Conditions: Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out the effects of giving durvalumab alone or in combination with tremelimumab on this type of cancer. In addition, this study will look at the side effects of durvalumab when given alone or in combination with tremelimumab.

Detailed description:
Durvalumab is a new type of drug for many types of cancer. Laboratory tests show that it works by allowing the immune system to detect cancer and stimulate the immune response. This may help to slow down the growth of cancer or may cause cancer cells to die. Durvalumab has been shown to shrink tumours in animals and has been studied in nearly 2000 people and seems promising but it is not clear if it can offer better results than standard treatment alone.

Tremelimumab is a new type of drug for various types of cancers. It works in a similar way to durvalumab and may improve the effect of durvalumab. This may also help slow the growth of the cancer cells or may cause cancer cells to die. Tremelimumab has been shown to shrink tumours in animals and has been studied in nearly 1500 people and seems promising but it is not clear if it can offer better results than standard treatment alone when used with durvalumab

Combinations of durvalumab and tremelimumab have also been studied and when combined have been shown to increase tumour shrinkage in animals compared to either drug alone. While the combination has been studied in 217 people, it is not clear if it can offer better results than standard treatment.

Arms:
arm 1: Durvalumab-IV for 60 minutes day 1 every 4 weeks Tremelimumab-IV every 60 minutes day 1, cycles 1-4 arm 2: Durvalumab-IV for 60 minutes day 1 every 4 weeks

Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
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CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION: 2016-APR-26 
 
AMENDMENT #1: 2017-JUN-05 
 
ADMINISTRATIVE UPDATE #1: 2018-JAN-10 
 
ADMINISTRATIVE UPDATE #2: 2019-NOV-14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE II STUDY OF DURVALUMAB (MEDI4736) WITH OR WITHOUT TREMELIMUMAB IN 
PATIENTS WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER 
 
CCTG Protocol Number: IND.232 
 
 
 
STUDY CHAIRS: 
Sebastien Hotte 
 
 
Eric Winquist 
 
 
SENIOR INVESTIGATOR: 
Lesley Seymour 
 
 
BIOSTATISTICIAN: 
Dongsheng Tu 
 
 
STUDY COORDINATORS: 
James Hutchenreuther 
 
 
Linda Hagerman 
 
 
REGULATORY SPONSOR: 
Canadian Cancer Trials Group (CCTG) 
 
 
SUPPORTED BY: 
AstraZeneca 
 
(For contact information of study personnel see Final Page.) 
 


 
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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 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION ............................................................................. 7 
3.1 
Durvalumab ............................................................................................................................................... 7 
3.2 
Tremelimumab .......................................................................................................................................... 8 
3.3 
Fixed Dosing in Durvalumab and Tremelimumab ................................................................................. 10 
 
4.0 
STUDY POPULATION ......................................................................................................................... 11 
4.1 
Eligibility Criteria ................................................................................................................................... 11 
4.2 
Ineligibility Criteria ................................................................................................................................. 14 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT......................................................................................................................................... 16 
5.1 
Follow-up for Ineligible or Patients That Go Off Study Prior to Starting Protocol Therapy ................ 17 
 
6.0 
ENTRY/RANDOMIZATION PROCEDURES ..................................................................................... 18 
6.1 
Entry Procedures ..................................................................................................................................... 18 
6.2 
Randomization ........................................................................................................................................ 18 
 
7.0 
TREATMENT PLAN ............................................................................................................................. 19 
7.1 
Durvalumab and Tremelimumab Treatment Plan .................................................................................. 19 
7.2 
Duration of Therapy ................................................................................................................................ 21 
7.3 
Concomitant Therapy .............................................................................................................................. 21 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS .......................................................... 23 
8.1 
Definitions ............................................................................................................................................... 23 
8.2 
RECIST 1.1 Response and Evaluation Endpoints .................................................................................. 23 
8.3 
iRECIST Response Assessment ............................................................................................................. 26 
8.4 
Response and Stable Disease Duration (RECIST 1.1 and iRECIST) .................................................... 28 
8.5  
Prostate Response according to PCWG3 ................................................................................................ 28 
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 ....................................................................................... 32 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting .................................................................... 33 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 35 
9.5 
CCTG Reporting Responsibility to AstraZeneca ................................................................................... 35 
9.6 
CCTG and AstraZeneca Reporting Responsibilities .............................................................................. 35 
9.7 
Reporting Safety Reports to Investigators .............................................................................................. 35 
 
 


 
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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 ......................................................................................................... 36 
 
11.0 
CENTRAL REVIEW PROCEDURES .................................................................................................. 37 
11.1 
Central Data Review ............................................................................................................................... 37 
11.2 
Central Radiology Review ...................................................................................................................... 37 
11.3 
Central Pathology Review ...................................................................................................................... 37 
 
12.0 
CORRELATIVE STUDIES ................................................................................................................... 38 
12.1 
Correlative Sample Collection ................................................................................................................ 38 
12.2 
Protocol-Mandated Correlative Studies .................................................................................................. 38 
 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................... 40 
13.1 
Objectives and Design ............................................................................................................................ 40 
13.2 
Primary Endpoints and Analysis ............................................................................................................. 40 
13.3 
Sample Size and Duration of Study ........................................................................................................ 40 
13.4 
Safety Monitoring ................................................................................................................................... 40 
 
14.0 
PUBLICATION POLICY ...................................................................................................................... 41 
14.1 
Authorship of Papers, Meeting Abstracts, Etc........................................................................................ 41 
14.2 
Responsibility for Publication................................................................................................................. 41 
14.3 
Submission of Material for Presentation or Publication ......................................................................... 41 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES....................................................... 42 
15.1 
Regulatory Considerations ...................................................................................................................... 42 
15.2 
Inclusivity in Research ............................................................................................................................ 42 
15.3 
Obtaining Informed Consent................................................................................................................... 43 
15.4 
Discontinuation of the Trial .................................................................................................................... 44 
15.5 
Retention of Patient Records and Study Files ........................................................................................ 44 
15.6 
Centre Performance Monitoring ............................................................................................................. 44 
15.7 
On-Site Monitoring/Auditing.................................................................................................................. 45 
 
16.0 
REFERENCES ........................................................................................................................................ 46 
 
APPENDIX I -  
PERFORMANCE STATUS SCALES/SCORES ................................................................. 49 
APPENDIX II - 
DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED 
REACTIONS ......................................................................................................................... 50 
APPENDIX III -  DRUG DISTRIBUTION, SUPPLY AND CONTROL ........................................................ 51 
APPENDIX IV -  DOCUMENTATION FOR STUDY ..................................................................................... 53 
APPENDIX V -  NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ...................... 54 
APPENDIX VII -  EMERGENCY SITUATIONS AND COMPLIANCE ......................................................... 55 
 
LIST OF CONTACTS ............................................................................................................................. Final Page 
 


 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to AstraZeneca.  
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG and 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. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
AstraZeneca and CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG IND.232 
 
CENTRE: ___________________________________________ 


 
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TREATMENT SCHEMA 
 
This is an open label multi-centre, phase II trial of durvalumab ± tremelimumab in patients with metastatic 
castration resistant prostate cancer (mCRPC).  
 
