the tumour 
microenvironment [Fife 2008]. Blockade of PD-1 engagement with its ligand PD-L1, induces 
immune responses in vitro and has been shown to mediate preclinical activity [Fife 2009]. Clinically, 
blockade of the PD-1 inhibitory checkpoint pathway by inhibiting PD-1/PD-L1 engagement, has 
been shown to induce tumour regression across many cancer types, including melanoma, renal cell, 
colon, lung and bladder cancers [Pardoll 2012; Brahmer 2012]. Single agent immunotherapy with anti-
PD-1 or anti-PD-L1 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 [Brahmer 2012; Topalian 2012; 
Antonia 2014]. 
 
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 patients with metastatic melanoma based on an improvement in overall survival (OS) 
of patients with advanced melanoma [Hodi 2010; Robert 2011]. 
 
In general, tumour response rates to anti-CTLA-4 therapy are low (~10%) in melanoma. However, 
in patients who respond, the responses are generally durable. Because these agents activate the 
immune system, responses can be delayed 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 expansion of neoplastic 
cells [Wolchok 2009]. Although the impact on conventionally-defined median progression free 
survival (PFS) can be small, durable response or stable disease seen in a proportion of patients can 
lead to significant prolongation of PFS and OS in a subset of patients. 
 
2.1.1. Tremelimumab  
 
Tremelimumab is a human IgG2 monoclonal antibody (MAb) 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. 
Tremelimumab has been evaluated as a single agent in a number of malignancies. 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]. The 
phase 3 study of tremelimumab in patients with metastatic melanoma did not meet the primary 
endpoints of improved OS. However, response duration (measured from date of random 
assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). These 
data suggest the drug can be administered safely and that there is activity of tremelimumab in 
melanoma [Kirkwood 2010; Ribas 2013]. 

 
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2.1.2. Durvalumab 
 
Durvalumab is a human 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 two identical heavy chains and two 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 [Stewart 2015; Ibrahim 2015]. 
 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80 [Stewart 2015; Ibrahim 2015]. 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 [Stewart 2015; Ibrahim 2015]. 
 
2.2. 
Rationale for the Combination of Durvalumab and Tremelimumab 
 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic anti-tumour activity 
because the mechanisms of action of CTLA-4 and PD-1 are non-redundant [Pardoll 2012]. The 
combination of nivolumab and ipilimumab to patients with advanced melanoma induced clinically 
and statistically significant improvement in PFS and response rate than those obtained with single-
agent therapy in a randomized phase III trial [Larkin 2015]. The frequency of grade 3 and 4 immune 
related toxicity was higher but manageable. Treatment-related adverse events of grade 3 or 4 
occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-
ipilimumab group, and 27.3% of those in the ipilimumab group. Importantly, responses appeared 
to be deep and durable [Wolchok 2013]. The higher response rate and improved survival suggests that 
the combination is able to induce an anti-tumour response in patients with cancers that are otherwise 
refractory to the individual agents. 
 
Promising results have been observed in the recently published phase 1B study of combination 
durvalumab and tremelimumab in 102 patients with NSCLC [Antonia 2016]. 
 
We hypothesize that one or more rare tumours will be sensitive to the combination of durvalumab 
and tremelimumab and sensitivity will be linked to identifiable biomarkers. 
 
The defined cohorts and rationale for testing the agents is provided in the following table: 
 
 

 
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2.3 
Rationale for Rare Cancer Cohorts 
 
For this trial, recent scientific and clinical literature were reviewed to determine rare cancers that 
might rationally be expected to be sensitive to combined immune check point therapy. Currently, 
expression of immune markers, PD1/PDL1, immune cell infiltrate of tumour and high mutation 
load correlative with activity in at least some settings. In addition, early clinical trials and case 
reports support sensitivity of some rare cancers. The proposed tumour types, rationale and relevant 
references are provided in the table below. Furthermore, the trial is designed to enhance the 
operational efficiencies of the study by allowing the enrolment of multiple tumour histologies into 
separate cohorts. By including multiple rare tumour histologies, many more patients can be 
enrolled/site under a single protocol. The two agent combination activity can be assessed within a 
single common protocol and this will allow the generation of data on objective response.  
 
Rare Tumour Cohort 
Comment/Rationale 
References 
1 
Salivary carcinoma 
Unmet medical need. SGTs are characterized by 
recurrent genetic alterations, particularly chromosome 
translocations. 
[Rettig 2016; 
Matthew 2015] 
2 
Carcinoma of unknown 
primary with tumour 
infiltrating lymphocytes 
(TILs) and/or expressing 
PD-L1 
Unmet medical need. A subset of CUPs have immune 
cell infiltration and may represent cancers sensitive to 
immunotherapies. 
[Hampig 2016] 
3 
Mucosal Melanoma 
Unmet medical need. Objective responses reported 
with nivolimab.  
[Larkin 2015; 
Lian 2014] 
4 
Acral melanoma 
Unmet medical need. Objective responses seen with 
ipilumumab 
[Johnson 2015] 
5 
Osteosarcoma 
High-grade osteosarcomas have complex chaotic 
karyotypes. Many immune signaling pathways are 
important in bone homeostasis. The success of the 
innate immune stimulant mifamurtide in the adjuvant 
treatment of non-metastatic osteosarcoma suggests that 
newer immune-based treatments are promising. 
[D’Angelo 2014; 
Kansara 2014] 
6 
Undifferentiated 
pleomorphic sarcoma 
Increased mutational load seen in these tumours may 
be predictive for response to immunotherapy agents 
[Lim 2015] 
7 
Clear cell carcinoma of 
the ovary(expanded to 
include 20 additional 
patients in Jan 2019) 
Objective responses were noted in a phase 1b study of 
avelumab, anti-PD-L1 monoclonal antibody in clear 
cell ovarian carcinoma, and in a phase II clinical trial 
in heavily-treated platinum-resistant ovarian cancer, 
OCCC subtypes. In addition, promising emerging 
preclinical and clinical data supports the further 
development of immune checkpoint inhibitors in 
gynecologic cancers. 
[Disis 2015; Oda 
2018; Heong 
2017] 
8 
Squamous cell carcinoma 
of the anal canal 
Seven/33 evaluable patients (21%) had a partial 
response to nivolimab 
[Morris 2016] 
 
 
 

 
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Rationale for the Expansion of the Clear Cell Ovarian Cohort:  
 
The clear cell carcinoma of the ovary cohort (#7) met its accrual goal of 20 patients in April of 
2018. Efficacy analysis showed objective responses in 7/19 patients, an overall response rate of 
> 30%. The combination was tolerable and toxicity profile was as expected for combined immune 
checkpoint inhibitors. Durvalumab/tremelimumab related events are mostly grade 1-2 with most 
common ones being fatigue, rash, diarrhea and hypothyroidism. Grade 3 related events reported as 
an SAE in this cohort were: auto-immune hepatitis in 2 pts, increased lipase (without pancreatitis), 
AA-amyloidosis, renal failure, colitis and rash. The majority of hematologic and biochemical 
events are grade 1-2, however anemia grade 3 was seen in 3 patients.  
 
