A Phase II/III Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma
Phase: PHASE2
Conditions: Mesothelioma
Sponsor: Canadian Cancer Trials Group

NCT02784171
IND227: A Phase II/III Randomized Study of Pembrolizumab in Patients with Advanced Malignant 
Pleural Mesothelioma
Date: 2021.Jun.21

 
PROTOCOL ADMINISTRATIVE UPDATE #2: 2021-JUN-21 
 
CCTG TRIAL: IND.227 
 
 
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HEALTH CANADA SUBMISSION: 2016-APR-19 
 
AMENDMENT #1: 2016-DEC-13 
 
ADMINISTRATIVE UPDATE #1: 2017-MAR-06 
 
AMENDMENT #2: 2018-APR-11 
 
AMENDMENT #3: 2019-JAN-03 
 
AMENDMENT #4: 2020-APR-14 
 
AMENDMENT #5: 2020-OCT-27 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE II/III RANDOMIZED STUDY OF PEMBROLIZUMAB  
IN PATIENTS WITH ADVANCED MALIGNANT PLEURAL MESOTHELIOMA 
 
CCTG Protocol Number: IND.227 
EudraCT Protocol Number: 2016-002286-60 
 
 
STUDY CHAIRS: 
Quincy Chu (Canada) 
 
 
Francesco Perrone (Italy) 
 
 
Laurent Greillier (France) 
 
 
SENIOR INVESTIGATORS: 
Lesley Seymour 
 
 
James Taylor 
 
 
BIOSTATISTICIAN: 
Dongsheng Tu  
 
 
QOL COORDINATOR: 
Christopher Lee 
 
 
HEALTH ECONOMICS COORDINATOR: 
Natasha Leighl 
 
 
STUDY COORDINATORS: 
Joana Sederias 
 
 
Kelsey Curran 
 
 
OTHER TRIAL COMMITTEE MEMBERS: 
Scott Laurie 
 
 
Marilina Piccirillo 
 
 
Arnaud Scherpereel 
 
 
Ming Tsao 
 
 
Penelope Bradbury 
 
 
SPONSORS: 
CCTG (Canada) 
 
 
National Cancer Institute of Naples (NCIN, Italy) 
 
 
Intergroupe Francophone de Cancerologie Thoracique 
(IFCT, France) 
 
This study is a collaboration between CCTG, NCIN and IFCT. 
 
(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 
Pembrolizumab ....................................................................................................................................... 7 
3.2 
Cisplatin (and Carboplatin if used) .......................................................................................................... 9 
3.3  
Pemetrexed .............................................................................................................................................. 9 
 
4.0 
STUDY POPULATION ....................................................................................................................... 10 
4.1 
Eligibility Criteria ................................................................................................................................. 10 
4.2 
Ineligibility Criteria ............................................................................................................................... 13 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT....................................................................................................................................... 15 
 
6.0 
ENTRY/RANDOMIZATION PROCEDURES .................................................................................... 17 
6.1 
Entry Procedures ................................................................................................................................... 17 
6.2 
Stratification .......................................................................................................................................... 17 
6.3 
Randomization ...................................................................................................................................... 17 
 
7.0 
TREATMENT PLAN ........................................................................................................................... 18 
7.1 
Premedication ........................................................................................................................................ 19 
7.2 
Patient Monitoring ................................................................................................................................ 19 
7.3 
Dose Interruptions and Management of Toxicity .................................................................................. 20 
7.4 
Duration of Therapy .............................................................................................................................. 26 
7.5 
Concomitant Therapy ............................................................................................................................ 26 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 28 
8.1 
Definitions ............................................................................................................................................. 28 
8.2 
Response and Evaluation Endpoints ..................................................................................................... 28 
8.3 
Immune-Related Response Assessment ................................................................................................ 31 
8.4 
Response Duration (mRECIST and iRECIST) ..................................................................................... 34 
8.5 
Stable Disease Duration ........................................................................................................................ 34 
8.6 
Methods of Measurement ...................................................................................................................... 34 
 
 

 
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9.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 36 
9.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 36 
9.2 
Serious Adverse Event Reporting Instructions...................................................................................... 37 
9.3 
Pregnancy Reporting and Exposure Reporting ..................................................................................... 38 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada and Other Regulatory 
Authorities Where the Trial is being Conducted ................................................................................... 39 
9.5 
CCTG Reporting Responsibility to Merck & Co., Inc. ......................................................................... 39 
9.6 
Merck & Co., Inc. Reporting Responsibilities ...................................................................................... 39 
9.7 
Reporting Safety Reports to Investigators............................................................................................. 39 
 
10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 41 
10.1 
Criteria for Discontinuing Protocol Treatment...................................................................................... 41 
10.2 
Duration of Protocol Treatment ............................................................................................................ 41 
10.3 
Therapy After Protocol Treatment is Stopped....................................................................................... 41 
10.4 
Follow-up Off Protocol Treatment ........................................................................................................ 41 
 
11.0 
CENTRAL REVIEW PROCEDURES ................................................................................................. 42 
11.1 
Central Data Review ............................................................................................................................. 42 
11.2 
Central Radiology Review .................................................................................................................... 42 
11.3 
Central Pathology Review ..................................................................................................................... 42 
11.4 
Tissue Collection (Mandatory) .............................................................................................................. 43 
11.5 
Blood Collection ................................................................................................................................... 43 
 
12.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 44 
12.1 
Objectives and Design ........................................................................................................................... 44 
12.2 
Study Endpoints and Analysis............................................................................................................... 44 
12.3 
Sample Size and Duration of Study ...................................................................................................... 45 
12.4 
Safety Monitoring ................................................................................................................................. 46 
12.5 
Interim Analysis .................................................................................................................................... 46 
12.6 
Multiplicity ............................................................................................................................................ 46 
12.7 
Quality of Life Analysis ........................................................................................................................ 48 
12.8 
Economic Analysis ................................................................................................................................ 49 
 
13.0 
PUBLICATION POLICY ..................................................................................................................... 50 
13.1 
Authorship of Papers, Meeting Abstracts, Etc. ..................................................................................... 50 
13.2 
Responsibility for Publication ............................................................................................................... 50 
13.3 
Submission of Material for Presentation or Publication ........................................................................ 50 
 
14.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 51 
14.1 
Regulatory Considerations .................................................................................................................... 51 
14.2 
Inclusivity in Research .......................................................................................................................... 51 
14.3 
Obtaining Informed Consent ................................................................................................................. 52 
14.4 
Discontinuation of the Trial .................................................................................................................. 53 
14.5 
Retention of Patient Records and Study Files ....................................................................................... 53 
14.6 
Centre Performance Monitoring (All Sites) .......................................................................................... 54 
14.7 
On-Site Monitoring/Auditing Monitoring (All Sites) ........................................................................... 54 
14.8 
Case Report Forms ................................................................................................................................ 54 
 
15.0 
REFERENCES ...................................................................................................................................... 55 
 
 

 
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APPENDIX I -  
PERFORMANCE STATUS SCALES/SCORES ............................................................. 59 
APPENDIX II -  
DRUG DISTRIBUTION, SUPPLY AND CONTROL .................................................... 60 
APPENDIX III -  
DOCUMENTATION FOR STUDY ................................................................................ 61 
APPENDIX IV -  
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .................. 63 
APPENDIX V -  
THE TNM CLASSIFICATION OF MALIGNANT TUMOURS .................................... 64 
APPENDIX VI -  
QUALITY OF LIFE ASSESSMENT ............................................................................... 65 
APPENDIX VII -  
HEALTH UTILITIES ASSESSMENT ............................................................................ 74 
APPENDIX VIII -  EMERGENCY SITUATIONS AND COMPLIANCE..................................................... 80 
 
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 Canadian Cancer 
Trials Group (CCTG). 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.  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 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 CCTG. The foregoing shall not apply to disclosure required 
by governmental regulations or laws; however, I will give prompt notice to CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
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.227 
 
CENTRE: ___________________________________________ 
 
 

 
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TREATMENT SCHEMA 
 
This is an academic open-label, multicentre, phase II/III randomized study in patients with malignant 
pleural mesothelioma (MPM) receiving first-line treatment for incurable advanced or metastatic disease. 
Patients will initially be randomized to one of 3 arms in 1:1:1 ratio, and then into one of 2 arms in a 1:1 
ratio (phase II part 2 and phase III). 
 
Patients will be stratified by histological subtype (epithelioid vs. other histology).  
 
Phase II Schema: 
 
 
 
 
 
ARM A N=42 
Cisplatin*/Pemetrexed 
 
 
 
 
 
Patients with untreated 
unresectable/metastatic 
MPM 
 Randomization 
1:1:1 
 
ARM B N=42 
Cisplatin*/Pemetrexed/Pembrolizumab → Pembrolizumab 
 
 
 
 
 
 
 
 
 
ARM C N=42 
Pembrolizumab 
 
 
Phase II/III Schema:  
 
 
 
 
 
ARM A N=220 
Cisplatin*/Pemetrexed 
Patients with untreated 
unresectable/metastatic 
MPM 
 
Randomization 
1:1 
 
 
 
 
 
 
 
 
 
 
ARM B N=220 
Cisplatin*/Pemetrexed/Pembrolizumab → Pembrolizumab 
 
* carboplatin is acceptable after CCTG approval 
 
 
 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
Phase II: 
• 
To evaluate whether pembrolizumab, alone or given to patients receiving standard 
chemotherapy, improves progression-free survival (modified RECIST 1.1 for mesothelioma 
(mRECIST)) in malignant pleural mesothelioma (MPM) compared to standard chemotherapy.  
 
Phase III: 
• 
To evaluate whether pembrolizumab improves overall survival when added to standard 
chemotherapy in malignant pleural mesothelioma (MPM). 
 
1.2 
Secondary Objectives 
 
Phase II/III: 
• 
To evaluate the tolerability of pembrolizumab, alone or given to patients receiving standard 
chemotherapy. 
• 
To assess antitumour activity of pembrolizumab, alone or given to patients receiving standard 
chemotherapy including objective response rate (complete and partial response), using 
mRECIST. 
• 
To evaluate the quality of life impact of pembrolizumab, alone or given to patients receiving 
standard chemotherapy as measured by time from randomization to first deterioration in the 
three common MPM Quality of Life scales. 
• 
To evaluate whether pembrolizumab improves progression-free survival (mRECIST) when 
added to standard chemotherapy in malignant pleural mesothelioma (MPM). 
 
Phase III: 
• 
To evaluate the incremental cost effectiveness and cost utility ratios between arms. 
 