 
 
 
 
 
 
 
 
mCRPC 
(Prior Abiraterone and/or 
Enzalutamide) 
12 patients  
durvalumab + tremelimumab 
12 patients  
durvalumab  
25 patients more 
durvalumab + 
tremelimumab 
No Further 
Enrollment 
No Response 
≥ 1 Response 
25 patients more 
durvalumab  
No Further 
Enrollment 
No Response 
≥ 1 Response 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To determine the objective response rate (RECIST 1.1 and iRECIST) in patients with metastatic 
castration resistant prostate cancer (mCRPC) treated with durvalumab alone or in combination with 
tremelimumab. 
 
1.2 
Secondary Objectives 
 
• 
To determine the prostate-specific antigen (PSA) response rate as time to PSA progression.  
• 
To evaluate time to objective disease progression.  
• 
To evaluate the toxicity and tolerability of durvalumab alone or in combination with 
tremelimumab. 
 
1.3 
Exploratory Objectives 
 
• 
To explore the utility of tissue and blood based biomarkers to select patients for treatment with 
durvalumab alone or in combination with tremelimumab.  


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
The current standard first-line therapy for patients with metastatic castration resistant prostate 
cancer (mCRPC) is therapy with androgen receptor antagonist therapies (ARAT) such as 
abiraterone acetate and enzalutamide (ENZ). Other agents that have shown improvements in overall 
survival include chemotherapy with docetaxel and cabazitaxel [Beer 2014, Ryan 2013, Tannock 2004]. 
Many patients do not receive chemotherapy because of advanced age and co-morbidities. The 
radiopharmaceutical radium-223 has recently been approved for use in patients with painful bone 
metastases without visceral metastases or significant nodal disease. Although a survival benefit was 
observed, the median time to progression was similar to placebo [Parker 2013].  
 
A dendritic cell based vaccine has been demonstrated to improve overall survival in patients with 
mCRPC, suggesting that an immune based approach is of relevance in the disease. This vaccine 
strategy has not seen widespread adoption due to availability and cost issues, but also the lack of 
any benefit on response, progression or symptom endpoints [Kantoff 2010]. This vaccine is not 
licensed in Canada. Trials with the immune checkpoint inhibitor ipilimumab are in phase III testing 
in mCRPC currently [Kwon 2014]. The first trial with ipilimumab in chemotherapy experienced 
patients was negative, although the subset of patients without liver metastases did have an overall 
survival advantage [Small 2007]. 
 
Initial phase I experience with PD-1/PD-L1 blockade in patients with mCRPC did not demonstrate 
any significant response rates [Topalian 2012], but this experience is clearly limited. Notably, all these 
studies were performed prior to the availability of abiraterone and enzalutamide. 
 
CTLA-4 is a co-inhibitory receptor expressed on activated T cells and regulates early stage T cell 
activation, reducing the amplitude of T cell activation. Ipilimumab, a FDA-approved fully human 
monoclonal antibody (IgG1) that blocks CTLA-4 to promote antitumour immunity, has received 
indication in patients with unresectable or metastatic melanoma based on improved overall survival 
[Hodi 2010, Robert 2011]. Clinical trials of ipilimumab in patients with mCRPC have demonstrated 
some clinical activity, but have largely been disappointing to date. In a phase III trial 799 were 
randomly assigned to ipilimumab or placebo in post-docetaxel mCRPC; the primary endpoint was 
overall survival (OS). Patients receiving ipilimumab had a median OS of 11.2 months versus 10.0 
months in the placebo group; results were not statistically significant (Hazard Ratio [HR] = 0.85, 
95% CI 0.72-1.00; p=0.053).  
 
Tremelimumab is a human IgG2 monoclonal antibody directed against the T-cell receptor protein 
cytotoxic T-lymphocyte-associated protein 4 (CTLA4) [Tarhini 2013]. Tremelimumab binds to 
CTLA4 and blocks the binding of the antigen-presenting cell ligands B7-1 and B7-2 to CTLA4, 
resulting in inhibition of B7-CTLA4-mediated downregulation of T-cell activation. Combinations 
of durvalumab and tremelimumab appear tolerable at doses of durvalumab 20 mg q4w and 
tremelimumab 1 mg/kg q4w. Higher doses did not result in greater antitumour activity but were 
generally associated with higher rates of AEs. Related Grade 3/4 events were reported in 4/18 
(22%) patients, while the most frequently reported events were diarrhea, pruritus, rash, and elevated 
AST/ALTs (11% for each AE). Only one patient discontinued study therapy due to drug-related 
AEs [Antonia, 2015]. 
 
 


 
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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 2009]. 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-L1/ PD-1 engagement, has 
been shown to induce tumour regression across many cancer types, including melanoma and renal 
cell, colon and lung cancers [Pardoll 2012, Brahmer 2012]. Single agent immunotherapy with anti-PD-
1 or anti-PDL-1 antibodies across many tumour types has been generally well tolerated, with 
common drug related adverse events mainly limited to grade 1 or 2 fatigue, diarrhea, rash, pruritus, 
nausea and decreased appetite. Immune-related adverse events are uncommon (<2%), and include 
pneumonitis, vitiligo, colitis, hepatitis and hypophysitis and thyroiditis [Antonia 2014]. Currently, 
Nivolumab and Pembrolizumab, an anti PD-1 and anti PD-L1 respectively, have received FDA 
approval for patients with unresectable or metastatic melanoma, patients with metastatic NSCLC 
and patients with metastatic renal cell carcinoma [Wolchok 2013, Postow 2015, Robert 2015, Larkin 2015, 
Brahmer 2015, Borghaei 2015, Motzer 2015]. 
 
Durvalumab is a novel IgG1-kappa PD-L1 inhibitor with potent and specific binding to PD-L1 at 
picomolar concentrations and has directed mutations in the Fc region, limiting off-target 
cytotoxicity in PD-L1-expressing immune cells [Khleif 2013; Stewart 2011]. Surrogate anti-PD-LI 
antibodies have been shown to increase T-cell activation in vitro by blocking PD-L1/PD-1 
engagement and inducing anti-tumour responses in tumour-bearing mice, with corresponding 
changes in peripheral immune markers. Durvalumab has also been shown to inhibit tumour growth 
in vivo xenograft models. In a phase I dose escalation study in advanced solid tumours evaluating 
doses (0.1-15.0 mg/kg every 2 weeks (q2w) or 3 weeks (q3w)), signals of durable clinical activity 
have been observed in the NSCLC expansion cohort [Antonia 2016]. 
 