Given the activity seen and with new literature showing that OCCC both tumour cells and tumour 
microenvironment may be associated with sensitivity to immune checkpoint inhibitors [Oda 2018], 
the cohort will be expanded an additional 20 more patients.  
 
 

 
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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 programmed 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 C 1q 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. 
 
 

 
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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. 
 
3.1.6 
Clinical Trials 
 
As of the most recent Investigator’s Brochure, over 12,000 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 
(thyroiditis, 
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, cholangitis sclerosing, cystitis, uveitis and other events 
involving the eye (e.g. keratitis and optic neuritis), skin (e.g. scleroderma, vitiligo and pemphigoid), 
hematological 
(e.g. 
hemolytic 
anemia, 
immune-mediated 
neutropenia 
and 
immune 
thrombocytopenic purpura) and rheumatological (e.g. polymyalgia rheumatic and autoimmune 
arthritis) events, vasculitis, non infectious encephalitis or non infectious meningitis. 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 IND.228 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). 
 
 

 
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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. 
 
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. 

 
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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. 
 
Route of Administration: 
Intravenous. 
 
Please refer to the IND.228 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 
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 1500mg 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. 
 
 

 
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4.0 
STUDY POPULATION 
 
The trial population will consist of patients with advanced (metastatic or locally advanced) 
histologically confirmed rare cancers as defined in section 4.1.1 that is unresectable and for which 
no curable therapy exist. 
 
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 registration. Questions 
about eligibility criteria should be addressed prior to registration. 
 
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 fulfill all of the following criteria to be eligible for admission to the study: 
 
4.1.1 
Patients must have histologically and/or cytologically confirmed cancer that is advanced / 
metastatic / recurrent or unresectable and for which no curative therapy exists as follows: 
1. Salivary carcinoma (excluding adenoid cystic carcinoma histology) 
2. Carcinoma of unknown primary with tumour infiltrating lymphocytes (TILs) and/or expressing 
PD-L1 
3. Mucosal melanoma 
4. Acral melanoma 
5. Osteosarcoma 
6. Undifferentiated pleomorphic sarcoma  
7. Clear cell carcinoma of the ovary 
8. Squamous cell carcinoma of the anal canal (SCCA) 
 
4.1.2 
All patients must have a tumour tissue from their primary or metastatic tumour available (See 
Section 11.2 for slide specifications, as well as section 12.1). 
 
4.1.3 
Presence of clinically and/or radiologically documented disease. All radiology studies must be 
performed within 28 days prior to registration (within 35 days if negative). 
 
All patients must have at least one measurable lesion as defined by RECIST 1.1 that has not been 
the site of the protocol mandated biopsy. The criteria for defining measurable disease are as follows: 
 
CT scan (with slice thickness of 5 mm) 
≥ 10 mm 
 longest diameter 
Lymph nodes by CT scan 
≥ 15 mm 
 measured in short axis 

 
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4.1.4 
Patients must be ≥ 16 years of age. 
 
4.1.5 
Patients must have an ECOG performance status of 0 or 1. 
 
4.1.6 
Previous Therapy 
 
Cytotoxic Chemotherapy: 
Patients may have received prior chemotherapy – no limit on number of prior regimens. 
 
Other Systemic Therapy: 
Patients may have received other prior therapies including, angiogenesis inhibitors, PARP 
inhibitors or signal transduction inhibitors (tyrosine kinase inhibitors). Prior therapy with PD-1/PD-
L1 or CTLA-4 inhibitors is not allowed. 
 
Patients must have recovered from all reversible toxicity related to prior chemotherapy or systemic 
therapy (unless grade 1, irreversible, or considered by investigator as not clinically significant) and 
have adequate washout as follows:  
 
Longest of one of the following: 
• 
Two weeks 
• 
5 half-lives for investigational agents  
• 
Standard cycle length of standard therapies 
 
Radiation: 
Prior external beam radiation is permitted provided a minimum of 28 days (4 weeks) have elapsed 
between the last dose of radiation and date of registration. Exceptions may be made for low-dose, 
non-myelosuppressive radiotherapy after consultation with CCTG senior investigator. Concurrent 
radiotherapy is not permitted. Patients planned for concurrent chemotherapy-radiation are not 
eligible. 
 
Surgery:  
Previous surgery is permitted provided that a minimum of 28 days (4 weeks) have elapsed between 
any major surgery and date of registration, and that wound healing has occurred. 

 
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4.1.7 
Laboratory Requirements 
(must be done within 7 days prior to registration) 
 
Hematology 
Absolute neutrophils  
≥ 1.5 x 109/L 
Platelets 
≥ 100 x 109/L 
Hemoglobin 
≥ 90 g/L 
Chemistry 
Bilirubin 
≤ 1.5 x ULN (upper limit of normal)* 
AST and ALT 
≤ 2.5 x ULN (if liver metastases are present, ≤ 5 x ULN) 
Serum creatinine 
or: 
Creatinine clearance** 
< 1.25 x ULN  
 
≥ 40 mLs/min 
* 
If confirmed Gilbert’s, eligible providing ≤ 3 x ULN. 
** 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 
 
4.1.8 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to registration in the trial and prior to 
tests which are considered to be study specific (see Section 5.0) to document their willingness to 
participate. 
 
Patients who cannot give informed consent (i.e. mentally incompetent patients, or those physically 
incapacitated such as comatose patients) are not to be recruited into the study. Patients competent 
but physically unable to sign the consent form may have the document signed by their nearest 
relative or legal guardian. Each patient will be provided with a full explanation of the study before 
consent is requested. 
 
4.1.9 
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. 

 
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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 Section 5.0); 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. 
 
4.1.10 Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 
(Call the CCTG office at 613-533-6430 if questions arise regarding the interpretation of this 
criterion.) Investigators must assure themselves the patients registered on this trial will be available 
for complete documentation of the treatment, response assessment, adverse events, and follow-up. 
 
4.1.11 Subjects should not donate blood while participating in this study, or for at least 90 days following 
the last infusion of durvalumab or tremelimumab. 
 
4.1.12 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
registration. 
 
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 cancers curatively treated with no 
evidence of disease for ≥ 5 years. 
 
4.2.2 
Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel 
disease (e.g. colitis or Crohn’s disease), diverticulitis with the exception of diverticulosis, celiac 
disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic 
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with 
polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the 
start of treatment. The following are exceptions to this criterion: 
• 
Patients with alopecia. 
• 
Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within the 
last 2 years). 

 
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• 
Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone 
replacement. 
 
4.2.3 
History of primary immunodeficiency, history of allogenic organ transplant that requires 
therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of 
registration*  
 
*  NOTE: Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day of 
prednisone or equivalent dose of an alternative corticosteroid are permissible. 
 
4.2.4 
Live attenuated vaccination administered within 30 days prior to registration. 
 
4.2.5 
History of hypersensitivity to durvalumab or tremelimumab or any excipient. Any previous 
treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including 
tremelimumab. 
 
4.2.6 
Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have 
symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction 
within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 
3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if 
controlled, should have a LVEF ≥ 50%. 
 