1.3 
Exploratory Objectives 
 
• 
To explore the predictive and prognostic value of PD-L1 expression and presence of 
inflammatory cell subsets within the tumour microenvironment. 
• 
To explore the predictive and prognostic value of exploratory blood-based biomarkers and 
genomic biomarkers. 
• 
To evaluate the quality of life impact of pembrolizumab, alone or given to patients receiving 
standard chemotherapy as measured by standard QoL analyses. 
• 
To assess antitumour activity of pembrolizumab, alone or given to patients receiving standard 
chemotherapy including immune (i) response rate (i-complete and i-partial response) using 
iRECIST modified for mesothelioma. 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Malignant Pleural Mesothelioma 
 
Malignant pleural mesothelioma (MPM) is a rare malignancy, with over 500 new cases diagnosed 
annually in Canada, [Canadian Cancer Statistics Report, 2015] and 3400 in the United States [Price 2009]. 
It is commonly associated with asbestos exposure. The incidence rates of mesothelioma are highest 
in Australia, Belgium and the United Kingdom, estimated at 30 cases per million [Bianchi 2007]. Due 
to the long latency period from initial exposure to asbestos and the presentation of MPM and 
continued use of asbestos in developing countries, the incidence of MPM will continue to rise 
around the world [Robinson 2005; Stayner 2013].  
 
Current Treatment Option and Outcome of Malignant Pleural Mesothelioma  
 
Patients who present with localized disease (stage I and some stage II) MPM, young age, good 
cardiac and respiratory function, good performance status and epithelioid subtype may be 
candidates for multimodality therapy with extrapleuropneumectomy, hemithoracic radiation and/or 
neoadjuvant chemotherapy [Sugarbaker 1999; Neragi-Miandoab 2008; de Perrott 2009; Cho 2014]. Improved 
survival and possible cure were observed in this highly selected MPM patient population at the 
expense of toxicity.  
 
However, the majority of MPM patients are not candidates for multimodality therapy and 
therapeutics options are palliative in nature. MPM patients with good performance status and organ 
function treated with the combination of cisplatin and an antifolate (pemetrexed or raltitrexed) 
derive less than 3 months of overall survival benefit (OS) over cisplatin alone, resulting in a median 
OS of approximately 1 year [Vogelzang 2003; van Meerbeeck 2005].  
 
High microvessel density, a marker for angiogenesis has been demonstrated in mesothelioma 
samples and was correlated with poor prognosis [Ohta 1999]. In addition, concurrent expression of 
VEGFR and VEGF in mesothelioma samples suggested the role of angiogenesis in the pathogenesis 
of mesothelioma [Konig 1999; Strizzi L 2001]. Bevacizumab as a single agent [Jackman 2008] and multi-
targeted small molecules to VEGFR in both untreated and previously treated MPM showed at best 
modest clinical activity [Papa 2013; Campbell 2012; Laurie 2011; Nowak 2012; Jahan 2012; Dubey 2010]. 
Zalcman et al. reported a phase II/III trial of carefully selected patients with unresectable MPM 
treated with cisplatin/pemetrexed (up to 6 cycles) with or without bevacizumab at 15 mg/kg every 
3 weeks (until progression or intolerable toxicity) [Zalcman 2015]. The bevacizumab-arm 
demonstrated a moderate improvement in median OS to 18.8 months from 16.1 months (HR=0.76, 
p=0.0127) and median progression-free survival (PFS) to 9.6 months from 7.5 months (HR=0.61, 
p<0.0001). The bevacizumab treated patients experienced statistically higher incidence of toxicity, 
particularly grade 3 or 4 hypertension, increase in creatinine, hemorrhage and arterial or venous 
thromboembolic events. Quality-of-life was similar between the two treatment arms. Patients with 
hemoglobin < 140 g/L, WBC ≥ 8.3 and poor prognosis (EORTC prognostic index [Francart J 2009]) 
did not appear to derive benefit from the combination (HR approximately 1). A trial comparing 
cisplatin/gemcitabine with or without bevacizumab in MPM patients failed to show any 
improvement in median OS, PFS or response rate [Kindler 2012]; second-line pemetrexed was used 
in this trial. A single arm phase II study of carboplatin/pemetrexed in combination with 
bevacizumab at 15 mg/kg every 3 weeks demonstrated a median PFS of 6.9 months and median 
OS of 15.3 months, failing to meet its primary endpoint of demonstrating an improvement in 
median PFS from 6 to 9 months [Ceresoli 2013].  
Currently bevacizumab is not considered standard of care, is not approved by Health Canada, and 
is not funded in Canada, Italy, France or other countries for MPM.  
 

 
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Immune System as a Target for the Management of Malignant Pleural Mesothelioma 
 
MPM appears to be an immunogenic malignancy. Tumour infiltrating lymphocytes (TILs) in MPM 
tumour samples were first demonstrated to correlate with improved OS [Leigh 1982]. The presence 
of CD8+ T-cells in tumour samples from extrapleural pneumonectomy was associated with an 
improvement in OS, PFS and the absence of mediastinal nodal disease [Anraku 2008; Yamada 2010], 
while the presence of CD4+, CD25+ or CD45RO+ T cells were associated with poorer OS. 
FOXP3+ on CD8+ T-cells, a marker for suppression of CD8+ T-cells, was not prognostic [Anraku 
2008]. Mudhar et al. was not able to demonstrate prognostic significance of CD3 (pan-T-cell 
marker), CD45 (leukocyte common antigen), CD 20 (B-cell marker) and CD56 (NK cell marker), 
in 15 MPM samples [Mudhar 2002].  
 
In addition, there have been reports of spontaneous regression in MPM and long-term survival 
[Robinson 2001; Pilling 2007; Allen 2007]. Sterman et al. instilled single, escalating dose of IFN-beta gene 
containing adenovirus vector into the pleural cavity in 7 MPM patients and 3 patients with 
malignant pleural effusion. Seven out of 10 patients demonstrated INF-beta gene transfer and 
immune system activation. Four patients had FDG-PET changes suggesting benefit [Sterman 2010]. 
 
PD-L1/2 and PD-1 and Cancer 
 
Like any biological system, an activated immune system is tightly controlled to maintain 
homeostasis and thus prevent the occurrence of autoimmunity. Activation of the immune system 
by cancer cells is mediated through the activation of cytotoxic T-cells. These activated T-cells then 
migrate to the peripheral tissue to exert their anti-tumour effect. In the peripheral tissues, the 
interaction of PD-L1 and PD-L2 with PD-1 on cytotoxic T-cells negatively regulates these T-cells. 
This pathway has been extensively reviewed [Yao 2013; Chen 2013; Naidoo 2014].  
 
PD-L1 is expressed in tumour cells as well as other immune cells, including regulatory T-cells, B-
cell, myeloid derived suppressor cells, natural killer (NK) cells, antigen presenting cells (APC) as 
well as vascular endothelial cells, whereas the expression of PD-L2 is more limited to APC in the 
lymphoid tissue or lymphoid organs, mast cells and selected tumour types including pancreas, 
ovarian and esophagus [Zou 2008; Lee 2008; Leffers 2009; Hiraoka 2010; Nishimura 2000]. PD-L1 is thought 
to dampen unwarranted T-cell function in the peripheral tissues and PD-L2 is thought to control T-
cell activation in the lymphoid organs [Lee 2008].  
 
PD-L1 expression on tumour cells has been found to be associated with poor prognosis in a number 
of solid tumours. Kindler et al. reported 27% of MPM expressed PD-L1 either in the stromal cells 
or the tumour cells [Kindler 2014]. Two retrospective series [Mansfield 2014; Cedrés 2015] studied the 
relationship of PD-L1 expression and prognosis in MPM using 2 different immunohistochemistry 
antibodies (5H1-A3 and E1L3N) and cutoffs for PD-L1 positivity (> 5% and >1%), respectively. 
PD-L1 was expressed in 20-40% of MPM and was more common in patients with non-epithelioid 
subtypes and was associated with significantly poorer prognosis (median OS 5 months versus not 
reached, p<0.0001 and 4.8 versus 16.3 months, p=0.012, respectively). 
 
Pembrolizumab is an IgG4 kappa isotype antibody with stabilizing sequence alteration at the Fc 
domain to eliminate antibody directed cytotoxicity, targeting PD-1. Pembrolizumab has activity in 
a number of tumour types [Hamid 2013; Robert 2014; Garon 2015; Patnaik 2015; Robert 2015].  
 
 

 
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Alley et al. reported the preliminary result of pembrolizumab at 10 mg/kg every 3 weeks in 
previously treated MPM patients in a phase Ib study. The overall response rate was 28% with stable 
disease in 48% of patients. Sixty-one percent of MPM had some reduction in the tumour size. The 
median PFS and duration of response were 5.8 months and not yet been reached (range 10-40+ 
weeks), respectively. Durable responses were observed in epithelioid and sarcomatoid subtypes of 
MPM, the latter is often considered as less chemotherapy sensitive. There was no correlation 
between PD-L1 expression and response to pembrolizumab [Alley 2015].  
 
Given the single agent activity of pembrolizumab, we plan to conduct a multi-centre, randomized 
phase II study of pembrolizumab given alone or with standard chemotherapy vs. standard 
chemotherapy alone in patients with malignant pleural mesothelioma.  
 
Quality of Life  
 
Assessment of quality of life (QoL) in all patients is an important aspect in this trial evaluating a 
new therapy given to patients with MPM. Any possible survival gains from new therapies need to 
be assessed in terms of their QoL impact. Patients on the standard regimen of cisplatin/pemetrexed 
are expected to see changes in self-reported QoL parameters reflecting an improvement in disease-
related symptoms and temporary adverse effects specific to the chemotherapy, while overall QoL 
is maintained [Arnold 2015]. Those on cisplatin/pemetrexed plus pembrolizumab may see 
improvements in QoL if the combination is more effective, with the addition of specific adverse 
effects from the immune checkpoint inhibitor that may be highlighted in the pembrolizumab alone 
arm. However, it is possible that the pembrolizumab alone may be as effective as the 
cisplatin/pemetrexed with fewer adverse treatment effects. A patient perspective of the impact of 
treatment is felt to be an important part of this study. 
 
Health Economics  
 
The adoption and governmental/third party payer funding of new cancer therapeutics is dependent 
on the demonstration of cost effectiveness. Therefore, accurate prospective economic data for any 
new therapeutic is critical to assist decision makers regarding funding issues.  
 
A prospective economic evaluation will be conducted to determine the incremental cost-
effectiveness and cost-utility of adding immunotherapy to standard platinum combination 
chemotherapy from a government payer perspective, by prospectively collecting economic and 
resource utilization information during the phase III portion of the trial. As part of the economic 
evaluation in this study, patient preferences, or utilities, will be measured using the EQ-5D 
questionnaire [Brooks 1996]. The EQ- 5D self-administered questionnaire consists of two pages 
comprising the EQ-5D descriptive system and the EQ Visual Analogue Scale (VAS). The EQ-5D 
descriptive system comprises five dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and each dimension comprises five levels (no problems, 
slight problems, moderate problems, several problems and extreme problems). A unique EQ-5D 
health state is defined by combining one level from each of the five dimensions. The VAS records 
the respondent's self-rated health status on a vertical graduated (0-100) visual analogue scale. The 
EQ-5D is a validated instrument that has been used in population surveys and clinical trial settings. 
Analysis will be performed as detailed in the statistical section of the protocol (see Section 13).  
 