Combination of anti-PD-L1 and anti-CTLA-4 is a promising approach because of non-redundant 
pathway blockade and synergy based on preclinical data as well as emergent clinical data, including 
in unresectable or metastatic melanoma and NSCLC where increase responses were observed with 
the combination although incremental toxicity is a concern [Pardoll 2012; Antonia 2015]. In patients 
with unresectable or metastatic melanoma the rate of confirmed objective response was 61% in the 
group that received both ipilimumab and nivolumab versus 11% in the group that received 
ipilimumab and placebo; progression free survival (PFS) was also significantly longer (HR=0.40; 
95% CI 0.23-068; p<0.001). However this benefit was accompanied by a significant increment in 
toxicity, drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who 
received the combination therapy as compared with 24% of the patients who received ipilimumab 
monotherapy [Postow 2015]. A phase Ib study of Durvalumab plus tremelimumab in non-small cell 
lung cancer has been reported; Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1mg/kg 
showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, 
and was selected as the dose for phase III studies [Postow 2015]. 


 
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Recently, it has been described that PD-L1 becomes highly expressed in enzalutamide resistant 
prostate cancer and patients progressing on enzalutamide had significantly increased PD-L1/2+ 
dendritic cells (DC) in blood compared to those naïve or responding to treatment [Bishop 2015]. 
These data support previous pre-clinical results, in which significantly increased circulating PD-
L1/2+ DCs and a high frequency of PD-1+T cells in mice bearing enzalutamide-resistant (ENZ-R) 
tumours were found. ENZA-R tumours expressed significantly increased levels of tumour-intrinsic 
PD-L1. The expression of PD-L1 on ENZ-R cells, or the ability to modulate PD-L1/2+ DC 
frequency, was unique to ENZ-R cell lines and xenografts that did not show classical activation of 
the androgen receptor. These results suggest that ENZ resistance is associated with the strong 
expression of anti-PD-1 therapy targets in circulating immune cells both in patients and pre-clinical 
models. We hypothesize that mCRPC progressing after therapy with ENZ or abiraterone may be 
more sensitive to PD-1/PD-L1 blockade. 
 
With this rationale, we plan a randomized trial in patients with mCRPC progressing after 
enzalutamide and/or abiraterone acetate to evaluate the antitumour activity of durvalumab alone or 
in combination with tremelimumab.  


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


 
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3.1.6 
Clinical Trials 
 
As of the most recent Investigator’s Brochure, over 5000 subjects have been enrolled and treated 
in ongoing durvalumab clinical studies. No studies have been completed or terminated prematurely 
due to toxicity. 
 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
appears consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumour types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include pneumonitis, hepatitis, diarrhea/colitis and intestinal perforation, 
endocrinopathies 
(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, 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 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.232 Pharmacy Manual for additional details. 
 
3.2 
Tremelimumab 
 
3.2.1 
Name and Chemical Information 
 
Tremelimumab is a human monoclonal antibody of the immunoglobulin G2 (IgG2) subclass that 
inhibits binding of B7 ligands (B7.1 (CD80) or B7.2 (CD86)) to cytotoxic T lymphocyte- 
associated antigen 4 (CTLA-4; cluster of differentiation [CD]152). 
 
See the current tremelimumab Investigator Brochure for additional details and the most up to date 
information.  
 
 


 
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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.232 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. This is not expected to be applicable to this trial of males 
with mCRPC.  
 
 


 
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4.0 
STUDY POPULATION 
 
Patients will have documented evidence of metastatic castration resistant prostate cancer.  
 
4.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed PRIOR to randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
4.1.1 
Patients must have histologically confirmed adenocarcinoma of the prostate that is castrate 
resistant. 
 
4.1.2 
Disease progression as defined as one or both of the following: 
 
PSA Progression: 
 
A rising PSA with 2 subsequent rises over a reference value (not necessarily consecutively), 
measured a minimum of one week apart. The PSA that confirms progression must have a value of 
≥ 2 ng/ml (µg/L).  
 
OR  
 
Objective Progression 
• 
RECIST 1.1 or 
• 
PCWG 3 Criteria for bone progression 
 
4.1.3 
Patients must be surgically or medically castrated, with testosterone levels of < 50 ng/dL 
(< 1.7 nM). Patients who have not undergone orchiectomy must continue (or restart if previously 
discontinued) LHRH therapy throughout the study. 
 
4.1.4 
All patients must have a tumour block from their primary or metastatic tumour available and 
consent to release the block/recently cut slides for correlative analyses (See Section 12.0) and the 
centre/pathologist must have agreed to the submission of the specimen(s). The site of planned 
biopsy must not be the measurable lesion (see Section 4.1.5).  
 
4.1.5 
Presence of clinically and/or radiologically documented disease. All radiology studies must be 
performed within 28 days prior to randomization (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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4.1.6 
Patients must be > 18 years of age. 
 
4.1.7 
ECOG performance status 0 or 1.  
 
4.1.8 
Prior Therapy 
 
Systemic Therapy: 
0-1 prior regimen of cytotoxic chemotherapy in the CRPC setting is permitted..  
 
Hormonal Therapy: 
• 
Patients must be castrate resistant. 
• 
Have failed/progressed on prior abiraterone and/or enzalutamide.  
• 
Patients must have discontinued anti-androgens for at least 4 weeks prior to study entry (at least 
6 weeks for bicalutamide). 
 
Other therapy: 
Prior treatment with other agents, such as tyrosine kinase or other targeted agents is permissible. 
• 
Systemic corticosteroids are permitted at a dose equivalent to ≤ 10 mg prednisone daily and 
are only permitted for reasons other than prostate cancer treatment (ex: fatigue, anorexia, etc.); 
topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or 
local injections (e.g. intra-articular) are permitted.  
• 
Bisphosphonates / denosumab are permitted for treatment of hypercalcemia, osteoporosis and 
skeletal-related events 
 
Immunotherapy: 
Patients may not have received prior immune check point inhibitors (anti PDL1 and anti CTL-4). 
Vaccines and treatment with oncolytic viruses is permissible.  
 
Patients must have recovered from all reversible toxicity related to prior systemic therapy 
(chemotherapy and hormone) and have adequate washout as follows:  
 
Longest of one of the following: 
• 
Two weeks; 
• 
The longer of 30 days or 5 half-lives for investigational agents; 
• 
Standard cycle length of standard therapies. 
 
Radiation: 
Prior external beam radiation or radium-223 is permitted provided a minimum of 28 days (4 weeks) 
have elapsed between the last dose of radiation and the date of randomization. Exceptions may be 
made for low-dose non-myelosuppressive radiotherapy after consultation with CCTG. Concurrent 
radiotherapy is not permitted. Prior strontium-89 at any time is not permitted. 
 
Prior Surgery: 
Prior major surgery is permitted provided that a minimum of 28 days (4 weeks) have elapsed 
between any major surgery and date of randomization, and that wound healing has occurred. 
 