4.2.7  Untreated symptomatic brain metastases or brain metastases in whom radiation or surgery is 
indicated. 
 
4.2.8 
Concurrent treatment with other investigational drugs or anti-cancer therapy. 
 
4.2.9 
Patients with serious illnesses or medical conditions which would not permit the patient to be 
managed according to the protocol (including corticosteroid administration), or would put the 
patient at risk. This includes but is not limited to: 
• 
History of significant neurologic or psychiatric disorder which would impair the ability to 
obtain consent or limit compliance with study requirements. 
• 
Active infection requiring systemic therapy; (including any patient known to have active 
hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or tuberculosis or any 
infection requiring systemic therapy). 
• 
Active peptic ulcer disease or gastritis. 
• 
Known pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary 
function. 
 
4.2.10  Pregnant or lactating women.  
 
Men and women of child-bearing potential must agree to use adequate contraception as described 
in Section 4.1.9. 
 
 

 
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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. 
 
Required Investigations 
Pre-study 
(< 7 days prior 
to registration) 
Day 1 each 
cycle, and as 
clinically 
indicated 
Day 1 
every 12 
weeks 
4 weeks after 
completion of 
protocol 
therapy 
3 month follow-up 
(only required for pts 
without confirmed PD and 
ongoing toxicities 1) 
History and Physical Exam 
 
 
 
 
 
Including: height and weight, ECOG performance 
status, documentation of all measurable and non-
measurable disease, clinical tumour measurements (if 
applicable); 
Vital signs2: blood pressure, heart rate, temperature 
X 
X 
 
X 
 
Laboratory Procedures/Assessments3 
 
 
 
 
 
CBC, neutrophils, lymphocytes , platelets 
X 
X 
 
X4 
X4 
PTT, PT/INR (if on anticoagulants) 
X 
X 
 
X4 
X4 
Serum creatinine, creatinine clearance (calculated), 
electrolytes (calcium, potassium, magnesium) 
bilirubin, ALP, AST, ALT, LDH, albumin, glucose, 
amylase5, lipase5, TSH6 
X 
X 
 
X4 
X4 
Pregnancy Test7 
X 
X8 
 
 
 
Radiology 
 
 
 
 
 
Tumour Imaging (Chest, abdomen and pelvis scan; 
other scans as necessary to document disease)  
Bone scan for osteosarcoma patients 
within 28 days 
prior to 
registration or 
35 if negative 
 
X9 
X10 
X10 
Other Investigations 
 
 
 
 
 
Tumour markers (i.e. CA-125, etc.) 11 if applicable 
X 
as clinically indicated 
 
LVEF12 
(within 28 
days prior to 
registration) 
Urinalysis (dipstick – including protein, specific gravity, 
glucose and blood) 
X 
Archival Tumour Tissue for assessment of TILs and 
PD-L1 expression (pre-screening – cohort #2 only) 
X13 
 
 
 
 
Correlative Studies Blood Collection  
X14 
See Section 12.0 for details 
Adverse events 
X 
Continuously 
X1 
 
footnotes on next page ... 
 
 

 
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1 
Every three months thereafter to follow adverse events felt related until resolved to ≤ Grade 2. Adverse Events to be evaluated using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE v4.0) (see Appendix V). 
2 
Patients will be monitored before, during and after the first cycle 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; a 1-hour observation period is recommended after the 
tremelimumab. Assessment of vital signs in subsequent cycles is required prior to the start of the infusion, and then as clinically indicated. If no 
clinically significant infusion reactions are observed during or after the first cycle of tremelimumab+durvalumab therapy, subsequent infusion 
observation periods can be at the investigator’s discretion. 
3 
Pre-treatment blood draws and physical exams may be done one working day prior to treatment if necessary (e.g. Friday for treatment on 
Monday, or to accommodate holidays). 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 II 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. 
4 
Required at 4 weeks. To be done additionally every 3 months thereafter to follow abnormal lab results felt related until resolved to ≤ Grade 2. 
5 
It is preferable that both amylase and lipase are assessed. For sites where only 1 of these parameters is routinely measured then either lipase or 
amylase is acceptable. 
6 
Free T3 and free T4 will be measured if TSH is abnormal. 
7 
For women of childbearing potential only (urine or serum test). Within 72 hours prior to registration. Pregnancy test (in women of childbearing 
potential), as part of Pre-Study Evaluation, may include an ultrasound to rule-out pregnancy. 
8 
As clinically indicated in WOCBP 
9 
To ensure comparability, baseline scans and subsequent scans to assess response 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). Maintain schedule every 12 weeks even if cycles are delayed. For osteosarcoma patients, every 3 months if bone mets are 
present at baseline. For patients remaining on study beyond January 2022, the frequency of imaging assessment may be reduced to every 6 
months at the description of the investigator and discussion with CCTG. 
10 To be done  every 12 weeks until relapse or progression (iCPD) for up to 2 years, for patients with CR/iCR, PR/iPR, SD/iSD response as 
defined in Section 8.  Patients with CR/iCR or PR/iPR or equivocal PD (pseudoprogression)/iUPD should have scans repeated after 4 weeks, 
but no more than 8 weeks, to confirm response. 
11 Depending on histology, applicable markers (i.e. CA-125 for the Clear Cell Carcinoma of the Ovary cohort) must be reported as per standard of 
care at local sites. 
12 Only if significant cardiac history (see section 4.2.6). 
13 Must be confirmed available prior to registration on ALL patients. Archival tissue submission should be sent at the same time that the baseline 
CRF is submitted for each patient. Prescreening of TIL and PDL1 expression is required for cohort 2 patients prior registration. See Section 
12.0 for details. 
14 After registration but before the first dose of study treatment. See lab manual for details. 
 
5.1 
Follow-up for Ineligible or Patients That Go Off Study Prior to Starting Protocol Therapy 
 
The follow-up requirements for ineligible patients/patients who have received no protocol therapy 
prior to going off study include submission of the Baseline Report plus an End of Treatment 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.  

 
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6.0 
ENTRY/REGISTRATION PROCEDURES 
 
6.1 
Entry Procedures 
 
All registrations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
registering patients will be provided at the time of study activation and are also available in the 
“EDC Data Management Guidebook”, posted on the IND.228 trial specific web-site. If sites 
experience difficulties accessing the system and/or registering/randomizing patients please contact 
the help desk (link in EDC) or the IND.228 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment 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 IND.228) 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
confirmation of the requirements listed in Section 4.0, including dates of essential tests and 
actual laboratory values 
 
6.2 
Registration  
 
Registration 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 participant 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 physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting registration. 
 
All registered 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 5.1. 
 
The follow-up requirements for ineligible patients who have received no protocol therapy include 
submission of the Baseline Report only. 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. 

 
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7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
registration. 
 
7.1 
Durvalumab and Tremelimumab Treatment Plan 
 
7.1.1 
Drug Administration 
 
When durvalumab is given with tremelimumab, tremelimumab will be administered first. 
Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. 
 