 
 

 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
Please consult the current pembrolizumab Investigator Brochure (IB) for additional details and the 
most up-to-date information.  
 
3.1 
Pembrolizumab 
 
3.1.1 
Name and Chemical Information 
 
Pembrolizumab is a human monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).  
 
3.1.2 
Chemical Structure 
 
Pembrolizumab is an IgG4/kappa immunoglobulin with a stabilizing S228P sequence alteration in 
the fragment crystallizable (Fc) region. The antibody is heterogeneously glycosylated at asparagine 
297 within the Fc domain of each heavy chain, yielding molecular weights typically ranging 
between 148.9 and 149.5 KDa, depending on the attached glycan chains. 
 
3.1.3 
Mechanism of Action 
 
Pembrolizumab with high affinity and specificity binds to human PD-1 and blocks the interaction 
between PD-1 and its ligands: PD-L1 and PD-L2. In vitro studies, pembrolizumab strongly 
enhances T-lymphocyte immune responses by modulation of interleukin-2 (IL-2), tumour necrosis 
factor alpha (TNFα) and interferon gamma (IFNγ) levels. Pembrolizumab potentiates existing 
immune responses only in the presence of antigen and does not non-specifically activate T-cells. 
Pembrolizumab does not induce antibody-dependent cell-mediated cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC).  
 
3.1.4 
Clinical Trials 
 
The profile of adverse events (AEs) and the spectrum of AE severity are similar across trials in 
both monotherapy and combination trials. The most common treatment related adverse events (all 
grades) were nausea, fatigue, diarrhea, cough, neutropenia, thrombocytopenia, anemia, decreased 
appetite, pruritus, rash, constipation, dysphonia, arthralgia, headache, vomiting, asthenia, pyrexia, 
back and abdominal pain, and increased AST and ALT. Hypothyroidism occurred in 237 (8.5%) 
of 2799 patients receiving pembrolizumab, including Grade 2 (6.2%) and Grade 3 (0.1%) 
hypothyroidism. 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile. Important 
identified risks for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, thyroid disorders (hypothyroidism and hyperthyroidism), hepatitis, hypophysitis, Type I 
diabetes mellitus, uveitis, and nephritis. After a recent review of data, events newly characterized 
as identified risks also include pancreatitis, myositis, and severe skin reaction; these are included 
in the reference safety information below. The majority of immune-mediated adverse events were 
mild to moderate in severity, were manageable with appropriate care, and rarely required 
discontinuation of therapy. 
 
 

 
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3.1.5 
Pharmaceutical Data 
 
Supplied: 
Pembrolizumab is provided as a sterile, non-pyrogenic aqueous solution supplied in single-use 
Type I glass vials containing 100 mg/4 mL of pembrolizumab.  
 
It is formulated with L-histidine as a buffering agent, polysorbate 80 as a surfactant and sucrose as 
a stabilizer/tonicity modifier and may contain hydrochloric acid and/or sodium hydroxide for pH 
adjustment (if necessary).  
 
Stability: 
The shelf life of pembrolizumab will be indicated on the vial label. 
 
Storage:  
Pembrolizumab must be stored at 2°C to 8°C.  
 
Route of Administration: 
The route of administration for pembrolizumab is intravenous.  
 
If needed pembrolizumab can be further diluted with normal saline or 5% dextrose in the 
concentration range of 1 to 10 mg/mL in IV containers made of polyvinyl chloride (PVC) or non-
PVC material. Diluted pembrolizumab solutions may be stored at room temperature for a 
cumulative period of 4 hours. This includes both the admixture solutions in IV bags and the duration 
of the infusion. Additionally IV bags can be stored at 2°C to 8°C for up to a cumulative time of 20 
hours. This recommendation is based on up to 24 hours of room temperature and up to 24 hours of 
refrigerated stability data of diluted pembrolizumab solutions in the IV bags.  
 
The solution should be administered intravenously over 30 minutes using a sterile, non-pyrogenic 
low-protein binding 0.2 to 5 μm in-line or add-on filter.  
 
3.1.6 
Rationale for Flat Dosing of Pembrolizumab 
 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). This dose is 
justified by: 
• 
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W); 
• 
Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 
mg Q3W across multiple indications, and; 
• 
Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumour (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg Q3W. 
 
 

 
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Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W 
versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 
3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 
and KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. The 
2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other tumour types 
including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumour type. These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation 
of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a PBPK analysis 
was conducted to predict tumour PD-1 saturation over a wide range of tumour penetration and PD-
1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 
saturation in both blood and tumour. 
 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics, and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected. 
 
3.2 
Cisplatin (and Carboplatin if used) 
 
Cisplatin and carboplatin are commercially available and approved for the treatment of patients 
with mesothelioma. This drug will not be supplied but should be dispensed from the centre’s 
pharmacy supply. Refer to package insert, product monographs and provincial formularies for 
further information.  
 
3.3  
Pemetrexed 
 
Pemetrexed is commercially available and approved for the treatment of patients with 
mesothelioma. This drug will not be supplied but should be dispensed from the centre’s pharmacy 
supply. Refer to package insert, product monographs and provincial formularies for further 
information.  
 
 

 
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4.0 
STUDY POPULATION 
 
This study is designed to include women and minorities, but is not designed to measure differences 
in intervention effects. 
 
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 malignant pleural mesothelioma. Patients must be 
eligible to receive standard chemotherapy with pemetrexed and cisplatin and have no 
contraindications to standard chemotherapy.  
 
4.1.2 
Patients must have unresectable advanced and/or metastatic disease, incurable by standard 
therapies. 
 
4.1.3 
All patients must have a cellular tumour block from their primary or metastatic tumour available 
and consent to release the block/recently cut slides for correlative analyses (See Section 11.0) and 
the centre/pathologist must have agreed to the submission of the specimen(s). 
 
4.1.4 
Presence of radiologically documented disease. At least one site of disease must be 
unidimensionally measurable* by mRECIST or RECIST 1.1 (see Section 8.0) as follows: 
 
CT scan (with slice thickness of ≤ 5 mm)  
≥ 10 mm  longest diameter  
Physical exam (using calipers)  
≥ 10 mm  
Lymph nodes by CT scan  
≥ 15 mm  measured in short axis  
 
Pleural rind as defined by Byrne et al [Byrne 2004]. 
 
* Consult CCTG if the patient does not have a measurable pleural rind; if RECIST 1.1 is used rather than 
mRECIST pleura is considered a non-target lesion and the patient may not be eligible. 
 
All radiology studies must be performed within 21 days prior to registration (exception: within 28 
days if negative). 
 
4.1.5 
Age ≥ 18 years.  
 
4.1.6 
ECOG performance status 0 or 1.  
 
 

 
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4.1.7 
Previous Therapy 
 
Cytotoxic Chemotherapy: 
• 
Patients must not have received prior chemotherapy for any stage of advanced/metastatic 
disease.  
• 
Patients who received previous (neo)adjuvant cisplatin-based systemic chemotherapy must 
have received the last dose of chemotherapy at least 12 months before registration. Please 
contact CCTG PRIOR to randomization for such patients. 
 
Other Anti-Cancer Therapy: 
• 
Patients may not have received targeted small molecule therapy, immunotherapies and viral 
therapies, biologic therapies and angiogenesis inhibitors for advanced/metastatic disease, or 
any prior immunotherapy for any stage of disease.  
 
Radiation: 
Patients may have had prior radiation therapy, but NOT to the thorax unless clear disease 
progression has been demonstrated and confirmed with CCTG. A minimum of 28 days must have 
elapsed between the end of radiotherapy and registration onto the study. Radiation must have 
involved < 30% of functioning bone marrow and there must be measurable disease outside the 
previously irradiated area (patients whose sole site of disease (for example pleural rind) is in a 
previously irradiated area are ineligible UNLESS there is evidence of progression, or new lesions 
have been documented, in the irradiated field). Please contact CCTG PRIOR to randomization if 
the patient has received prior thoracic radiation. Patients must have recovered from any acute toxic 
effects from radiation prior to registration. 
 
Previous Surgery: 
Previous major surgery is permitted provided that it has been at least 28 days prior to patient 
registration and that wound healing has occurred. 
 
4.1.8 
Laboratory Requirements (must be done within 7 days prior to registration). 
 
Hematology 
Absolute neutrophils  
≥ 1.5 x 109/L 
Platelets 
≥ 100 x 109/L 
Hemoglobin 
≥ 90 g/L* 
Chemistry 
Bilirubin 
≤ 1.5 x ULN (upper limit of normal)** 
AST and ALT 
≤ 2.5 x ULN  
Serum creatinine 
or: 
Creatinine clearance*** 
< 1.25 x ULN  
 
≥ 50 mL/min 
* 
Contact CCTG if patient is not decompensated, is asymptomatic and transfusion is not indicated.  
** If confirmed Gilbert’s, eligible providing ≤ 3 x ULN. 
*** Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by 
Cockcroft and Gault equation below: 
 
Females: GFR = 1.04 x (140-age) x weight in kg 
 
  
serum creatinine in μmol/L 
 
Males: GFR  
= 1.23 x (140-age) x weight in kg 
 
  
serum creatinine in μmol/L 
 
 

 
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4.1.9 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to registration in the trial to document 
their willingness to participate. Patients who cannot give informed consent (i.e. mentally 
incompetent patients, or those physically incapacitated such as comatose patients) are not to be 
recruited into the study. Patients competent but physically unable to sign the consent form may 
have the document signed by their nearest relative or legal guardian. Each patient will be provided 
with a full explanation of the study before consent is requested. 
 
4.1.10 Patients must be accessible for treatment, response assessment and follow-up. Patients registered 
on this trial must be treated and followed at the participating centre. This implies there must be 
reasonable geographical limits (for example: 1 ½ hour’s driving distance) placed on patients being 
considered for this trial. (Call the CCTG office (613-533-6430) if questions arise regarding the 
interpretation of this criterion.) Patients must agree to return to the participating centre for 
management of any adverse events which may occur through the course of the trial. This implies 
there must be reasonable geographical limits placed on patients being considered for this trial. Sites 
are encouraged to contact CCTG (or their respective Cooperative Group for sites outside Canada) 
for any questions regarding the interpretation of this criterion. Investigators must assure themselves 
the patients registered on this trial will be available for complete documentation of the treatment, 
response assessment, adverse events, and follow-up. 
 
4.1.11 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization.  
 