 


 
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4.1.9 
Laboratory Requirements 
(Must be done within 7 days prior to randomization) 
 
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  
< 5.0 x ULN (if patient has liver metastases) 
Serum creatinine 
or: 
Creatinine clearance*** 
< 1.25 x ULN 
 
> 40 mL/min 
*  
Contact CCTG if exception on medical grounds is appropriate to minimize risk of unnecessary transfusion.  
** 
If confirmed Gilbert’s, eligible provided ≤ 3 x ULN. 
*** Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft and 
Gault equation below: 
 
Males: GFR  
= 1.23 x (140-age) x weight in kg 
 
 
  serum creatinine in μmol/L 
 
4.1.10 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. See Section 9.3.1 for additional details. 
 
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. 
 
4.1.11  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 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial 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. 
 
 


 
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4.1.13 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. 
The patient’s city of residence may be required to verify their geographical proximity. (Call the 
CCTG office (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, adverse events, and follow-up. 
 
Patients must agree to return to their primary care facility for any adverse events which may occur 
through the course of the trial. 
 
4.1.14 In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient 
randomization. 
 
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 requiring concurrent anticancer therapy. 
 
4.2.2 
Patients with brain metastases are not eligible.  
 
4.2.3 
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).  
• 
Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone 
replacement. 
 
4.2.4 
History of primary immunodeficiency, history of allogenic organ transplant that requires 
therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of 
randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other 
immune therapy or grade ≥ 3 infusion reaction. 
 
4.2.5 
Live attenuated vaccination administered within 30 days prior to randomization or within 30 days 
of receiving durvalumab. 
 
4.2.6 
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. 
 
 


 
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4.2.7 
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%. 
 
4.2.8 
Concurrent treatment with other investigational drugs or anti-cancer therapy (except LHRH in 
patients not surgically castrated). 
 
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. 
• 
Pneumonitis. 
 
 
 


 
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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 
randomization) 
Day 1 each 
cycle, and as 
clinically 
indicated 
Every 12 
weeks after 
randomization 
4 weeks after 
completion of 
protocol 
therapy 
3 month follow-up 
(only required for 
pts without 
confirmed PD and 
ongoing 
toxicities1) 
6 month 
follow-up 
(required for all 
patients with 
confirmed PD) 
History and Physical Exam 
 
 
 
 
 
 
Including: height, weight, BSA, 
performance status, clinical tumour 
measurements (if applicable) 
X 
X 
 
X 
 
 
Blood pressure, heart rate, 
temperature 
X 
X2 
 
X 
 
 
Laboratory Procedures/Assessments3 
 
 
 
 
 
CBC, differential, platelets 
X 
X 
 
X4 
X4 
 
PTT, PT/INR (if on anticoagulants) 
X 
X 
 
X4 
X4 
 
Serum creatinine, bilirubin, AST, 
ALT, ALP, LDH, albumin, glucose, 
amylase5, lipase5, electrolytes 
(potassium, calcium, magnesium) 
X 
X 
 
X4 
X4 
 
PSA 
X6 
X7 
 
X8 
X8 
 
TSH9 
X 
X 
 
 
 
 
Testosterone (to confirm biochemical 
castration only) 
X 
 
 
 
 
 
Radiology10,11 
 
 
 
 
 
 
Chest/abdomen/pelvis CT scan 
Other scans as necessary to 
document disease12 
X 
(within 28 days prior 
to randomization or 
35 if negative) 
 
X 
X 
X 
 
Bone Scan12,13 
X 
(within 28 days prior 
to randomization or 
35 if negative) 
 
X 
X 
X  
(if positive at 
baseline and does not 
yet have confirmed 
PD) 
 
Other Investigations 
 
 
 
 
 
 
Urinalysis14 
X 
 
 
 
 
 
LVEF15 
X 
(within 28 days prior 
to randomization) 
 
 
 
 
 
Adverse Events 
X 
Continuously  
X 
X1 
 
Survival/Anti-cancer Treatment 
Follow-up  
 
 
 
 
X 
Correlative Studies (mandatory) 
 
 
 
 
 
 
Fresh tumour biopsy16 
X 
 
 
 
 
 
Archival Tumour Tissues 
X 
 
 
 
 
 
Blood Collection 
X17 
 
 
X18 
 
 
 
footnotes on next page … 
 
 


 
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1. Every three months thereafter to follow adverse events felt related until resolved to ≤ grade 2. 
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. Then 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 parameters are assessed. For sites where only 1 of these parameters is routinely measured then 
either lipase or amylase is acceptable as long as the same one is followed throughout. 
6. At least three previous PSA values with the interval between of > 4 weeks, should be recorded for the patient to estimate doubling time as 
well as one prior to registration. 
7. PSA should also be done at the end of the last cycle. 
8. All patients at 4 weeks. For patients without PSA progression, repeat every 4 to 8 weeks until progression or until new systemic therapy is 
initiated.  
9. Free T3 and free T4 will be measured if TSH is abnormal.  
10. 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. 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). 
12. Maintain schedule every 12 weeks even if cycles are delayed. 
13. Bone scan is required and must be repeated every 12 weeks and end of study, regardless if positive or negative at baseline, as well as when 
clinically indicated. If NEW bone lesion(s) are noted on the patient’s bone scan, see Section 8.5.4 for details.  
14. Only as clinically indicated after baseline 
15. Only if significant cardiac history (see section 4.2.7) 
16. Fresh Biopsy is mandatory for all patients after consent but prior to randomization, see Section 12.0. 
17. To be collected after randomization and prior to cycle 1 treatment.  
18. To be collected at end of treatment/disease progression 
 
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/RANDOMIZATION PROCEDURES 
 
6.1 
Entry Procedures 
 
All randomizations 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/randomizing patients will be provided at the time of study activation and will also be 
included in the “EDC Data Management Guidebook”, posted on the IND.232 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.232 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.232) 
• 
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 
• 
height and weight  
 
6.2 
Randomization 
 
Randomization will be provided electronically. This is a parallel cohort phase II study. Patients will 
be randomized between two cohorts when both cohorts are enrolling. After the interim analysis, 
depending on the results, patients may be randomized to one of two cohorts, or a single cohort if 
one has closed.  
 
At the time of randomization, all data reported within the Patient Enrollment folder must be 
accurate, complete and verifiable against source documentation. If a system query is issued 
indicating that the patient is not eligible, enrollment within the EDC system will not proceed. CCTG 
should be contacted for assistance if needed. Under no circumstances should inaccurate data be 
entered in order to permit randomization. 
 
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 randomization. 
 
All randomized patients are to be followed until death or until sites are informed by CCTG that 
further follow-up is no longer required. The follow-up requirements for ineligible patients are 
outlined in Section 5.1. 


 
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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 5 working days of patient 
randomization. 
 
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. 
 