One cycle will be defined as 4 weeks. Tremelimumab will only be given for the first 4 cycles. 
 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Durvalumab 
1500 mg 
IV 
60 min 
Day 1 every 4 weeks 
Tremelimumab 
75 mg 
IV 
60 min 
Day 1, cycles 1-4 
Patients with a body weight of less than or equal to 30kg should be dosed using a weight based dosing schedule.  
See Section 3.3. 
 
7.1.2 
Premedication 
 
No routine premedication (e.g. for nausea) or prophylaxis for hypersensitivity is required. 
Management of symptoms should take place as necessary (See Appendix II). Premedication is 
not expected to be required. See Appendix II 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 
 
Patients will be monitored before, during infusion and after the infusion of tremelimumab and 
durvalumab with assessment of vital signs as specified in Section 5.0. A 1-hour observation period 
is recommended after the first infusion of durvalumab and tremelimumab. If no clinically 
significant infusion reactions are observed during or after the first cycle, subsequent infusion 
observation periods can be at the Investigator’s discretion (suggested 30 minutes after each 
durvalumab and tremelimumab infusion). 
 
Guidelines for management of infusion-related reaction are summarized in Appendix II. 
 
All patients should be closely monitored according to guidelines in Section 5.0 and be advised to 
contact the treating centre in the case of significant toxicities. 
 
 

 
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7.1.4 
Dose Modifications 
 
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 and tremelimumab leading to T-cell activation and 
proliferation. Potential immune related AEs include pneumonitis, hepatitis, diarrhea/colitis and 
intestinal perforation, endocrinopathies (thyroiditis, 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, cholangitis sclerosing, cystitis, uveitis and other events 
involving the eye (e.g. keratitis and optic neuritis), skin (e.g. scleroderma, vitiligo and pemphigoid), 
hematological 
(e.g. 
hemolytic 
anemia, 
immune-mediated 
neutropenia 
and 
immune 
thrombocytopenic purpura) and rheumatological (e.g. polymyalgia rheumatic and autoimmune 
arthritis) events, vasculitis, non infectious encephalitis or non infectious meningitis. It is possible 
that events with an inflammatory or immune mediated mechanism could occur in nearly all organs. 
 
The guidelines which follow outline dose adjustments for several of these toxic effects. 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). 
 
Dose adjustments (slowing/interruption of infusion rate, omission of a dose, or permanent 
discontinuation) will be made for hematologic and other adverse events. 
 
If the infusion cannot be administered, it should be omitted until the next planned infusion. 
 
The next cycle should not be given until the laboratory criteria in Section 4.1.7 are met and 
resolution of all drug related toxicity to ≤ grade 2. Discuss with CCTG if asymptomatic/not felt to 
be clinically significant. 
 
7.1.5 
Management of Toxicity 
 
Please refer to detailed toxicity management guidelines in Appendix II. 
 
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
 
 

 
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7.1.6 
Management of Infusion Reactions 
 
Guidelines for management of infusion-related reaction are summarized in Appendix II. 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. 
 
7.1.7 
Dose Adjustments for Immune Related Adverse Events and Other (Non-Immune Related) Adverse 
Events Related to Study Therapy 
 
Guidelines for dose modification and toxicity management of immune related and non-immune 
related adverse events are summarized in Appendix II. 
 
Centres must contact CCTG in the event of severe event(s), especially when the use of drugs such 
as infliximab are considered. 
 
7.2 
Duration of Therapy 
 
Treatment with durvalumab ± tremelimumab (to a maximum of 4 doses, cycles 1-4) will continue 
until disease progression or unacceptable toxicity. 
 
Exceptions to the duration of treatment for patients with continued response may be made after 
consultation with CCTG. 
 
7.3 
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). 
 
7.4 
Concomitant Therapy 
 
Details of any concomitant medications (prescription, non-prescription, or over-the-counter 
medications) taken by the patient at study entry and during protocol therapy must be recorded on 
the appropriate electronic case report forms (eCRFs). 
 
7.4.1 
Permitted 
• 
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 senior 
investigator in the case of patients experiencing multiple delays as exceptions may be made for 
patients who are benefitting from protocol therapy. 
• 
Other 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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7.4.2 
Not Permitted 
• 
Cytokines; 
• 
Other anti-cancer treatment; 
• 
Other investigational therapy; 
• 
Concurrent radiation treatment; (Note: if patients require palliative radiation or prophylactic 
radiation (e.g. of brain) consult CCTG for exception to this rule; protocol therapy will need to 
be held prior to and during the radiation). 
• 
 Corticosteroids IV or PO (except for the treatment of ≥ grade 3 infusion reaction, treatment-
related toxicity (See Appendix II), 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. Patients who are on low oral doses of prednisone 
(5 mg BID or dexamethasone equivalent) must discontinue prior to study entry unless 
medically contraindicated. 
• 
Live attenuated vaccines within 30 days of durvalumab dosing (i.e. 30 days prior to the first 
dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab. 
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 [Seymour 2017]. 
 
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 modified iRECIST guidelines [Seymour 2017]. Investigators should note the different 
requirements for confirmatory scans as well as follow up for the two criteria. 
 
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 modified RECIST. Investigators should continue treatment, as appropriate, 
in the absence of unacceptable toxicity, until unequivocal disease progression. 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 (nodal, subcutaneous, lung parenchyma, solid organ metastases) 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 ≥ 15mm 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 
Response. 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment 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 < 10mm (Note: continue 
to record the measurement even if < 10mm and considered CR). Residual lesions (other than nodes 
< 10mm) thought to be non-malignant should be further investigated (by cytology specialized 
imaging or other techniques as appropriate for individual cases [ref RECIST 1.1]) before CR can 
be accepted. Confirmation of response is only required in non-randomized studies. 
 
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. Confirmation of response is only required in non-
randomized studies. Patients with CR/iCR or PR/iPR should have scans repeated after 4 weeks, but 
no more than 8 weeks, to confirm response. 
 
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. 
 
 

 
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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 ≥ 5mm. 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 appears to have increased by at least 73% in volume or, in select instances 
where tumour burden has increased sufficiently to require urgent medical intervention (e.g. 
radiation for spinal cord compression or drainage of a fluid collection. 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. 
 
Patients that are clinically well may continue on therapy following RECIST progression with new 
lesions or increase in target lesions if the increase in disease burden does not meet the definition of 
PD by immune response criteria [Seymour 2017]. In this situation, patients do not have unequivocal 
progression until immune response criteria are met (see Table 4 below). 
 
Table 3: Integration of Target, non-Target and New Lesions into Response Assessment: 
 
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 <10mm 
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 wks. 
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 < 10mm 
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. 
*  
Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may be continued 
pending further assessments – see table 5.  
 
 

 
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8.3 
Immune-Related Response Assessment  
 
Overall response will also be assessed using  iRECIST [Seymour 2017]. Immunotherapeutics may 
result in infiltration of immune cells leading to transient increase in the size in malignant lesions, 
or undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumour burden, 
or the appearance of new lesions, does not reflect true tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are designated 
with a prefix. iRECIST time-point and best overall responses will be recorded separately. 
 