4.1.12 Women/men of childbearing potential must have agreed to use two highly effective contraceptive 
methods during the study and for six months after discontinuation. A woman is considered to be of 
"childbearing potential" if she has had menses at any time in the preceding 12 consecutive months. 
In addition to routine contraceptive methods, "effective contraception" also includes heterosexual 
celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) 
defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or 
vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to 
become heterosexually active during the time period for use of contraceptive measures outlined in 
the protocol, he/she is responsible for beginning contraceptive measures. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Section 5.0); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin (β-HCG) is 
high and partner is vasectomized, it may be associated with tumour production of hCG, as seen 
with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
Should a woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
4.1.13 Patient must be able (i.e. sufficiently fluent) and willing to complete the quality of life 
questionnaires. The baseline assessment must already have been completed. Inability (illiteracy, 
loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient 
ineligible for the study. However, ability but unwillingness to complete the questionnaires will 
make the patient ineligible. 
 
 

 
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4.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
4.2.1 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at doses more than 
10 mg prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days 
prior to the first and any dose of trial treatment. 
 
4.2.2 
Has active autoimmune disease that has required systemic treatment in the past 3 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs) or history of 
allogeneic transplantation. Replacement therapy (e.g. thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.  
 
4.2.3 
Must not have received a live vaccine within 30 days of planned start of study therapy. 
 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and 
are not allowed. 
 
4.2.4 
Patients with known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging for at least four weeks prior to the first dose of 
trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new 
or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. 
This exception does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
 
4.2.5 
Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have 
symptomatic cardiac dysfunction ( including cardiac ventricular arrhythmias requiring medication, 
history of 2nd or 3rd degree atrioventricular conduction defects) or who have had unstable angina 
congestive heart failure or myocardial infarction within the previous year. Patients with a 
significant cardiac history, this includes hypertension, even if controlled, should have a LVEF 
≥ 50%. 
 
4.2.6 
Patients with a history of other malignancies unless having undergone curative therapy (i.e. 
resection, radiation, etc.) and do not require concurrent anticancer therapy. 
 
4.2.7 
History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to pembrolizumab or any of the other chemotherapy agents. 
 
4.2.8 
Concurrent treatment with other investigational drugs or anti-cancer therapy. 
 
4.2.9 
Patients with serious illness or medical condition that would not permit the patient to be managed 
according to the protocol including, but 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) [note: testing in asymptomatic 
patients is not required] or tuberculosis). 
 
 

 
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• 
Known history of, or any evidence of active, non-infectious pneumonitis. 
• 
Any other medical conditions that might be aggravated by treatment. 
• 
Serious or non-healing wound, ulcer, or bone fracture. 
 
4.2.10 Patients with evidence of interstitial lung disease. 
 
4.2.11 Patients with severe/ uncontrollable tumor pain that requires radiation prior to starting on systemic 
therapy. 
 
4.2.12 Pregnant or lactating women. (N.B.: All women of childbearing potential must have a negative 
pregnancy test within 72 hours prior to registration). 
 
 

 
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5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT  
 
Required Investigations 
Pre-study 
(< 7 days 
prior to 
registration) 
Day 8 
for 
cycle 1 
only 
Day 1 each 
cycle, and 
as clinically 
indicated 
Every 6 
weeks for 3 
assessments 
then every 12 
weeks 
4 weeks after 
completion of 
all protocol 
therapy 
Post-treatment: Every 
12 weeks until 
confirmed PD, then 
every 24 weeks until 
death 1 
History and Physical Exam 
 
 
 
 
 
 
Including: height and weight, ECOG 
performance status, documentation of all 
measurable and non-measurable disease, 
clinical tumour measurements (if applicable); 
Vital signs: blood pressure, heart rate, 
temperature 
X 
 
X 
 
X 
 
Laboratory Procedures/Assessments* 
 
 
 
 
 
 
CBC, neutrophils, lymphocytes, platelets 
X 
X2 
X 
 
X3 
X3 
PTT, PT/INR (only for patients on 
anticoagulants) 
X 
X15 
X15 
 
X15 
X15 
Serum creatinine, (calculated creatinine 
clearance as required), bilirubin, ALP, AST, 
ALT, LDH, albumin, glucose, amylase4, 
lipase4, TSH5, CRP 
X16 
X2 
X 
 
X3 
X3 
Pregnancy Test6 
X 
 
X7 
 
 
 
Urinalysis 
X15 
 
X15 
 
 
 
Radiology 
 
 
 
 
 
 
Tumour Imaging (Chest/upper abdomen CT 
scan; other scans as necessary to document 
disease) 
X8 
 
 
X8 
X9 
X9 
Quality of Life10 
 
 
 
 
 
 
EORTC QLQ-C30 & QLQ-LC13 
X 
 
X 
 
X 
X10 
Health Economics (Phase III) 
 
 
 
 
 
 
Heath Utilities Index (EQ-5D 5L) 
X 
 
X 
 
X11 
X11 
Other Investigations 
 
 
 
 
 
 
EKG  
X15 
 
X15 
 
 
 
LVEF 
X12 
 
 
 
 
 
Archival Tumour Tissue  
X13 
 
 
 
 
 
Correlative Studies Blood Collection 
(plasma and serum) 
X14 
See Section 11.0 for details 
Adverse events 
X 
Continuously 
X1 
 
footnotes on next page … 
 
 

 
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* Pre-treatment blood draws and physical exams may be done two 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. 
1 Patients must be followed for 90 days after last dose of protocol therapy for any SAE or Event of Clinical Interest (See Section 9.0). 
Thereafter, only SAEs related to protocol therapy are reported. Other adverse events felt to be related to protocol therapy will be followed until 
resolved to ≤ Grade 2. Adverse Events to be evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0) (see 
Appendix IV).  
2 Only for first 12 pts in each arm (no longer applicable as of May 15, 2017). 
3 Required at 4 weeks. To be done additionally every 3 months thereafter to follow abnormal lab results felt related until resolved to ≤ Grade 2. 
4 It is preferable that both amylase and lipase are assessed. For sites where only 1 of these parameters is routinely measured then either lipase or 
amylase is acceptable. 
5 TSH to be done at baseline and every six weeks; If abnormal, T3 and T4 must be measured.  
6 For women of childbearing potential only (urine or serum test). Within 72 hours prior to registration. Pregnancy test (in women of childbearing 
potential), as part of Pre-Study Evaluation, may include an ultrasound to rule-out pregnancy. 
7 As clinically indicated in WOCBP 
8 To ensure comparability, baseline scans and subsequent scans to assess response must be performed using identical technique (i.e. scans 
performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast agent, and 
preferably the same scanner). Maintain schedule every 6 weeks even if cycles are delayed. 
9 To be done additionally every three months thereafter until confirmed relapse or progression for patients with CR, PR, SD response. If iUPD 
occurs, confirmatory scans must be performed at least 4 weeks, but no longer than 8 weeks, after iUPD was identified. 
10 Quality of Life Questionnaires will be completed at baseline, prior to each cycle, 4 weeks after completion of protocol therapy and at each 
follow-up visit. Short follow-up until confirmed progressive disease. Questionnaires to be completed up to and at time of confirmed 
progressive disease (if not done within 2 weeks prior to PD). 
11. The EQ-5D-5L will be completed at baseline, prior to each cycle, 4 weeks after completion of protocol therapy and at each follow up visit. 
Short follow up until confirmed progressive disease. Questionnaires to be completed up to and at time of confirmed progressive disease (if not 
done within 2 weeks prior to PD). 
12 Only if significant cardiac history (see Section 4.2.5) and for patients who develop persistent, confirmed T wave repolarization abnormality 
(inversion or flattening) and then if abnormal EKG or LVEF on treatment and/or clinically indicated. At investigator’s discretion for all other 
patients. Ejection fraction must be determined using the same technology used at baseline (ECHO or MUGA). Recommended within 7 days 
but up to 28 days permissible. 
13 Must be confirmed available prior to registration on ALL patients. Archival tissue submission should be sent at the same time that the baseline 
CRF is submitted for each patient. See Section 11.0 for details. 
14 After registration but before the first dose of study treatment. 
15. Only at baseline and thereafter as clinically indicated. 
16. Electrolytes only in phase II. 
 
 

 
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6.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
6.1 
Entry Procedures 
 
All registrations and 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 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.227 trial 
specific web-site. If sites experience difficulties accessing the system and/or randomizing patients 
please contact the help desk (link in EDC) or the IND.227 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.227) 
• 
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 
• 
BSA, height and weight  
• 
stratification factors  
 
6.2 
Stratification 
 
Subjects will be stratified at the time of randomization by: 
• 
Histological subtype: 
− 
epithelioid 
− 
other histological subtypes 
 
6.3 
Randomization 
 
Randomization will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission  (including the completion and submission of questionnaires such as 
QoL) 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. 
 
 

 
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7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
registration. 
 
Pemetrexed and cisplatin will be administered after pembrolizumab at the doses specified below. 
A maximum of 6 cycles will be administered based on ASCO guidelines which recommend 4-6 
cycles [Kindler 2018].  
 
Administration and hydration will be performed according to the product monograph as well as 
national, provincial and local guidelines. Patients must be informed of the need to discontinue non-
steroidal anti-inflammatory drugs (NSAIDs) and other nephrotoxic drugs and be given standard 
vitamin supplementation.  
 
Doses will be reduced for hematologic and other adverse events. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity. Adverse events will be graded 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (see Appendix IV). 
Investigators must consult the product monographs for each chemotherapy agent, or follow their 
local or provincial formulary guidelines for dose modifications.  
 
Alternatively, standard protocols are available on the Cancer Care Ontario website: 
https://www.cancercare.on.ca/toolbox/drugformulary. 
 
Patients should receive standard premedication according to the product monograph and local and 
provincial formulary guidelines:  
• 
antiemetics  
• 
hydration (for cisplatin)  
• 
vitamin supplementation for pemetrexed (both starting ≥ 1 week prior to pemetrexed 
administration) continue throughout and 3 weeks after last dose of pemetrexed:  
− 
Vitamin B12 (1000 mcg IM every 9 weeks);  
− 
folic acid 0.4-1 mg PO OD  
• 
steroid prophylaxis (for pemetrexed):  
− 
dexamethasone 4 mg PO BID for 3 days starting day before chemotherapy suggested for 
rash prophylaxis 
 
Note:  The use of steroids for the prevention and treatment of emesis should be minimized where 
feasible and other effective anti-emetics used where possible. If emesis is well controlled, 
investigators should consider reducing or discontinuing steroids (above that given for rash 
prophylaxis) for subsequent cycles.  
 
Note:  Contact CCTG if cisplatin is contraindicated. The substitution of carboplatin (AUC 5-
6) for cisplatin is permitted on a case-by-case basis but only after review and approval by 
CCTG. 
 