Arm 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
1 & 2 
Durvalumab 
1500 mg 
IV 
60 min 
Day 1 every 4 weeks 
1 
Tremelimumab 
75 mg 
IV 
60 min 
Day 1, cycles 1-4  
Patients with a body weight of less than or equal to 30 kg 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 Adjustments 
 
The major toxic effects of durvalumab or tremelimumab which are anticipated to limit dosing are 
hypersensitivity/ infusion related reactions and possible class related immune related AEs, based 
on the mechanism of action of durvalumab ± tremelimumab leading to T-cell activation and 
proliferation. Potential immune related AEs include pneumonitis, hepatitis, diarrhea/colitis and 
intestinal perforation, endocrinopathies (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, 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 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 that outline dose adjustments for these toxic effects can be found in Appendix II. 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 4.1.9 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 
See Appendix II for full details of toxicity management. 
 
The following general guidance should be followed for management of toxicities: 
1. Treat each of the toxicities with maximum supportive care (including slowing / interrupting / 
omitting the agent suspected of causing the toxicity where required). 
2. If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab ± tremelimumab along with appropriate continuing 
supportive care.  
3. All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
In addition to the detailed toxicity management guidelines described in Appendix II, the following 
principles are suggested: 
• 
Patient evaluation to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature should be 
considered to be immune-related. 
 
 


 
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• 
Symptomatic and topical therapy should be considered for low-grade events. 
• 
For persistent (greater than 2 to 3 days) low-grade (Grade 2) or severe (Grade ≥ 3) events 
promptly start prednisone PO 1-2 mg/kg/day or IV equivalent. 
• 
If symptoms recur or worsen during corticosteroid tapering (> 4 weeks of taper), increase the 
corticosteroid dose (prednisone dose [e.g. up to 2-4 mg/kg/day or IV equivalent]) until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate. 
• 
More potent immunosuppressives (refer to individual sections of the immune related adverse 
event for specific type of immunosuppressive) should be considered for events not responding 
to systemic steroids. 
• 
Discontinuation of study drug is not mandated for Grade 3 / Grade 4 inflammatory reactions 
attributed to local tumour response (e.g. inflammatory reaction at sites of metastatic disease, 
lymph nodes, etc.). Continuation of study drug in this situation should be based upon a 
benefit/risk analysis for that patient and be discussed with CCTG. 
 
7.1.6 
Management of Infusion Reactions 
 
Guidelines for management of infusion-related reactions 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 
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). 
 
 


 
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7.3.1 
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 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. 
• 
Bisphosphonates / denosumab are permitted for the treatment of hypercalcemia, osteoporosis 
and prevention of skeletal related events for patients with bone metastases. However, the need 
to initiate or increase the dose of these therapies during the study will be considered as 
indicative of disease progression leading to the discontinuation of patient unless disease 
progression can be completely ruled out. 
 
7.3.2 
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. Patients who exhibit objective 
disease progression prior to the end of cycle 1 are considered to be 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 
[Eisenhauer 2009] 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. 
 
See Section 10 for criteria for continuing treatment past RECIST 1.1 disease progression. 
 
8.2 
RECIST 1.1 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 Immune-Related modified RECIST criteria. 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 are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray 
and as ≥ 10 mm with CT scan or clinical examination. Bone lesions are considered measurable only 
if assessed by CT scan and have an identifiable soft tissue component that meets these requirements 
(soft tissue component ≥ 10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short 
axis to be considered measurable; only the short axis will be measured and followed. All tumour 
measurements must be recorded in millimetres (or decimal fractions of centimetres). Previously 
irradiated lesions are not considered measurable unless progression has been documented in the 
lesion. 
 
8.2.2 
Non-measurable Disease. All other lesions (or sites of disease), including small lesions are 
considered non-measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, lymphangitic involvement of lung or skin and abdominal masses 
followed by clinical examination are all non-measurable. Lesions in previously irradiated areas are 
non-measurable, unless progression has been demonstrated. 
 
 


 
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8.2.3 
Target Lesions. When more than one measurable tumour lesion is present at baseline all lesions up 
to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. Note that pathological nodes must meet the criterion of a 
short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed (see 8.2.4). At baseline, the sum of the target 
lesions (longest diameter of tumour lesions plus short axis of lymph nodes: overall maximum of 5) 
is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately measured 
but are deemed to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be used. 
 
8.2.4 
Non-target Lesions. All non-measurable lesions (or sites of disease) plus any measurable lesions 
over and above those listed as target lesions are considered non-target lesions. Measurements are 
not required but these lesions should be noted at baseline and should be followed as “present” or 
“absent”. 
 
8.2.5 
Response. 
 
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 < 10 mm (Note: 
continue to record the measurement even if < 10 mm and considered CR). Residual lesions (other 
than nodes < 10 mm) thought to be non-malignant should be further investigated (by cytology 
specialized imaging or other techniques as appropriate for individual cases [Eisenhauer 2009]) before 
CR can be accepted. Confirmation of response is required in this small randomized control trial. 
 
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 required in this small 
randomized control trial. 
 
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 2 below). 
 
Table 1: 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 < 10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
Documented at least once ≥ 4 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 < 10 mm 
No Target 
Non-CR/non-PD 
No 
Non-
CR/non-
PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 


 
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8.3 
iRECIST 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, 
resulting in previously 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. 
 
8.3.1 
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 progression, compared to the last assessment, is seen as evidenced by 
one or more of the following: 
• 
Continued progression where RECIST 1.1 definitions of progression had been met (from nadir) 
in target, non-target disease or new lesions (from uPD): 
- 
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); 
• 
RECIST 1.1 criteria are met 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 is 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 3, 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. 
 
8.3.2 
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 meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of target lesions 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. These data will enable the development and testing of alternate response 
criteria, or further modifications of RECIST. 
 
 


 
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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 2: Time-point (TP) iResponse 
 
Target 
Lesions* 
Non-Target Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD** 
CR / iCR 
CR 
No 
CR 
iCR 
CR/iCR 
Non-CR/Non-PD 
Non-iCR/Non-iUPD 
No 
PR 
iPR 
PR/iPR 
Non-CR/Non-PD 
Non-iCR/Non-iUPD 
No 
PR 
iPR 
SD/iSD 
Non-CR/Non-PD 
Non-iCR/Non-iUPD 
No 
SD 
iSD 
iUPD with no 
change 
OR 
decrease from 
last TP 
iUPD with no change 
OR decrease from last 
TP 
Yes 
NA 
The appearance NLs confirms PD if  
Additional NLs or 
iUPD in last TP based on NLs and increase in size 
(≥ 5 mm for NLT or any increase for NLNT) 
If no change in NLs from last TP, remains iUPD 
PD 
Non-CR/Non-PD 
Non-iCR/Non-iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in sum of at least 5 mm, otherwise 
remains iUPD 
PD 
PD 
No 
iUPD 
iCPD 
if 
further 
increase 
in 
previously 
identified***  
T lesion iUPD ≥ 5 mm and / or NT lesion iUPD  
PD 
PD 
Yes 
iUPD 
iCPD if further increase in previously identified 
T lesion iUPD ≥ 5 mm and / or NT lesion iUPD 
and / or size or number of new lesion 
Non-iUPD 
Non-iUPD 
Yes 
iUPD 
iCPD if increase in size of previously identified 
new lesions of increased number of new lesion 
* 
Using RECIST 1.1 principles. If no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for CR, PR and 
SD would be the same. 
** In any category. 
*** Previously identified in assessment immediately prior to this time-point (TP) 
NA = not applicable. 
 