Confirming Progression 
 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen as 
evidenced by one or more of the following: 
• 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
- 
Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum 
- 
Continued unequivocal progression in non-target disease with an increase in tumour burden 
- 
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions. 
• 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in table 2, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. 
 
New Lesions 
 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow 
clear differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of NLT should NOT be included in the sum of measures of original target lesions 
identified at baseline. Rather, these measurements will be collected on a separate table in the case 
record form. 
 
 

 
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PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with either 
an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but not 
necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of additional new 
lesions. 
 
Table 4: Time-point (TP) iResponse 
 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non-
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR decrease 
from last TP 
iUPD with no 
change OR 
decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously 
identified and increase in size (≥5 mm in SOM for 
NLT or any increase for NLNT) or number. If no 
change in NLs (size or number) from last TP, 
remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in 
further increase in size of NT disease (need not 
meet RECIST 1.1 criteria for unequivocal PD) 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
- further increase in SOM of at least 5 mm, 
otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
- previously identified T lesion iUPD SOM ≥5 
mm and / or 
- NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
- previously identified T lesion iUPD ≥5 mm and 
/ or 
- previously identified NT lesion iUPD (need not 
be unequivocal) and /or 
- size or number of new lesions previously 
identified 
Non-
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
- increase in size or number of new lesions 
previously identified 
*  
Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD would be the 
same. 
** In any lesion category. 
*** Previously identified in assessment immediately prior to this TP. 
 
 

 
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Table 5: iRECIST Best Overall Response (iBOR) 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, iPR, 
iUPD, NE 
iCR, iPR, iUPD,  
NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, 
NE 
iCR 
iCR, iPR, iSD, 
iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, 
NE 
iPR, iSD, iUPD, 
NE, iCPD 
iPR, iSD, iUPD, NE, iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, 
NE 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, 
NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
• 
Table assumes a randomized study where confirmation of CR or PR is not required. 
• 
NE = not evaluable that cycle. 
• 
Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
• 
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each TPR 
but is not shown in the table for ease of presentation. 
 
8.4 
Response Duration (RECIST 1.1 and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(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). 
 
8.5 
Stable Disease Duration 
 
Stable disease duration will be measured from the time of start of registration until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
 
8.6 
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”. 

 
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8.6.1 
Clinical Lesions 
 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10mm as 
assessed using calipers (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. 
 
8.6.2 
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. 
 
8.6.3 
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 cases. 
 
8.6.4 
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. 
 
8.6.5 
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. 
 
8.6.6 
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. 
 
8.6.7 
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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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 
 
• 
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 
• 
Adverse events that are suspect to be immune mediated AND that require intervention with 
high doses of steroids are considered to be medically important events that require intervention 
to prevent a fatal, life-threatening or hospitalization event. They should be reported as 
expedited events using the SAEs reporting system. 
• 
In addition, if a patient shows an AST or ALT ≥3 x ULN together with total bilirubin ≥2 x 
ULN, refer to Appendix II 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. 
 
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. 
 
 
 

 
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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 IND.228 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 7 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: 
 
IND.228 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2411 
 
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 IND.228 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. 
 
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 and Exposure Reporting 
 
9.3.1 
Pregnancy Prevention 
 
Women of childbearing potential (WOCBP) and men who are enrolled in the trial must have agreed 
to use contraceptive method(s) as described in Eligibility Criteria 4.1.9. Investigators may wish to 
additionally advise the female partners of male participants about pregnancy prevention guidelines 
when appropriate and compliant with local policy. 
 
 

 
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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. 
 
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). 
 
 

 
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If the pregnancy results in death, spontaneous miscarriage; 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 
CCTG and 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 IND.228 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 IND.228 web-based safety monitoring utility. 
 
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 
IND.228 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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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
10.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients who are clinically stable but meet the criteria for iUPD should be continued on treatment 
until the next disease assessment at least 4 weeks later. It is recommended that the next imaging 
assessment be no longer than 8 weeks later in order to ensure patients remain fit for salvage 
therapies. Clinical stability is defined as:  
• 
Stability or improvement in performance status. 
• 
No clinically relevant increase in disease related symptoms such as pain or dyspnea (generally 
understood to mean a requirement for increased palliative intervention as below). 
• 
No requirement for increased management of disease related symptoms including increased 
analgesia, radiation or other palliative care. 
 
Patients may stop protocol treatment (durvalumab ± tremelimumab) 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. 
• 
Tumour progression or disease recurrence as defined in Section 8.0; note: investigators are 
encouraged to continue treatment if pseudoprogression is suspected or mixed responses are 
seen [Wolchok 2009]. 
• 
Request by the patient. 
• 
Completion of therapy as outlined in Section 10.2. 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 
(see Section 8.0 for response definition) 
• 
For complete responders, therapy will continue until progression (refer to Section 7.2). 
• 
For partial responders, therapy will continue until progression. For stable patients, therapy will 
continue until progression (refer to Section 7.2). 
• 
Patients who progress (treatment failure) will stop all treatment and go off study at the time 
unequivocal progression is documented clinically and/or radiographically. 
 
10.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
 
 

 
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10.4 
Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy. Thereafter, continued 
follow-up is not required for patients who go off protocol treatment with iCPD, 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/iCR, PR/iPR, SD/iSD or iPD ongoing and have 
not already started other systemic therapy, follow-up will be required every 3 months until relapse 
(see Section 5 for investigations to be performed). Please note for patients who go off protocol 
treatment with iUPD, confirmatory scans should be performed at least 4 weeks, but no longer 8 
weeks, after iUPD was documented. 
 
Final report (Form 6) will be required for all patients while study is open. Due within 2 weeks of 
knowledge of death (see Appendix IV - Documentation for Study). 
 
 

 
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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Central Radiology Review 
 
At the conclusion of the trial, a central review of x-rays and/or scans may be carried out if any 
responses have been claimed. For purposes of reporting, the results of both local and central 
radiology reviews will be included. 
 
11.2 
Central Pathology Review 
 
There will be central pathology review for this study. Expert pathology review will be done for all 
patients to confirm the original diagnosis. At least one disease site specialty pathologist with 
recognized diagnostic expertise for the tumour type will review digital image from the 
original/recut HE slides and pathology report of the case. Another expert pathologist will be 
consulted to resolve significant diagnostic discordance if it arises. Results of the central pathology 
review will not be provided to the originating institution, the patient or patient record. The 
consistency of diagnosis of rare tumours will be assessed through central review of pathology 
specimens. 
 
11.2.1 Patients with questionable local pathology (i.e. uncertain as to rare tumour diagnosis) MUST have 
their pathology reviewed by a Central Reference Pathologist to confirm eligibility BEFORE the 
patient can be registered on this study. 
 
11.2.2 Archival primary tissue block or the following materials, will be required for central pathology 
review: 
• 
Original slides or one H&E stained re-cut on all tissue blocks (representative formalin-fixed - 
if formalin is unavailable B5 block may be submitted). 
• 
Five unstained slides (pretreated for immunostaining) from each representative formalin-fixed 
tissue block. 5 additional unstained slides if B5 block is available and formalin is unavailable. 
• 
Copy of all pathology reports. 
• 
Copy of any ancillary reports, whether performed on the tissue, (i.e. immunophenotyping, 
cytogenics, molecular genetics, FISH etc.). 
 