 

 
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Note:  For pembrolizumab sites should make every effort to target infusion timing to be as close 
to 30 minutes as possible. However, given the variability of infusion pumps from site to 
site, a window of -5 minutes and +10 minutes is permitted (i.e. infusion time is 30 minutes: 
-5 min/+10 min). 
 
Arm A 
Agent(s) 
Dose 
Route 
Schedule 
Pemetrexed 
500 mg/m2 
IV 
Day 1 every 21 days for 6 cycles 
Cisplatin 
75 mg/m2 
IV 
Day 1 every 21 days for 6 cycles 
 
Arm B 
Agent(s) 
Dose 
Route 
Schedule 
Pembrolizumab 
200 mg* 
IV 
Day 1 over 30 min every 21 days for a total of 2 years 
Pemetrexed 
500 mg/m2 
IV 
Day 1 every 21 days for 6 cycles 
Cisplatin 
75 mg/m2 
IV 
Day 1 every 21 days for 6 cycles 
* 
Patients who have discontinued pembrolizumab for toxicity may NOT restart pembrolizumab even after they 
complete standard chemotherapy. 
 
Arm C (Phase II only) 
Agent 
Dose 
Route Duration 
Schedule 
Pembrolizumab 
200 mg* 
IV 
30 min 
Day 1 every 21 days for a total of 2 years 
* 
Patients who have discontinued pembrolizumab for toxicity may NOT restart pembrolizumab. 
 
7.1 
Premedication  
 
For patients receiving pembrolizumab the use of premedication (e.g. for nausea) or hypersensitivity 
prophylaxis is not required. Management of symptoms should take place as necessary (see Section 
7.3 below). See Section 7.3.1 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). 
 
7.2 
Patient Monitoring  
 
Patients will be monitored during the infusion and after the infusion with assessment of vital signs 
as per local procedures. A 1-hour observation period is recommended after the first infusion of 
pembrolizumab-containing regimen. 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 pembrolizumab-containing regimen infusion).  
 
Guidelines for management of infusion-related reaction are summarized in Section 7.3.1. 
 
All patients should be closely monitored according to guidelines in Section 7.3 and be advised to 
contact the treating centre in the case of significant toxicities. 
 
 

 
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7.3 
Dose Interruptions and Management of Toxicity  
 
The major toxic effects of pembrolizumab that are anticipated to limit dosing are 
hypersensitivity/infusion related reactions and possible class related immune related AEs (irAEs), 
based on the mechanism of action of pembrolizumab leading to T-cell activation and proliferation. 
These adverse events may occur shortly after the first dose or several months after the last dose of 
treatment. Potential immune related AEs include pneumonitis, colitis, thyroid disorders 
(hypothyroidism/hyperthyroidism), hepatitis, hypophysitis, Type I diabetes mellitus, uveitis, 
nephritis, pancreatitis, myositis, myocarditis, sarcoidosis, encephalitis and severe skin reaction 
(dermatitis). Mild irAEs are usually treated symptomatically and do not require dosing delays or 
discontinuation. Higher grade and persistent lower grade irAEs typically necessitate withholding 
or discontinuing treatment and administration of systemic steroids or other immunosuppressive 
agents (such as tumour necrosis factor blockers), when systemic steroids are not effective. Early 
recognition of irAEs and initiation of treatment are critical to reduce the risk of complications, since 
the majority of irAEs are reversible with the use of steroids and other immune suppressants. See 
Section 7.3.2 for supportive care guidelines, including use of corticosteroids. 
 
If an irAE is suspected, a thorough evaluation should be conducted in an effort to possibly rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes prior to diagnosing an irAE. 
Serological, immunological, and histological (biopsy) data should be considered to support the 
diagnosis of an immune-related toxicity. 
 
The next cycle should not be given until the laboratory criteria in Section 4.1.8 are met and 
resolution of all clinically significant drug related toxicity to ≤ grade 2 and steroids, if used, have 
been tapered to ≤ 10 mg prednisone equivalents per day.  For patients continuing on 
pembrolizumab alone, dosing may be based on requirements of the current product monograph (for 
example for renal function) for pembrolizumab but must be discussed with CCTG. 
 
The guidelines that follow outline dose adjustments for several of these toxic effects. If a patient 
experiences several adverse events and there are conflicting recommendations, please use the 
recommended dose adjustment that requires the greatest dose hold or discontinuation. Adverse 
events will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
(see Appendix IV).  
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g. elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 
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 pembrolizumab along with appropriate continuing supportive care.  
 
In addition to the dose adjustments shown in this section, the following are recommended:  
• 
Patient evaluation to identify any alternative etiology.  
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature should be 
considered to be immune-related.  
 
 

 
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• 
Symptomatic and topical therapy should be considered for low-grade events.  
• 
For persistent (greater than 3 to 5 days) low-grade (Grade 2) or severe (Grade ≥ 3) events 
promptly start prednisone PO 1-2 mg/kg/day or IV equivalent.  
• 
If symptoms recur or worsen during corticosteroid tapering (> 4 weeks of taper), increase the 
corticosteroid dose (prednisone dose [e.g. up to 2-4 mg/kg/day or IV equivalent]) until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate.  
• 
More potent immunosuppressive drug (refer to individual sections of the immune related 
adverse event for specific type of immunosuppressive drugs) 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. 
 
7.3.1 
Infusion Reactions 
 
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. Table 1 below shows treatment guidelines for subjects who 
experience an infusion reaction associated with administration of pembrolizumab. 
 
 
 

 
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Table 1: Treatment Guidelines for Treatment of Infusion Reaction Associated With 
Administration of Pembrolizumab. 
 
Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g. antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for ≤24 
hrs 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment. 
Participant may be 
premedicated 1.5h (±30 
minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g. renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov 
 
 

 
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7.3.2 
Immune Related Adverse Events 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and summarized in Table 2.  
 
The next cycle should not be given until the laboratory criteria in Section 4.1.8 are met and 
resolution of all drug related toxicity to ≤ grade 2 and steroids, if used, have been tapered to ≤ 10 mg 
prednisone equivalents per day. Discuss with CCTG if clarification is required. 
 
Table 2: Dose Modification Guidelines for Drug-Related Adverse Events 
 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. 
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does 
not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last treatment.  
3. 
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after 
the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAEv4.0) 
Action With 
Pembrolizuma
b 
Monotherapy, 
Coformulations 
or IO 
Combinations 
Corticosteroid and/or 
Other Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
• 
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Recurrent 
Grade 
2 
or 
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea 
/ 
Colitis  
Grade 2 or 3 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
• 
Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) 
and of bowel perforation (ie, 
peritoneal signs and ileus) 
• 
Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis 
• 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid 
and electrolytes should be substituted 
via IV infusion. 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
 
 
 
• 
 
• 
 

 
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irAEs 
Toxicity 
Grade 
(CTCAEv4.0) 
Action With 
Pembrolizuma
b 
Monotherapy, 
Coformulations 
or IO 
Combinations 
Corticosteroid and/or 
Other Therapies 
Monitoring and Follow-up 
AST / ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 0.5-
1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable) 
Grade 3 or 4  
Permanently 
discontinue 
• 
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
T1DM 
or 
Hyperglycem
ia 
New 
onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold a 
• 
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
• 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
• 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
• 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue a 
Hyperthyroid
ism  
Grade 2 
Continue 
• 
Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and symptoms of 
thyroid disorders 
Grade 3 or 4 
Withhold or  
Permanently 
discontinue a 
Hypothyroidi
sm 
Grade 2-4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per 
standard of care 
Monitor for signs and symptoms of 
thyroid disorders 
 
 

 
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irAEs 
Toxicity 
Grade 
(CTCAEv4.0) 
Action With 
Pembrolizuma
b 
Monotherapy, 
Coformulations 
or IO 
Combinations 
Corticosteroid and/or 
Other Therapies 
Monitoring and Follow-up 
Nephritis and 
renal 
dysfunction 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper 
• 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
 
Grade 1  
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 
All 
Other 
irAEs 
Persistent 
Grade 2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 
Withhold 
or 
discontinue b 
Recurrent 
Grade 
3 
or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations 
is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab 
monotherapy, coformulations or IO combinations may be resumed. 
b Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, 
SJS, TEN and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be 
made to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
 
If after the evaluation the event is determined not to be related, the investigator does not need to 
follow the treatment guidance (as outlined below). Refer to Section 7.3.2 for dose modification. It 
may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
 
 
 

 
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7.3.3 
Other (Non-Immune Related) Adverse Events Related to Study Therapy 
 
CTCAE Grade 
Dose Adjustment 
Grade 1 
• None 
Grade 2 * 
• If clinically significant, hold/omit until resolution to ≤ Grade 1 or baseline and next 
planned infusion. 
Grade 3 
• Hold/omit until resolution to ≤ Grade 1 or baseline and next planned infusion. 
• For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or 
baseline within 14 days, resume at next planned infusion. 
• Otherwise, discontinue 
Grade 4 
• Discontinue. (Note for Grade 4 labs, decision to discontinue would be based on 
accompanying clinical signs/symptoms and as per Investigator’s clinical judgment and 
in consultation with CCTG). 
* Excluding: fatigue, alopecia; inadequately controlled/managed diarrhea, nausea or vomiting. 
 
7.4 
Duration of Therapy  
 
Treatment will continue until the criteria for removal from protocol treatment have been met (see 
Section 10.1). 
 
7.5 
Concomitant Therapy 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with the 
CCTG Clinical Trial team. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject’s primary physician.  
 
7.5.1 
Permitted Concomitant Therapy 
 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. All 
concomitant medication will be recorded on the case report forms (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. 
 
Growth factors may be used according to centre policy but cannot be used in place of protocol 
defined dose adjustments or delays. Please consult CCTG in the case of patients experiencing 
multiple delays as exceptions may be made for patients who are benefitting from protocol therapy. 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
Events of Clinical Interests as defined in Section 9.0. 
 
 
 

 
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7.5.2 
Not Permitted Concomitant Therapy 
 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• 
antineoplastic systemic chemotherapy or biological therapy, 
• 
radiation therapy, patients who require radiation must receive this prior to entry, bearing in 
mind this may preclude participation (see Section 4.1.7 and 4.2.11). Patients who require 
radiation on study are considered to have disease progression (contact CCTG if clarification is 
required). 
• 
live vaccines, 
• 
systemic glucocorticoids other than specified in this protocol. Note: Topical applications (e.g. 
rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-
articular) are allowed, as are oral dose of steroids equivalent to 10 mg or less of prednisone. 
 
 

 
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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for adverse events. All patients will be evaluable for adverse event evaluation from the 
time of their first treatment. 
 
8.1.2 
Evaluable for response. All patients who have received at least one cycle of therapy and have their 
disease re-evaluated will be considered evaluable for response (exceptions will be those who 
exhibit objective disease progression prior to the end of cycle 1 who will also be considered 
evaluable). Patients on therapy for at least this period and who meet the other listed criteria will 
have their response classified according to the definitions set out below [Seymour 2017]. 
 