 
 


 
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Table 3: 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 
CR 
CR, 
PR, 
iUPD, NE 
CR/iCR, 
PR/iPR, 
iUPD, iCPD, NE 
iUPD 
iCPD 
iCR 
iUPD 
PR, SD, NE CR 
CR, PR, SD, iUPD, NE CR, PR, SD, iUPD, 
iCPD, NE 
iCR 
iUPD 
PR 
PR, SD, iUPD, NE 
PR, SD, iUPD, NE, 
cPD 
PR, SD, iUPD, NE, 
iCPD 
iPR 
iUPD 
SD, NE 
PR 
PR, SD, iUPD, NE 
PR, SD, iUPD, iCPD, 
NE 
iPR 
iUPD 
SD 
SD, iUPD, NE 
SD, iUPD, iCPD, NE 
SD, iUPD, iCPD, NE 
iSD 
iUPD 
iUPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
1. 
Table assumes a randomized study where confirmation of CR or PR is not required. 
2. 
NE = not evaluable that cycle. 
3. 
Designation “I” for BOR can be used to indicate prior uPD to aid in data interpretation. 
4. 
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 and Stable Disease 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). 
 
Stable disease duration will be measured from the time of registration/randomization until the 
criteria for progression are met, taking as reference the smallest sum on study (including baseline). 
 
8.5  
Prostate Response according to PCWG3  
(as defined by Scher 2016)  
 
All patients will be evaluable for PSA response provided follow-up PSA values are obtained to 
allow application of the definitions below [Bubley 1999].  
 
Response: 50% fall in PSA from baseline maintained for ≥ 4 weeks, and without evidence of 
disease progression documented at time of confirmatory values.  
 
Non Response: Failure to achieve PSA response criteria.  
 
PSA response duration will commence on the date of the first 50% decline in PSA. The response 
duration ends when the PSA value increases by 50% above the nadir value, provided that the 
increase is at least 2 ng/mL (µg/L) (or back to baseline).  
 
 


 
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8.5.1 
PSA Progression  
(as defined by Scher 2016)  
 
In PSA non-responders: PSA progression is defined as the date that a 25% or greater increase and 
an absolute increase of 2 ng/mL (µg/L) or more from the nadir (or baseline if no decrease from 
baseline is documented), which is confirmed by a second value obtained 3 or more weeks later. 
 
In PSA responders: rise in PSA of 25% (minimum 2 ng/ml (µg/L)) above nadir value and confirmed 
by a second increasing value obtained 3 or more weeks later.  
 
Time to PSA progression will be calculated from date of randomization to date of PSA progression. 
If interval PSA values are collected or reported during cycle, only the end of cycle PSA (PSA 
collected for Day 1) will be used in response evaluation. 
 
NOTE: Because with systemic treatment an initial rise in PSA is followed by a drop, it is 
recommended patients receive at least 12 weeks of therapy even if PSA is rising, provided no other 
evidence of progression is seen, palliative radiation is not required and protocol therapy is tolerable 
(see Section 10.0). 
 
8.5.2 
Clinical Benefit 
 
Clinical benefit is defined for the purpose of this protocol as one of the following: 
• 
PSA decline ≥ 50% 
• 
Complete or partial objective response 
• 
Stable disease for ≥ 12 weeks 
 
8.5.3 
Clinical Progression 
 
Clinical progression is defined as the need for palliative radiotherapy, change in anti-cancer 
therapy, or cancer related decrease in ECOG performance status to ≥ 3. 
 
8.5.4 
Bone Disease Progression 
 
For the purpose of evaluation of bone disease in this study, a bone scan will be done at baseline 
and must be repeated every 12 weeks after randomization and at end of study, regardless if positive 
or negative at baseline. 
 
For progressive disease in bone lesions, if at least 2 new bone lesions are seen by bone scan on the 
first post treatment scan, then these lesions are confirmed by a second bone scan done 6 or more 
weeks later that also shows at least 2 additional new bone lesions (2 + 2 rule) then the date of 
progression is the date of the first post-treatment scan.  
 
For scans after the first post treatment scan, if 2 new bone lesions are visualized, then these lesions 
need to be seen on a subsequent scan confirming disease progression. If confirmed, the date of PD 
is the date of the first scan. In general, unequivocal progression of bone lesions will not be accepted 
as evidence of disease progression unless the criteria above are met and are confirmed. 
 
Additionally, if a new bone lesion(s) are seen on the patient’s CT it will also need to be confirmed 
with a bone scan and will ONLY be considered PD if the criteria above are met. 
 
 


 
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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, which may be treatment 
arm dependent. While on study, all lesions recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned. For lesions which fragment/split add together the 
longest diameters of the fragmented portions; for lesions which coalesce, measure the maximal 
longest diameter for the “merged lesion”. 
 
8.6.1 
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 case [Eisenhauer 2009]. For example, while PET 
scans are not considered adequate to measure lesions, PET-CT scans may be used providing that 
the measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
 
8.6.4 
Bone Scan. 99mTc-methylene diphosphonate radionuclide bone scintigraphy is the standard for bone 
imaging. 
 
8.6.5 
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. 
 
8.6.6 
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. 
 
8.6.7 
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.  
 
 


 
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8.6.8 
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 unexpected and 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 
• 
Any immune related adverse event (irAE) requiring high dose steroids is by definition 
medically significant and must be reported as such. 
• 
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. 
 
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.232 section of the CCTG website (www.ctg.queensu.ca). 
 
 


 
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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.232 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.232 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  
 
9.3.1 
Pregnancy Prevention 
 
Males who are enrolled in the trial must have agreed to use contraceptive method(s) as described 
in Eligibility Criterion 4.1.10. Investigators may wish to additionally advise the female partners of 
male participants about pregnancy prevention guidelines when appropriate and compliant with 
local policy.  
 
Not engaging in sexual activity for the total duration of the trial and the drug washout period is an 
acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception. 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 is responsible for beginning contraceptive measures.  
 
Females of childbearing potential are defined as those who are not surgically sterile (i.e. bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (defined as 
12 months with no menses without an alternative medical cause). 


 
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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 
 
The investigator is required to report to CCTG any pregnancy occurring in female partners of male 
participants. Pregnancies occurring up to 6 months after the last dose of study treatment must also 
be reported. 
 