 

 
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12.0 
CORRELATIVE STUDIES 
 
A detailed Correlative Studies Manual will be provided on the IND.228 trial specific website, 
which will include details regarding sample preparation, handling and shipping. 
 
Specimens collected may be used by researchers to better understand the nature of rare cancers and 
how patients respond to treatment. 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 for hereditary genetic defects predisposing to malignant disease will not be carried out 
without the expressed consent of the patient. 
 
All patients on whom a diagnostic tumour block is collected will be aware of this retrieval and will 
have given their consent. 
 
12.1 
Protocol-Mandated Correlative Studies 
 
12.1.1 Tissue Collection (Mandatory) 
 
Archival Tumour Collection: 
The submission of a representative block of the diagnostic tumour tissue at the request of the CCTG 
Central Tumour Bank is mandatory for participation in this trial. One tumour block and one 
adjacent normal tissue block are requested from any of the biopsies or resections of the tumour. If 
no primary cancer blocks are available, one block of metastatic tissue can be sent instead. The 
preferred tumour sample for the determination of a patient’s PD-L1 status is the one taken following 
the completion of the most recent prior line of therapy. 
 
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. This will optimize the amount of tissue available to investigators and permit the 
preservation of the 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. 
 
Where local centre regulations prohibit submission of blocks of tumour tissue, the approval of the 
CCTG must be sought prior to registering of the first patient to allow cores (two 2 mm cores of 
tumour from the block) and slides (see Section 11.0 for slide specifications) of representative 
tumour tissue to be substituted in response to the Central Tumour Bank request. 
 
Diagnostic pathology reports are received as part of the supporting documentation required for this 
trial. Receipt of these will initiate a request directly from the Queen’s Department of Pathology to 
pathology departments for a representative tumour block. 
 
Planned Priority Assays on Tumour Tissue Include:  
• 
PD-1, PD-L1. 
• 
Evaluation of lymphocyte infiltration (TILs) including subtypes by immunohistochemistry 
(CD8 and FOXP3). 
• 
Expression profiling of immune markers 
• 
Genomic profiling. 

 
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12.2 
PD-L1 and TILs Pre-Screening - Tumour Tissue 
Mandatory for Cohort 2 patients only. 
 
Pre-screening for PD-L1 and TILs can occur at any time prior to registration. All patients must sign 
the pre-screening consent prior to tissue being sent. 
The screening tests will be performed on slides created from an archival tumour block. 
 
The TILs infiltration will be assessed on H&E slides and PD-L1 and expression will be performed 
by quantitative immunohistochemistsry (IHC). Results will be made available within about 
14 days. 
 
Patients will not be identified by name. The only identification on the tissue will be 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. 
 
Diagnostic pathology reports are received as part of the supporting documentation required for this 
trial. A copy should be submitted with the Baseline Folder  
 
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out. 
 
Please refer to the IND.228 Laboratory Manual for details. 
 
12.3 
Blood 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 pharmacodynamics 
effects. Serum samples will be collected for planned studies from all patients. 
 
Exploratory assays include: 
• 
Genomic aberrations (mutations, copy number changes) from circulating cell-free DNA 
(cfDNA). 
 
Detailed instructions for sample acquisition, preparation, and shipping are found in the IND.228 
Laboratory Manual. 
 
12.4 
Genomic Analyses 
 
Genomic analyses will be performed on tumour and normal DNA. Technologies for genome 
sequencing are rapidly evolving and the most appropriate methods will be considered at the time 
of execution. Methods available include: Copy Number Variation, Structural variation, Targeted 
sequencing of specific gene sets, Hybridization capture and high-throughput PCR, Exome 
sequencing, Whole genome sequencing. 
 
12.5 
Statistical Analysis 
 
The relationships between the tumour response and genetic mutation statuses will be investigated 
using Fisher’s exact test, while the relationships between the time to progression and genetic 
mutations will be investigated using the log-rank test. Statistical testing will not be conducted in 
this hypothesis generating evaluation.  

 
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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
This is a phase II study to investigate the efficacy of durvalumab and tremelimumab in 8 cohorts 
of patients with rare tumours. The study will accrue up to 160 patients in one treatment arm. Each 
disease cohort will be evaluated independently. 
 
In order to minimize the expected number of patients treated in the event that the regimen proves 
to be very disappointing or very unsuccessful, a two-stage design will be used for patient accrual 
[Simon 1989]. 
 
13.2 
Primary Endpoints and Analysis 
 
Primary endpoint of this study is objective response rate, defined as the proportion of response 
evaluable patients who had complete response (CR) or partial response (PR) as their best response 
as assessed by RECIST version 1.1 criteria (i.e. a 30% decrease in the sum of the longest diameters 
of the target lesions maintained for at least 4 weeks (CR), or complete disappearance of disease and 
cancer related symptoms, also maintained for at least 4 weeks (CR)). Early progression is defined 
as progressive disease at or prior to the first assessment. The exact 95% confidence interval for the 
response rate will be calculated. The median and range of the duration of response, defined as the 
time from date of CR or PR to the date when progression or death is observed, will be estimated 
based on Kaplan-Meier method. 
 
Sample Size for Each of 8 Disease Cohorts 
 
Stage 1 of Accrual: 10 response evaluable patients will be entered in the first stage. Using response 
hypotheses of H0 ≤ 5% and Ha ≥ 25%, we would reject the drug at the end of the first stage of 
accrual if no responses were seen. Otherwise, additional 10 patients will be accrued to the cohort. 
 
Stage 2 of Accrual: Additional 10 response evaluable patients will be accrued. We would accept 
the drug as active if four or more responses are observed from 20 patients accrued. 
 
Significance Level and Power: The procedure described above tests the null hypothesis (H0) that 
the response rate is 5% versus alternating hypotheses (H1) that the response rate is 25%. The 
significance level (i.e. the probability of rejecting H0 when it is true) is α=0.02 and the power 
(i.e. the probability of rejecting H0, i.e. deciding the regimen is active, when H1 is true) is 0.76. In 
addition, if the true response rate of an agent is 10%, it would be identified as ineffective with 
probability of 0.87. If the true response rate of the agent is 30%, it would be identified as effective 
with probability of 0.88. 
 
Since the eligibility will not initially be limited to patients with tumours expression of PD1/PDL1 
and or TILs (with the exception of cohort 2); before closing the original cohort when no response 
was observed after the first stage of the accrual, where feasible, a minimum of 10 patients with 
tumours with TILs and/or PD-L1 expression will be included in the response analysis. This 
modified cohort may be expanded to the second stage of accrual if there is at least one response 
observed. 
 
 

 
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Accrual and Duration of Study 
 
A minimum of 10 and maximum of 20 response evaluable patients per cohort will be accrued. 
Should a disease cohort meet or exceed its activity goal, and recruitment is not limiting, additional 
enrollment beyond 20 patients/cohort may be considered to improve the estimate of anti-tumour 
activity and exploration of biomarkers outcome correlations. Evidence of anti-tumour response in 
the first stage will lead to the implementation of optional fresh tumour biopsies in patients 
subsequently enrolled to allow for more detailed genomic analyses. If an unusually high level of 
activity is seen (i.e. > 4/10 patients with objective response) the data will be made available to 
AstraZeneca for regulatory submission. 
 