Response and progression will be evaluated in this study using mRECIST, based on the revised 
international criteria (RECIST 1.1) proposed by the RECIST (Response Evaluation Criteria in Solid 
Tumours) committee as well as iRECIST guidelines [Armato 2018; Seymour 2017]. Investigators should 
note the different requirements for confirmatory scans as well as follow up for the two criteria. 
 
8.2 
Response and Evaluation Endpoints 
 
Response and progression on all arms of this study will be evaluated in this study using a modified 
RECIST (mRECIST) developed by Byrne and Nowak [Armato 2018; Byrne 2004] for assessment of 
response in malignant pleural mesothelioma. The modification is based on the international criteria 
proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee. In addition, 
as an exploratory endpoint, iRECIST  will be used. 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 confirmed disease progression has occurred. See 
8.2.1 for measurement of the pleural unidimensional measure.  
 
Note: consult CCTG if the patient does not have measurable pleural rind; if RECIST 1.1 is used 
primarily, note that pleura is considered a non-target lesion and the patient may not be eligible. 
 
8.2.1 
Pleural Tumour Measurement  
 
The pleural tumour thickness should be measured perpendicular to the chest wall or mediastinum. 
It should be measured in 2 positions at 3 different levels (‘cuts’) on the thoracic CT scan. The 
‘pleural unidimensional measure’ is the sum of these 6 measurements. The transverse cuts should 
be at least 1 cm apart, and must lend themselves to repeated measures for ease of re-assessment, be 
related to anatomical landmarks in the thorax. Cuts should preferably superior to left atrium or 
below the aortic arch. At reassessment, the pleural thickness must be measured at the same level 
and position. Fissural disease can be measured, using perpendicular to a tangent to pleura, once 
measured at baseline it must be oriented in the same direction for all subsequent scans. 
 
The pleural unidimensional measure is considered to be one organ (8.2.4) and only one value should 
be provided. 
 
 

 
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8.2.2 
Other Measurable Disease 
 
Other measurable tumour lesions (nodal, subcutaneous, lung parenchyma, solid organ metastases) 
are defined as those that can be accurately measured in at least one dimension (longest diameter to 
be recorded) as ≥ 20 mm with chest x-ray and as ≥ 10 mm with CT scan or clinical examination. 
Bone lesions are considered measurable only if assessed by CT scan and have an identifiable soft 
tissue component that meets these requirements (soft tissue component ≥ 10 mm by CT scan). 
Malignant lymph nodes must be ≥ 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. 
 
8.2.3 
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. 
 
8.2.4 
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. 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. 
 
8.2.5 
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”. Note: For this 
study, skin lesions will be considered as non-target lesions. 
 
 

 
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8.2.6 
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 < 10mm (Note: continue 
to record the measurement even if < 10mm and considered CR). Residual lesions (other than nodes 
< 10mm) thought to be non-malignant should be further investigated (by cytology specialized 
imaging or other techniques as appropriate for individual cases [Eisenhauer 2009]) before CR can be 
accepted. Confirmation of response is only required in non-randomized studies. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumour 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD. Confirmation of response is only required in non-
randomized studies. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND an 
absolute increase of ≥ 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 has increased sufficiently to merit discontinuation of treatment or where the 
tumour burden appears to have increased by at least 73% in volume. Modest increases in the size 
of one or more non-target lesions are NOT considered unequivocal progression.  
See Section 8.3. 
 
 

 
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Table 3: Integration of Target, non-Target and New Lesions into Response Assessment: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions* 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes <10mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least once ≥ 4 wks. 
from baseline  
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes* 
PD 
 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10mm 
No Target 
Non-CR/non-PD 
No 
Non-CR / 
non-PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes* 
PD 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
*  
Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may be continued 
pending further assessments  
 
8.3 
Immune-Related Response Assessment  
 
Overall response will also be assessed using iRECIST [Seymour 2017]. Immunotherapeutics may 
result in infiltration of immune cells leading to transient increase in the size in malignant lesions, 
or undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumour burden, 
or the appearance of new lesions, does not reflect true tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are designated 
with a prefix. iRECIST time-point and best overall responses will be recorded separately. 
 
Confirming Progression 
 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
 

 
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iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen as 
evidenced by one or more of the following: 
• 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
- 
Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum 
- 
Continued unequivocal progression in non-target disease with an increase in tumour burden 
- 
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions. 
• 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in table 2, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. 
 
New Lesions 
 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow 
clear differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of NLT should NOT be included in the sum of measures of original target lesions 
identified at baseline. Rather, these measurements will be collected on a separate table in the case 
record form. 
 
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. 
 
 
 

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

 
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Table 5: iRECIST Best Overall Response (iBOR) 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, iPR, 
iUPD, NE 
iCR, iPR, iUPD,  
NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, 
NE 
iCR 
iCR, iPR, iSD, 
iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, 
NE 
iPR, iSD, iUPD, 
NE, iCPD 
iPR, iSD, iUPD, NE, iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, 
NE 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, 
NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
• 
Table assumes a randomized study where confirmation of CR or PR is not required. 
• 
NE = not evaluable that cycle. 
• 
Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
• 
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each TPR 
but is not shown in the table for ease of presentation. 
 
8.4 
Response Duration (mRECIST and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(whichever is first recorded) are first met until the first date that recurrent or progressive disease is 
objectively documented, taking as reference the smallest measurements recorded on study 
(including baseline). 
 
8.5 
Stable Disease Duration 
 
Stable disease duration will be measured from the time of start of randomization until the criteria 
for progression are met, taking as reference the smallest sum on study (including baseline). 
 
8.6 
Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 

 
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8.6.1 
Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and 
≥ 10mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation 
by colour photography including a ruler to estimate the size of the lesion is recommended. If 
feasible, imaging is preferred. 
 
8.6.2 
Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions ≥ 20 mm on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.  
 
8.6.3 
CT, MRI. CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). Other specialized imaging or other 
techniques may also be appropriate for individual 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 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
 
8.6.5 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
 
8.6.6 
Tumour Markers. Tumour markers alone cannot be used to assess objective tumour response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response.  
 
8.6.7 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare cases 
if required by protocol (for example, residual lesions in tumour types such as germ cell tumours, 
where known residual benign tumours can remain). When effusions are known to be a potential 
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumour has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease. 
 
 
 

 
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9.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ or 
reportable Event of Clinical Interest (ECI) is used in the definitions which follow to describe those 
SAEs which are subject to expedited reporting to CCTG. Any event which meet these criteria must 
be reported from the time the patient is registered/randomized. All registered/ randomized patients 
must be followed for SAEs or ECIs until 90 days after last dose of protocol therapy and thereafter 
any related SAE. See below for reporting requirements.  
 
9.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events irrespective of relation to pembrolizumab or standard chemotherapy 
must be reported in an expedited manner (see Section 9.3 for reporting instructions). These 
include events occurring during the treatment period (until 30 days after last protocol treatment 
administration) and for these events considered related to pembrolizumab or standard 
chemotherapy at any time afterwards. 
• 
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 (see 9.3) 
− 
Pregnancy or exposure (pembrolizumab patients only see 9.3) 
− 
Diagnosis of a non MPM cancer  
− 
An overdose of pembrolizumab; defined as any dose of 1,000 mg or greater (≥ 5 times the 
indicated dose). No specific information is available on the treatment of overdose of 
pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. If an 
adverse event(s) is associated with the overdose of pembrolizumab, the adverse event(s) is 
also reported as a serious adverse event.  
− 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 
2X the upper limit of normal, as determined by way of protocol-specified laboratory testing 
or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the 
criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  
 
 

 
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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. 
 
Lack of efficacy (i.e. disease progression) is not considered to be an adverse event. 
 
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.227 section of the CCTG website (www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
IND.227 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.227 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).  
 
 

 
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9.3 
Pregnancy Reporting and Exposure Reporting  
 
9.3.1 
Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criteria 4.1.12. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy.  
 
9.3.2 
Pregnancy and Lactation Reporting 
 
The investigator is required to report to CCTG any pregnancy and lactation occurring during the 
study in female participants, and female partners of male participants.  
 
Pregnancies and lactations that occur from the time of treatment allocation/randomization through 
120 days following cessation of Sponsor’s product, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported. 
 
Such events must be reported within 24 hours to CCTG. 
 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
 
The investigator should report the pregnancy in a timely manner, within 1 working day of learning 
of the pregnancy without delay 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. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or terminated. 
The outcome of the pregnancy will be reported to the CCTG. If the outcome is a serious adverse 
experience (e.g. death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn) CCTG must be notified within 1 working day. All follow-
up reports must be submitted to CCTG in a timely manner. For pregnant partner of trial participant 
(and pregnant participants, if required by local policy), a copy of the signed signature page of the 
pregnancy follow-up consent must be submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca).  
 
 

 
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If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada and Other 
Regulatory Authorities Where the Trial is being Conducted  
 
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). 
 
CCTG will provide expedited reports of SAEs to the local sponsors 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). NCIN is responsible for reporting 
relevant events to the European authorities (EudraVig).  
 
9.5 
CCTG Reporting Responsibility to Merck & Co., Inc. 
 
Merck & Co., Inc. Global Safety will be notified of all protocol reportable serious adverse events, 
ECIs and pregnancy/lactation reports (as defined in Section 9.0) within one working day of receipt 
of report at CCTG. CCTG, as sponsor, will determine regulatory reportability. 
 
9.6 
Merck & Co., Inc. Reporting Responsibilities 
 
Merck & Co., Inc. will report all pembrolizumab regulatory reportable serious adverse events from 
non-CCTG trials (Safety Updates) to Health Canada and other Regulatory Authorities (when 
applicable) and will also provide line listings of regulatory reportable safety updates to CCTG in 
the format and within the timelines specified in the contract.  
 
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 
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.227 web-based safety monitoring utility. 
 
Canadian Sites: 
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.227 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. 
 
 

 
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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. 
 
Non-Canadian Sites: 
Investigators must notify their REB according to national and local policies. Additional reports 
may be required and will be provided by the local sponsor as appropriate.  
 
 

 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
10.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness that would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 7.0. 
• 
Tumour progression or disease recurrence as defined in Section 8.0. Note: investigators may 
continue treatment in the face of equivocal disease progression (iUPD) until the next 
assessment (see Section 10.2).  
• 
Request by the patient.  
• 
Completion of therapy as outlined in Section 7.0. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
 
10.2 
Duration of Protocol Treatment  
• 
Patients should continue standard chemotherapy for a maximum of 6 cycles in the absence of 
unacceptable toxicity. Contact CCTG if clarification is required. 
• 
Patients should continue pembrolizumab (with or without standard chemotherapy) for a 
maximum of two years.  
• 
Patients on pembrolizumab containing arms who progress with confirmed progression 
according to iRECIST will discontinue pembrolizumab as well as standard chemotherapy (if 
applicable) at the time progression is documented. 
• 
Patients on non-pembrolizumab containing arms who progress with progression according to 
RECIST 1.1 will discontinue standard chemotherapy at the time progression is documented, 
however, centres are strongly encouraged to ‘confirm’ progression after at least 4 weeks 
providing that subsequent anticancer treatment has not been initiated at that time.  
 