Pregnancy itself - occurring in 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 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, a copy of the signed signature 
page of the pregnancy follow-up consent must be submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/safety-desk@ctg.queensu.ca).  
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above.  


 
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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.232 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.232 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.232 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 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. 
• 
Patients who are not clinically stable or who have confirmed disease progression (iCPD) 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. 
 
10.2 
Duration of Protocol Treatment  
• 
Treatment with durvalumab will continue until disease progression or unacceptable toxicity.  
• 
Patients randomized to durvalumab + tremelimumab will receive durvalumab as above and 
tremelimumab for cycles 1-4. 
 
10.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
10.4 
Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy. For patients who go off 
protocol treatment with iCPD, and have ongoing toxicities (until resolved to ≤ grade 2) and late 
toxicities (including second malignancies) follow-up will be required every 3 months.  
 
For patients with no ongoing or late toxicities and have confirmed disease progression, follow-up 
will be required every 6 months for survival data and other anti-cancer treatment only. For patients 
who go off protocol treatment with CR/iCR, PR/iPR, SD/iSD or iUPD ongoing, and have not 
already started other systemic therapy follow-up will be required every 3 months until relapse (see 
Section 5.0 for investigations to be performed) and then every 6 months until death.  
 
Death Report will be required for all patients, 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 Data Review 
 
CCTG receives core support from the Canadian Cancer Society. To ensure efficient use of limited 
funding, the CCTG has, over the past 40 years, optimized their risk based trial oversight and 
monitoring program. A critical component is central data review of submitted deidentified source 
documents, allowing source data verification and confirmation of key aspects including eligibility, 
endpoints and safety outcomes. Depending on the trial’s design, these source documents may 
include such source documents as surgical and histopathology reports to confirm disease stage and 
type, imaging reports to confirm extent of disease and assess efficacy, or include submission of 
tumour samples (to confirm diagnosis and eligibility or DICOM images (to verify response or 
radiation therapy planning). These source documents are reviewed by experienced data managers 
and physicians and are critical to ensuring the accuracy of the data and consistency of conclusions 
drawn. 
 
The collection of this critical data involves uploading documents through the password protected 
and secure CCTG electronic Supporting Document Upload Tool (SDUT) data capture linked 
system. See Appendix III (Documentation for Study) for details of supporting document 
requirements for this trial and for requirements for the redaction of personal identifiers. Although 
it remains the centres responsibility to ensure adequate redaction of any information provided to 
CCTG, submitted source documents are reviewed prior to acceptance at CCTG; in the case of 
incomplete redaction, documents are removed and the site assigned a violation and required to 
resubmit. 
 
All patients will provide written informed consent for submission of source documents, and the 
rationale and documents to be collected will be detailed in the informed consent document. 
 
11.2 
Central Radiology Review 
 
During conduct of the trial, a central review of x-rays and/or scans may be carried out if responses 
have been claimed. For purposes of reporting, the results of both local and central radiology reviews 
will be included. 
 
11.3 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
 


 
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12.0 
CORRELATIVE STUDIES 
 
A detailed Correlative Studies Manual will be provided on the IND.232 trial specific website, 
which will include details regarding sample preparation, handling and shipping. 
 
All patients on whom a diagnostic tumour block is collected will be aware of this retrieval and will 
have given their consent. 
 
12.1 
Correlative Sample Collection 
 
Summary 
 
Sample 
Baseline 
Progression/End of Treatment 
Archival Tissue* 
X 
 
Fresh Tumour Biopsy* 
X 
 
Whole Blood (cfDNA)** 
X 
X 
* 
Mandatory for all patients after consent and prior to randomization. If archival tissue cannot be obtained, please 
contact CCTG. 
**  Mandatory for all patients after randomization and prior to cycle 1 treatment. 
 
12.2 
Protocol-Mandated Correlative Studies 
 
Tissue Collection (mandatory for all patients) 
 
Archival Tumour Block/Slides: 
The collection of a representative block/slides of the diagnostic tumour tissue (from primary or 
metastatic tumour) is an important part of this trial. Blocks/slides will be carefully stored at the 
CCTG tissue/tumour bank at Queen’s University in Kingston, Ontario, until the study specific 
assays are done. All patients on whom a diagnostic tumour block is collected will be aware of this 
retrieval and will have given their consent. 
 
Blocks are the preferred material to collect, as it is well known that tissue materials (including 
protein and nucleic acid integrity) on unstained sections deteriorate rapidly within 3-6 months after 
preparation. 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. 
 
Samples will be used for the purposes of this study 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.  
 
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 testing for hereditary genetic defects predisposing to malignant disease will not be carried 
out.  
 
 


 
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Centres should contact CCTG if they are unable to submit a tumour block, as sufficient tissue is 
required for the tests described below. Upon receipt, the CCTG pathology coordinator will then 
send appropriate material, along with information regarding CCTG protocol number and an 
assigned unique tumour bank ID number to the research laboratory(ies) where these assays will be 
done.  
 
Fresh Tumour Biopsies: 
ALL patients registered/randomized on the trial will have fresh tumour biopsies performed prior to 
Cycle 1 treatment. If a bone lesion is the only site of disease possible for biopsy, please contact 
CCTG to discuss. 
 
Planned priority assays on tumour tissues from all patients include: 
• 
Expression of PD-L1 and T-cell subsets (infiltrating). 
 
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 pharmacodynamic 
effects. Blood samples will be collected from all patients and stored for planned studies.  
 
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.232 
lab manual. 
 
 


 
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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
The primary objective of this randomized, open-label, and non-comparative phase II trial is to 
determine the objective response rate in patients with metastatic castration resistant prostate cancer 
treated with durvalumab alone or in combination with tremelimumab. Secondary objectives include 
determining the PSA response rate, evaluating the time to progression based on measurable disease, 
bone progression or PSA, and the toxicity and tolerability in patients receiving durvalumab ± 
tremelimumab. Patients will be randomized in 1:1 ratio to receive durvalumab alone or in 
combination with tremelimumab. Between 24 and 74 patients will be enrolled. 
 
13.2 
Primary Endpoints and Analysis 
 
The primary endpoint of this study is the objective response rate, using iRECIST criteria defined 
in Section 8. Objective response rate using RECIST 1.1 will also be reported. 95% confidence 
interval for objective response rate in both definitions will be calculated. 
 
13.3 
Sample Size and Duration of Study 
 
A Simon’s optimal two-stage design will be employed for both treatment arms. An objective 
response rate in either arm of 5% or less would not be of interest for further study (null hypothesis). 
If the objective response rate for either cohort were 20% or greater, then this would be considered 
of interest to further evaluate in larger trials (alternative hypothesis). Using an alpha error of 0.1 
and a beta error of 0.1, 12 patients per arm will be initially accrued to stage 1. If 1 or more patients 
had objective response rate on either arm at end of stage 1, the arm will be expanded to a total of 
37 evaluable patients. If ≥ 4 measurable responses are observed from these 37 patients in an arm 
then that arm would be considered for further testing in phase III trials. 
 