Following a survey of the CCTG IND members, the minimum estimated recruitment is 
10 patients/year/cohort. If after 2 years, fewer than 10 patients have been registered in any given 
disease cohort and no responses have been observed, that cohort will close to accrual due to lack 
of enrolment. The minimum number of patients recruited is estimated to be 70 and the maximum 
number is estimated to be 140, assuming some patients will be registered, while some cohorts will 
close early for inactivity or lack of accrual feasibility. The maximum number will be increased if 
there are cohorts which will be modified to include patients with TILs and/or PD-L1 expression or 
additional enrolment beyond 20 patients/cohort is considered. 
 
Patients will be accrued from approximately 15 cancer treatment centres across Canada over a 
period of approximately 24-48 months. 
 
Following accrual of 20 eligible patients on the OCCC cohort, it was decided to expand the sample 
size to include 20 additional patients since with a total of 40 evaluable patients, the half-length of 
the 95% confidence interval for the response rate would be reduced from 21% with 20 patients to 
15% when the observed response rate is 35%. Exploratory analysis will assess for correlations 
between biomarkers and objective response.  
 
13.3 
Analysis of Secondary Endpoints: Efficacy Outcomes 
 
Following completion of the study, the following will be described: 
• 
The median and range of the duration of stable disease, defined as the time from date of stable 
disease as the best response to the date when progression or death is observed, based on Kaplan-
Meier method.  
• 
The median and its 95% confidence interval for time to progression, defined as time from the 
date of randomization to the date of progression, based on Kaplan-Meier method. 
• 
The median and its 95% confidence interval for progression free survival, defined as time from 
the date of randomization to the date of progression or death, based on Kaplan-Meier method. 
• 
The median and its 95% confidence interval for overall survival, defined as time from the date 
of randomization to the date of death , based on Kaplan-Meier method. 
 
13.4 
Analysis of Secondary Endpoints: Translational Research 
 
Primary tumour tissue specimens and baseline blood samples, will be obtained from all subjects 
prior to first dose for genetic analysis and other evaluation.. 
 
 

 
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Genetic abnormalities common to the rare tumours and relevant to the mechanisms of action or 
resistance of the drugs and possibly other putative predictors of response will be assessed. The 
relationship between these markers and objective response will be explored. Statistical testing will 
not be conducted in this hypothesis generating evaluation. 
 
Data from the correlative studies will be sent from the central laboratory(ies) to the CCTG for 
incorporation into the trial database. 
 
Central review of the pathology specimens will be done and we will assess the consistency of 
diagnosis of rare tumours through central review of pathology specimens. 
 
13.5 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually/ semi-annually at investigators’ meetings. 

 
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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 and AstraZeneca, 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. 
 
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 study closure the manuscript has 
not been submitted, the central office reserves the right to make other arrangements to ensure timely 
publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
14.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by AstraZeneca, 
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 enrollment 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. 
 
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. 

 
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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. 
 
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). 

 
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As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
The above mentioned documentation, in addition to any submitted source documents, may be 
accessed remotely in the event of a public health emergency either through remote access to 
Electronic Medical Records or through a secure file sharing portal. 
 
The drug company, AstraZeneca, has reserved the right to audit CCTG activities. If AstraZeneca 
requests to audit participating centres they can only do so after consultation with CCTG and can 
only perform the audit as a co-audit with CCTG. 
 
15.8 
Case Report Forms 
 
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 IND.228 area 
of the CCTG web-site (www.ctg.queensu.ca). 
 
 
 

 
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16.0 
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Lian B, Guo J. Checkpoint inhibitors in treatment of metastatic mucosal melanoma. Chin Clin Oncol 2014;3:37. 
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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 - 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) 
 
The Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion Related 
and Non Immune-Mediated Reactions can be downloaded at: 
DoseMod-ToxicityMgmntGuidelines_28Oct2021.pdf 
 
 
 
 

 
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APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Drug Distribution 
 
Durvalumab and tremelimumab will be supplied by AstraZeneca to the distributor, Bay Area Research 
Logistics (BARL), and distributed by BARL to participating centres. 
 
Drug Labelling 
 
Drug supplies for this study will be labelled in accordance with Health Canada regulations. 
 
Initial Drug Supply 
 
Once a centre is locally activated (following receipt and review of all required documentation), CCTG will 
authorize a start-up supply of durvalumab and tremelimumab to be shipped directly to the centre. Drug will 
be shipped to the centre within 5 working days of local activation. Note: shipment will not be made on 
Fridays and weekends. 
 
Drug accountability and drug re-order forms will be available on the IND.228 trial website. 
 
Drug Ordering (Re-supply) 
 
Subsequent requests for more drug should be made by authorized personnel at each centre. A copy of the 
Request for Drug Shipment form (available on the IND.228 trial website) should be faxed to the distributor. 
 
Please allow sufficient time for shipment of drug. Note: shipment will not be made on Fridays and 
weekends. 
 
Drug Accountability 
 
The investigational products are to be prescribed only by the Qualified Investigator and /or Co-Sub-
Investigators having this delegated duty on the participants list. Under no circumstances will the 
investigator allow the drug to be used other than as directed by the protocol. Accurate records must be 
maintained accounting for the receipt, dispensation, return and/or destruction of the investigational product 
and for the disposition of the product (utilizing the Drug Accountability Log, available on the IND.228 trial 
website). At the end of the study, it must be possible to reconcile shipment records with records of 
usage/returned stock by completion of the study drug accountability form. Any discrepancies must be 
accounted for and documented. 
 
Drug Destruction 
 
Drug Destruction of Patient Returns  
Unused trial medication returned by the patient may be destroyed per local policy, AFTER accountability 
and reconciliation has been completed and documented by the site. Documentation of destruction must be 
kept on file in the site pharmacy and is subject to on site monitoring/audit.  
 
 
 

 
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Drug Destruction of Expired Medication  
The CCTG Study Coordinator must be contacted prior to destruction of expired medication to ensure an 
extension of expiry date is not expected. Expired trial medication may be destroyed per local policy, AFTER 
accountability and reconciliation has been completed and documented by the site. Documentation of 
destruction must be kept on file in the site pharmacy and is subject to on site monitoring/audit. 
 
** PLEASE NOTE ** 
DRUG FROM THIS SUPPLY IS TO BE USED 
ONLY FOR PATIENTS REGISTERED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite 
pharmacy, provided separate drug accountability records are maintained in each pharmacy and appropriate 
storage is available. Investigational agent may NOT however, be transferred to pharmacies or physicians 
outside the participating centre. 
 
 

 
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APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of registration and will apply to all eligible and ineligible 
patients. This trial will use a web-based Electronic Data Capture (EDC) system for all data collection 
including SAE reporting (see Section 10.0 for details regarding SAE reporting). For details about accessing 
the EDC system and completing the on-line Case Report Forms, please refer to the Data Management 
Guidebook posted on the IND.228 area of the CCTG web-site (www.ctg.queensu.ca). 
 