10.3 
Therapy After Protocol Treatment is Stopped 
 
Further treatment, if any is at the discretion of the investigator. No cross-over is planned.  
 
10.4 
Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy. Follow-up will be required 
every 3 months until relapse (see Section 5.0 for investigations to be performed) and every 6 
months until death. 
 
If patient is unable to return to participating centre for follow up, please contact CCTG to discuss 
possible options prior to considering ‘withdrawal of consent’ processes. Remote oversight allowing 
data submission may be feasible. Death Report will be required for all patients, due within 2 weeks 
of knowledge of death (see Appendix III - 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 
 
A central review of x-rays and/or scans is planned to confirm the date of progression. A blinded 
independent review (BICR) will be conducted. For purposes of reporting, the results of both local 
(investigator assessment of response) and BICR will be included. Sites must submit copies of all 
imaging (see Radiology Submission Manual). 
 
11.3 
Central Pathology Review 
 
Central pathology review is planned for this study. Pathology review may be done for all patients 
to confirm the histology and subtype of the previously diagnosed pleural mesothelioma. 
Pathologist(s) will review digital images from the original HE slides but may require submission 
of additional sections for staining and evaluation. Results of the central pathology review will not 
be provided to the originating institution, nor included in the patient record. 
 
 

 
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11.4 
Tissue Collection (Mandatory) 
 
Archival Tumour Block/Slides: 
The collection of a representative block of the diagnostic tumour tissue is an important part of this 
trial. Blocks or freshly cut slides will be sent to the CCTG tissue/tumour bank at Queen’s University 
in Kingston, Ontario. Tumour blocks will be the preferred material to collect, as one of the 
objectives will be to create tissue micro arrays. These will optimize the amount of tissue available 
to investigators and permit the preservation of the tumour block submitted. If, 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. 
 
The tissue will be used by researchers to better understand the nature of malignant pleural 
mesothelioma and how patients respond to treatment by the tests described in the protocol. Samples 
will be used for research purposes in this protocol 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 randomization to the trial the surgical/ histology number and/or patient initials. Material 
issued to researchers to perform the protocol defined tests will be anonymized and only identified 
by a coded number. 
 
Diagnostic pathology reports are received as part of the supporting documentation required for this 
trial. Receipt of these will initiate a request directly from the Queen’s Department of Pathology to 
pathology departments for a representative tumour block. 
 
Genetic Testing 
 
Planned testing for hereditary genetic defects predisposing to malignant disease will not be carried 
out. All patients on whom a diagnostic tumour block is collected will be aware of this retrieval and 
will have given their consent. 
 
Planned priority assays on tumour tissue include:  
• 
PD1, PD-L1, PD-L2.  
• 
Evaluation of lymphocyte, macrophage and other cellular infiltration including subtypes by 
immunohistochemistry (including TILs, CD8 and FOXP3).  
• 
Genomic profiling.  
 
11.5 
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, serum and plasma samples will be collected for planned studies from all patients. 
Samples will be used for research purposes in this protocol only and will not be sold. 
 
Exploratory assays include:  
• 
Mesothelin 
• 
Genomic profiling 
• 
HLA subtyping 
 
Detailed instructions for sample acquisition, preparation, and shipping are found in the IND.227 
lab manual. 
 
 

 
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12.0 
STATISTICAL CONSIDERATIONS 
 
12.1 
Objectives and Design 
 
The primary objective of this randomized phase II/III trial is to evaluate whether pembrolizumab, 
single agent or added to standard chemotherapy, improves overall survival (OS) in malignant 
pleural mesothelioma. Secondary objectives include evaluation of the safety and tolerability, 
progression free survival (PFS), objective response rate (ORR; using modified RECIST 1.1 for 
mesothelioma (mRECIST) for both PFS and ORR), quality of life, and health economic evaluation. 
Exploratory objectives include evaluating predictive and prognostic value of exploratory blood-
based biomarkers, additional QoL analyses, and evaluating efficacy using iRECIST. 
 
A randomized phase II study with progression free survival as the primary endpoint was planned 
be conducted first randomizing patients in 1:1:1 ratio by a minimization algorithm into the 
following three arms: cisplatin/pemetrexed (Arm A), cisplatin/pemetrexed/pembrolizumab 
(Arm B), pembrolizumab (Arm C) after stratification by histological subtype (epithelioid vs. other).  
 
A full safety review by the trial committee was performed when 12 patients have been randomized 
to each arm and followed for at least 6 weeks to ensure the tolerability and safety of combining 
pembrolizumab with chemotherapy.  
 
A phase II interim analysis based on 16 week disease control rate (DCR) was performed in 
November 2017 during the phase II trial, which included a total of 61 randomized patients (21 on 
Arm A, 19 on Arm B, and 21 on Arm C), to determine whether the trial should be stopped or 
whether one of or both Arm B and Arm C would be continued if the trial is not stopped. It was 
decided to discontinue Arm C based on the recommendation of CCTG Data and Safety Monitoring 
Committee after their review of interim analyses results. The trial was continued as a two-arm trial 
comparing Arm A to Arm B. The primary endpoint PFS for the original phase II trial became the 
secondary endpoint of the phase III trial and will be analyzed in the end of phase III trial together 
with other endpoints. 
 
12.2 
Study Endpoints and Analysis 
 
The primary endpoint of the phase III component of this trial is overall survival (OS), defined as 
time from randomization to the date of death from any cause.  If a patient has not died, OS will be 
censored on the date the patient last known as alive. All patients from Arms A and B, except those 
included in the phase II interim DCR analysis, will be included in the analysis based on the arm 
they were randomized. A stratified log-rank test adjusting for stratification factor at randomization 
will be the primary method to compare OS between Arms A and B. 
 
Progression free survival (PFS), a primary endpoint for phase II component and secondary endpoint 
for phase III component, is defined as time from randomization to the date when 
relapse/progression or death is first observed. If a patient has not relapsed/progressed or died, PFS 
will be censored on the date of last disease assessment. 
 
Objective response rate (ORR), a secondary endpoint for both phase II and III components of the 
study, is defined as the proportion of observed CR/PR among all randomized patients.  
 
 

 
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Response assessments:  
• 
mRECIST will be used for ORR and PFS while  iRECIST will be used for exploratory analyses 
of ORR and PFS. 
• 
ORR and PFS as assessed by blinded independent central review (BICR) will be used; ORR 
and PFS based on investigator assessment will be used as sensitivity analyses and will also be 
published by CCTG. 
 
ORR and PFS will be secondary endpoints to undergo formal statistical hypothesis testing, with 
details provided in Section 12.3 and 12.6. For PFS by BICR, the analysis method will be same as 
the primary endpoint of OS. For ORR by BICR, the stratified Miettinen and Nurminen’s method 
(stratified based on the stratification factor) will be used for the comparison between the two 
treatment groups. The difference in ORR and its 95% CI from the stratified Miettinen and 
Nurminen’s method with strata weighting by sample size will be reported. 
 
All patients who have received at least one dose of study treatment will be included in the safety 
analysis. The incidence of toxicities will be summarized by type of adverse event and severity. A 
Fisher’s exact test will be used as needed to compare toxicities between the two arms. 
 
12.3 
Sample Size and Duration of Study 
 
Phase II (original sample size calculation) 
 
The median PFS for Arm A was estimated as 7.5 months. To detect an increase of median PFS to 
11.5 months (HR=0.65) by one of the experimental treatment arms with 80% power at a 1-sided 
0.2 level, a minimum of 63 events would be required to observe from the three treatment arms. The 
required number of events would be observed by accruing up to 126 patients (42 per arm) during 
24 months of accrual with 8 months follow-up. 
 
Phase III 
 
The median OS for Arm A is estimated as 16 months. To detect an increase of median OS to 22.9 
months (HR=0.70) by Arm B with 90% power at a 2-sided 0.05 level, a minimum of 334 events 
would be required to observe from two treatment arms. The required number of events would be 
observed by accruing a total of up to 430 patients during 34 months of accrual with 31 months 
follow-up. If the median OS for Arm A is 13.5 months as originally estimated, the total duration of 
the trial may be shortened from 65 months to 59 months. Assuming 10 patients would drop out 
earlier, the final sample size of randomized patients would be 440 (220 per arm). 
 
If the success criterion for OS is met, 70% of its alpha (two-sided 0.035) will be passed to PFS by 
BICR and 30% of its alpha (two-sided 0.015) will be passed to ORR by BICR. The median PFS 
for Arm A is estimated as 7 months. To detect an increase of median PFS to 10 months (HR=0.70) 
by Arm B with 90.6% power at a 2-sided 0.035 level, a minimum of 376 events would be required 
to observe from two treatment arms with a total of 440 patients randomized, assuming an annual 
dropout rate of 13%. With 440 patients randomized, the power for ORR testing at a 2-sided 0.015 
level is approximately 87.5% to detect a 17% difference between an underlying ORR of 43% in 
arm A and 60% in arm B. 
 
 

 
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Note: A total of 520 patients will be enrolled: 440 to phase III, 40 were enrolled to Arm A and B 
and included in the interim DCR analysis of the phase II component and 40 patients were enrolled 
to Arm C before that arm was closed to accrual. The primary analysis population for the phase III 
analysis will exclude the 40 participants from the phase II Arms A and B that were included as part 
of the phase II interim analysis. Arm C patients are also excluded. 
 
12.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported bi-annually at investigators' meetings.  
 
The CCTG DSMC will review progress, safety (including SAEs and fatal SAEs) and planned 
interim analyses bi-annually. 
 
12.5 
Interim Analysis 
 
Phase II 
 
An interim analysis was performed when 22 patients on each treatment arm had been evaluated for 
16 weeks disease control (DC) status (percentage of patient’s with CR, PR and SD at 16 weeks). If 
the DC rate in Arm B or C was no worse than the control arm (Arm A), we would continue to full 
accrual. Otherwise, the accrual to the arm with DC rate worse than Arm A will be stopped. If the 
DC rates in both Arms B and C were worse than the control arm, the trial would be stopped. 
Assuming a 70% DC rate on control arm (Arm A) at 16 weeks, if the DC rate in one of the 
experimental arms is 16 % or better we would have an 80% chance of proceeding to trial with at 
least one experimental arm. 
 
Phase III  
 
The interim efficacy analysis will be conducted on OS, PFS and ORR 11 months after last patient 
is randomized.  
 