If no objective response rates are observed in the first stage of an arm, then PD-L1 expression will 
be evaluated as a predictive biomarker, and expansion of that arm to 12 patients with PD-L1+ 
tumours will be considered. If fewer than 4 responses are seen after accrual to the second-stage of 
the study, then PD-L1 expression in biopsies will be evaluated and expansion of that arm to 37 
patients with PD-L1+ tumours will be considered. 
 
13.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported bi-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 enrollment 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 Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner) 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 partner), 
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. 


 
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15.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
The lead group/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.  


 
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16.0 
REFERENCES 
Antonia SJ, Larkin J, Ascierto PA. Immuno-oncology combinations: a review of clinical experience and future 
prospects. Clin Cancer Res 2014;20(24):6258-68. 
Antonia SJ, Goldberg SB, Balmanoukian AS et al. Phase Ib study of MEDI4736, a programmed cell death 
ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 
(CTLA-4) antibody, in patients (pts) with advanced NSCLC. J Clin Oncol 33, 2015 (suppl; abstr 3014).Fife BT, 
BuestoneJA Immunol Rev. 2008 Aug;224:166-82. 
Antonia S, Goldberg SB, Balmanoukian A. Safety and antitumour activity of durvalumab plus tremelimumab in 
non-small cell lung cancer; a multicentre, phase 1b study. Lancet Oncol. 2016 Feb 5. 
Beer T.M., Armstrong A.J., Rathkopf D.E., et al. Enzalutamide in metastatic prostate cancer before 
chemotherapy. N Engl J Med 2014; 371:424-433. 
Bishop JL, Sio A, Angeles A. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget. 
2015 Jan 1;6(1):234-42. 
Borghaei H., Paz-Ares L., Horn L., et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-
Cell Lung Cancer. N Engl J Med 2015; 373:1627-1639. 
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, et al. Phase I study of single agent anti-programmed 
death-1 (MDX-1106) in refractory solid tumours: safety, clinical activity, pharmacodynamics, and immunologic 
correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75.  
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 
antibody in patients with advanced cancer. N Engl J Med. 2012;28;366(26):2455-65.  
Brahmer J., Reckamp K.L., Baas P., et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-
Cell Lung Cancer. N Engl J Med 2015; 373:123-135. 
Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D et al. Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: recommendations from the Prostate Specific Antigen 
Working Group. J Clin Oncol. 1999 Nov;17(11):3461-7.  
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney 
M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in 
solid tumors: Revised RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009. 
Fife BT, Pauken KE, Eagar TN et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the 
TCR-induced stop signal. Nat Immunol 2009; 10: 1185-1192. 
Hodi FS, O'Day SJ, McDermott DF et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. N Engl J Med 2010;363:711-23. 
Kantoff P.W., Higano C.S., Shore N.D., et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate 
Cancer. N Engl J Med 2010; 363:411-422. 
Khleif S, Lutzky J, Segal N et al. MEDI4736, an anti-PD-L1 antibody with modified Fc domain: preclinical 
evaluation and early clinical results from a phase I study in patients with advanced solid tumors. (Abst 802) 
European Cancer Congress 2013, Amsterdam, Netherlands Sept 27-Oct 1; 
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castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA 184-043): a 
multicentre, randomised, double blind, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):700-12. 
Larkin J., Chiarion-Sileni V., Gonzalez R., et al. Combined Nivolumab and Ipilimumab or Monotherapy in 
Untreated Melanoma. N Engl J Med 2015; 373:23-34. 
Motzer R.J., Escudier B., McDermott D.F., et al. Nivolumab versus Everolimus in Advanced Renal-Cell 
Carcinoma. N Engl J Med 2015; 373:1803-1813. 
 
 


 
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Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of ifalimumab, an investigational anti-
interferon-α monoclonal antibody, in systemic lupus erythematosus. Clinical Pharmacokinet, 2013 
Nov;52(11)1017-27.  
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in cancer patients 
based on population pharmacokinetic analysis. Pharm Res. 2006 Jun;23(6):1275-84. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 
22;12(4):252-64. 
Parker C., Nilsson S., Heinrich D., et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. 
N Engl J Med 2013; 369:213-223. 
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melanoma. N Engl J Med 2015; 372:2006-2017. 
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melanoma. N Engl J Med 2011; 364:2517-2526. 
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N Engl J Med 2015; 372:320-330. 
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chemotherapy. N Engl J Med 2013; 368:138-148. 
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Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, 
Humphrey R, Hodi FS. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-
Related Response Criteria. Clin Cancer Res 2009;15(23):7412-7420. 
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and proteins in adults. J Clin Pharmacol. 2012Jan;52(1):18-28. 


 
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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_17Nov2020.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 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. The drug 
will be shipped to the centre within 5 working days of local activation. Note: shipment will not be made on 
Fridays and weekends.  
 
Resupply 
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.232 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 (Drug Accountability Log, available on the IND.232 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.  
 
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. 
 
 


 
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** 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 randomization 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 9.0 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.232 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 optional consent 
forms; relevant pathology & 
radiology reports. 
TREATMENT REPORT  
To be completed every 4 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 12.0. 
 
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 the end of 
the last cycle date. Due within 2 weeks after contact with 
patient. 
Relevant radiology reports. 
3 MONTH 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 or unconfirmed progression 
ongoing, Follow-up Report to be completed every 3 months 
until relapse/progression. Due within 2 weeks after contact 
with patient. 
Relevant radiology reports. 
6 MONTH FOLLOW-UP 
REPORT 
Required for all patients with confirmed PD to confirm 
survival status and other anticancer treatment.  
 
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. 
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 and other 
documentation, as 
requested.. 
* Source documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, and/or serious 
adverse events. 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 9.0. 


 
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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 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. 
 


 
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Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
PATIENT REGISTRATION 
All patients must be registered with CCTG before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca  
under: Clinical Trials 
613-533-6430 
613-533-2411 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
James Hutchenreuther 
Study Coordinator, CCTG 
Email: jhutchenreuther@ctg.queensu.ca 
or 
Linda Hagerman 
Study Coordinator, CCTG 
Email: lhagerman@ctg.queensu.ca  
or: 
Dr. Lesley Seymour 
Senior Investigator, CCTG 
Email: lseymour@ctg.queensu.ca 
STUDY CHAIR 
Dr. Sebastien Hotte 
Study Chair 
Email: hotte@HHSC.ca  
905-387-9495 
905-575-6324 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for details 
of reportable events. 
Dr. Lesley Seymour 
Senior Investigator, CCTG 
or 
James Hutchenreuther 
Study Coordinator, CCTG 
or 
Linda Hagerman 
Study Coordinator, CCTG 
613-533-6430 
613-533-2411 
DRUG ORDERING 
See Appendix III for full details. 
See Appendix III and IND.232 website 
 
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