The ELECTRONIC CRFs to be used in this trial are: 
 
Electronic Case Report Form 
To be Completed/Submitted Electronically: 
Supporting Documentation to be 
sent using Supporting Document 
Upload Tool* 
BASELINE REPORT 
Due within 2 weeks of patient registration.  
Copies of signature pages of main 
and pre-screening consent forms; 
relevant pathology & radiology 
reports. 
TREATMENT REPORT  
To be completed every 3 weeks (i.e. after each cycle). Due 
within 2 weeks of end of course. This report documents 
treatment, adverse events, investigations and response 
assessment for each course. 
Relevant radiology reports. 
CORRELATIVE STUDIES See Section 12. 
 
END OF TREATMENT 
REPORT 
To be completed when patient goes off protocol treatment. 
Due within 2 weeks of end of protocol treatment. 
 
4 WEEK POST 
TREATMENT REPORT 
To be completed once on all patients, 4 weeks after going off 
protocol treatment. Due within 2 weeks after contact with 
patient. 
Relevant radiology reports. 
FOLLOW-UP REPORT 
Continued in-person follow-up is not required for patients 
who go off protocol treatment with 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 response, stable disease ongoing, or unconfirmed 
progression, Follow-up Report to be completed every 3 
months until relapse/progression. Due within 2 weeks after 
contact with patient. 
Relevant radiology reports. 
RELAPSE/ 
PROGRESSION REPORT  
To be completed at the time of disease relapse or 
progression. Due within 2 weeks after contact with patient. 
Relevant radiology reports. 
FOLLOW-UP FOR 
SURVIVAL 
Follow-up for survival will continue every 3 months for 
2 years (e.g. by telephone). 
 
DEATH REPORT** 
Required for all patients while study is open. Due within 
2 weeks of knowledge of death. 
Autopsy report, if done. 
SERIOUS ADVERSE 
EVENT (SAE) REPORT 
All reportable serious adverse events must be reported as 
described in Section 9.0. Preliminary CCTG Serious 
Adverse Event Report due within 24 hours. Updated CCTG 
Serious Adverse Event Report due within 7 days. 
All relevant test reports, 
admission, discharge 
summaries/notes. 
* Supporting documents should be uploaded immediately after the report they refer to has been submitted electronically. 
** NB It is the investigator's responsibility to investigate & report the date/cause of death of any patient who dies during this period. 
Any death that occurs during this protocol therapy or within 30 days after last dose must also be reported as a Serious Adverse Event 
as described in Section 10.0. 

 
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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 - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS 
 
The 7th Edition of the TNM Classification of Malignant Tumours has recently been released. To facilitate 
this process, educational resources have been made available to promote the use of staging (visit 
http://www.cancerstaging.org). These staging criteria should be used for new trials. 
 
 

 
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APPENDIX VII - EMERGENCY SITUATIONS AND COMPLIANCE 
 
Management of Protocol Variances in Emergency Situations 
 
Compliance with the trial protocol, its amendments and any information that may be added to this document 
or provided as a part of the conduct of this trial as well as any associated sub-studies should be ensured to 
every extent possible, however in emergency situations, specific variances from the protocol that occur as 
a result of efforts to minimize or eliminate hazards and protect the safety and well-being of patients are 
permissible. 
 
In these rare circumstances, minor deviations that do not impact patient safety or willingness to participate 
or trial integrity, which have been justified and documented in the medical record by the QI/SI will not be 
considered to be REB reportable deficiencies requiring action, but must be reported to CCTG (e.g. in 
Electronic Data Capture (EDC) or using trial specific deviation logs as directed by CCTG) within 4 weeks 
of the end of the Emergency Situation, unless otherwise instructed by CCTG, and to your REB at the next 
amendment or annual approval. 
 
Centres should also discuss these reporting requirements with their local REB, and review the trial website 
for additional guidance specific to the trial. 
 
Minor Protocol Deviations: 
• 
Missed or delayed protocol mandated visits or investigations on treatment or in follow up. 
• 
Changes in study drug distribution (e.g. drug distributed remotely or IV drug given at satellite site), 
providing permitted by local SOPs, or written procedure established and is approved by CCTG or 
acceptable per further instruction from CCTG. Note there will be no exceptions for injectable/IV 
investigational agents as must be administered at participating site. 
• 
Alternative methods for safety assessments (e.g. telephone contact, virtual visit, alternative location for 
assessment). 
• 
Patient care and evaluations provided by non-research staff, providing overseen by QI/SI who must 
make all treatment decisions and ensure that all required information and results will be reported to 
allow central data submission. Includes physical exam, clinical laboratory tests, research blood 
collections that can be shipped centrally, imaging, non-investigational drug therapy*, standard radiation 
therapy, surgery, and other interventions that do not require protocol-specified credentialing*.  
*Must be approved by CCTG or acceptable per further instruction from CCTG. 
• 
Re-treatment following extended treatment delays if protocol specifies that excessive delays require 
discontinuation, providing other protocol requirements for discontinuation have not been met and either 
discussed with CCTG or acceptable per further instruction from CCTG. 
 
Note:  
− Applicable only to COVID-19 and other CCTG designated emergency situations. 
− No waivers will be given for eligibility, including performance of protocol mandated tests/imaging.  
− Deficiencies will be issued if patients are enrolled when trial is on accrual hold, for unreported Serious 
Adverse Events as well as changes in drug distribution/administration and/or re-treatment after 
extended treatment delays when not discussed and approved by CCTG or acceptable per further 
instruction from CCTG. 
− Deviations or changes that are believed to impact patient safety, compromise the study integrity or 
affect willingness to participate are still considered Major Protocol Violations and must be reported to 
CCTG and your REB. These include more than a minimal delay in protocol therapy administration.  
 

 
ADMINISTRATIVE UPDATE #5: 2022-JAN 26- 
 
CCTG TRIAL: IND.228 
 
 
CONFIDENTIAL 
60 
CONFIDENTIAL 
 

 
ADMINISTRATIVE UPDATE #5: 2022-JAN 26- 
 
CCTG TRIAL: IND.228 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
PATIENT REGISTRATION 
All patients must be registered with CCTG before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Joana Sederias 
Study Coordinator, CCTG 
Email: 
jsederias@ctg.queensu.ca 
or: 
Dr. Janet Dancey 
Senior Investigator, CCTG 
Email: 
jdancey@ctg.queensu.ca 
613-533-6430 
613-533-2411 
STUDY CHAIR 
Dr. Abha Gupta 
Abha.gupta@sickkids.ca 
416-813-7744 
416-813-5327 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for details 
of reportable events. 
Dr. Janet Dancey 
Senior Investigator, CCTG 
or 
Joana Sederias 
Study Coordinator, CCTG 
613-533-6430 
613-533-2411 
DRUG ORDERING 
See Appendix IV for full details. 
See Appendix III and trial website: 
http://www.ctg.queensu.ca/trials/ind/228/228.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