Early termination will be considered when the two-sided p-value of the stratified log-rank test for 
the comparison of OS between two treatment arms is significant as indicated by the methodology 
of Lan-DeMets with O’Brien-Fleming type boundaries. The nominal significant value for the final 
analysis of OS will be adjusted based on actual number of events observed to ensure the overall 
type I error of OS hypothesis testing is controlled at a two-sided 0.05 level. 
 
12.6 
Multiplicity 
 
The trial uses the graphical method of Maurer and Bretz [Mauer 2013] to control multiplicity for 
multiple hypotheses as well as interim analyses. Figure 1 shows the initial two-sided α allocation 
for each hypothesis in the ellipse representing the hypothesis.  
 
 

 
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PFS by BICR will be tested only when the hypothesis test for OS is significant, either at time of 
the OS interim analysis or  the final analysis. The stratified log-rank test for the comparison of PFS 
between the two treatment arms will be used to indicate the statistical significance using the 
methodology of Lan-Demets with O’Brien-Fleming type boundaries. In the scenario that PFS 
events accrue slower than expected, and the observed number of events is less than the expected 
number of events, the final analysis for PFS will use the remaining Type I error that has not been 
spent at the interim analysis. The nominal significance value for the interim and final analyses of 
PFS will be adjusted based on the actual number of events observed to ensure that the type I error 
of testing PFS upon success of the OS hypothesis testing is controlled at a two-sided 0.035 level.  
 
ORR by BICR will be tested at the interim analysis at 0.015 alpha level (2-sided) if OS hypothesis 
is rejected at the interim analysis. Note that if the OS hypothesis is not rejected at the interim 
analysis but at the final analysis, then the 0.015 alpha (2-sided) will be rolled over to ORR at the 
final analysis, but the test statistics previously computed at time of the interim analysis for the ORR 
hypothesis will be used for inferential testing to ensure that the type I error of testing ORR upon 
success of the OS hypothesis testing is controlled at a two-sided 0.015 level.  
 
When the PFS hypothesis is rejected, its alpha can be further passed to ORR to be tested at the full 
two-sided 5% level; conversely, when the ORR hypothesis is rejected, its alpha can be further 
passed to PFS to be tested at the full two-sided 5% level.  
 
The overall type I error of the trial is strictly controlled at a two-sided 0.05 level. 
 
Figure 1 Multiplicity Graph for Type I Error Control 
 
 

 
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12.7 
Quality of Life Analysis  
 
The quality of life (QoL) of patients will be assessed using the EORTC QLQ-C30 core 
questionnaire [Aaronson 1993] and the lung cancer module (QLQ-LC13) [Bergman 1994]. Both 
instruments have been used extensively in studies involving patients with MPM, and in clinical 
trials assessing immune checkpoint inhibitors in the setting of non-small cell lung cancer. 
 
The EORTC QLQ-C30 [Aaronson 1993] is a self-administered cancer specific questionnaire with 
multi-dimensional scales. It consists of both multi-item scales and single item measures, including 
five functioning domains, a global quality of life domain, three symptom domains and six single 
items. For each domain or single item measure a linear transformation will be applied to standardize 
the raw score to range between 0 and 100. The QLQ-LC13 lung cancer module [Bergman 1994] 
includes questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and 
site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy and 
alopecia) and pain medication. The validity and reliability have been studied by the EORTC Study 
Group on Quality of Life. The EORTC QLQ-C30 and module will be scored according to the 
EORTC QLQ-C30 Scoring Manual, and analyzed accordingly.  
 
Both the EORTC QLQ-C30 and QLQ-LC13 have demonstrated validity in patients with MPM 
[Nowak 2004]. In patients treated with platinum-based combination chemotherapy, there are no issues 
with floor or ceiling effects for symptoms typically associated with pleural-based disease. Fatigue 
is a common complaint but may not change much on treatment. Also common, and more obviously 
directly related to tumour location, are cough, dyspnea, and pain. 
 
The primary endpoint of the QoL analysis is defined as the time from baseline to first deterioration 
in the following three common MPM symptoms: cough (Question 1 in QLQ-LC13), dyspnea 
(Question 8 in QLQ-C30), and chest pain (QLQ-LC-13, item 10). Patients will be considered as 
deteriorated for a given symptom if their change score from baseline was 10 points or worse at any 
time-point after baseline with a confirmation by a subsequent visit of a 10 point or worse 
deterioration. For each symptom, all patients who have a baseline and at least one follow-up QOL 
assessment for this symptom will be included in the time-to deterioration analysis. Patients will be 
censored at the time of the last QOL questionnaire completion if they had not deteriorated before 
that. The log-rank test will be the primary method to compare the time to deterioration in MPM 
symptoms between the two treatment arms. Time to deterioration in each of MPM symptoms will 
also be compared similarly and the Hochberg procedure [Hochberg 1988] will be used to adjust the P 
values of the log-rank tests for these three comparisons.  
 
Changes in the quality of life scores while on treatment versus baseline will be examined using 
descriptive statistics and the standard CCTG QoL response analysis. Specific time points will be 
checked to explore treatment side effect on patients QoL, and the benefit of the study treatment. In 
addition, baseline scores will be compared using a Wilcoxon rank sum test, and a pattern mixture 
model [Little 1995] identifying drop-out patients as a special category, will be performed to evaluate 
the effect of missing data. PRO compliance summary, including completion and compliance rates 
of QLQ-C30 and LC13 will be described for patients with at least one dose of study treatment and 
at least one QOL assessment. Additional analyses will be conducted using CCTG standard analysis 
method [Osoba 2011]. 
 
 

 
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12.8 
Economic Analysis 
 
The purpose of the economic evaluation is to determine the incremental cost-effectiveness and cost-
utility of pembrolizumab added to standard chemotherapy from a government payer perspective, 
over a lifetime time horizon by prospectively collecting economic and resource utilization 
information during the clinical trial. Medical costs will be censored using methods previously 
described [Bang 2002].  
 
The objectives are:  
a) determine an incremental cost effectiveness ratio reported as a cost per life-year (LY) gained 
of pembrolizumab plus standard chemotherapy versus chemotherapy alone. The mean 
incremental survival using the restricted Kaplan Meier method and overall cost per patient for 
each of the two study treatment arms will be calculated to determine the addition cost per life-
year gained. 
b) determine an incremental cost utility ratio as a cost per quality-adjusted life-year (QALY) 
gained of pembrolizumab plus standard chemotherapy versus chemotherapy alone. Preference 
weights for comparator arms will be determined through the Canadian and European Valuation 
of the EQ-5D-5L Health States [Xie 2016; Devlin 2017], with EQ-5D scores taken directly from 
the study database. Quality-adjusted survival in the two treatment arms will be generated by 
multiplying the utility value by the amount of time spent in that utility state. The mean 
incremental cost per QALY between treatment arms will be calculated.  
 
The robustness of the model results will be assessed using one-way and multi-way sensitivity 
analyses. Major drivers of medical care costs, namely hospitalization, immunotherapy drug 
acquisition cost and survival, will be varied ± 20%, to examine the impact on the base-case 
incremental cost effectiveness ratios (ICERs). Patient preferences will also be varied across an 
acceptable range. A cost-effectiveness acceptability curve will be generated through bootstrapping 
samples. The economic data analysis will only include data from groups/regions that participate in 
the economic study. The CCTG and ISPOR recommendations for Good Research Practices for 
Cost-Effectiveness Analysis Alongside Clinical Trials will be followed [Mittmann 2014; Ramsey 2015]. 
Relevant subgroup analyses will be performed for clinical or biomarker-defined populations that 
benefit most from the novel therapy in the clinical trial. The net monetary benefit approach may be 
used as an alternative in the case of very small gains in QALY or OS.  
 
 

 
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13.0 
PUBLICATION POLICY 
 
13.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
13.1.1 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(s) will generally be the chair(s) of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group and National Cancer 
Institute Naples (NCI Naples) and IFCT 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. 
 
13.1.2 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)." 
 
13.2 
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). 
 
13.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by National 
Cancer Institute, Naples (NCI Naples), other participating Groups, 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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14.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
14.1 
Regulatory Considerations 
 
All institutions must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
In Canada 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). 
 
Outside of Canada this trial is being conducted by academic groups who will act as sponsors and 
obtain all necessary approvals (regulatory, REB) for the conduct of an academic clinical trial in 
their countries.  
 
14.2 
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).  
 
 

 
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Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation.  
 
14.3 
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 certified 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.  
 
14.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up consent form will not be required by 
CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure 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). 
 
 

 
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Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 
 
Obtaining Consent for Research on Children  
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian.  
 
For reporting an exposure, the parent/guardian is required to sign an “Exposure Follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
14.4 
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. 
 
14.5 
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/Principal 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.  
 
In Canada 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.  
 
In other countries the local sponsor Group will advise participating sites of the required period that 
essential documents must be retained according to national regulations.  
 
 
 

 
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14.6 
Centre Performance Monitoring (All Sites) 
 
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. 
 
14.7 
On-Site Monitoring/Auditing Monitoring (All Sites) 
 
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). 
 
Your site may be subject to an inspection by the Health Canada Inspectorate or other regulatory 
agencies. 
 
The above mentioned documentation, in addition to any submitted source documents, may be 
accessed remotely in the event of a public health emergency either through remote access to 
Electronic Medical Records or through a secure file sharing portal. 
 
14.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates are to be found in Appendix III. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except. 
For details of accessing the EDC system and completing the on-line Case Report Forms please refer 
to the “Registration/Randomization and Data Management Guidebook” posted on the IND.227 area 
of the CCTG web-site (www.ctg.queensu.ca). 
 
 

 
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15.0 
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Chen DS et al. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10.  
Cho BC et al. A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" 
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Dubey S et al. A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group 
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Eur J Can 2009;45:228-247. 
 
 

 
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Francart J et al. A prognostic index for progression-free survival in malignant mesothelioma with application to 
the design of phase II trials: a combined analysis of 10 EORTC trials. Eur J Cancer 2009;45:2304-11. 
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Hamid O et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 
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Jackman DM et al. Erlotinib plus bevacizumab in previously treated patients with malignant pleural 
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(CALGB 30107). Lung Cancer 2012;76(3):393-396.  
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gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol 
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Kindler HL et al. T-cell inflamed phenotype and PDL1 expression in malignant mesothelioma. J Clin Oncol 
32:5s, 2014 (suppl; abstr 7589).  
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Clinical Practice Guideline. J Clin Oncol . 2018; 36:1343–1373. 
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malignant mesothelioma of the pleura. Eur J Surg Oncol 2002;28(5):564-565. 
Naidoo J et al. Immune modulation for cancer therapy. Br J Cancer 2014;111(12):2214-229.  
 
 

 
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Neragi-Miandoab S et al. Morbidity, mortality, mean survival, and the impact of histology on survival after 
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Sterman DH et al. A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for 
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van Meerbeeck JP et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with 
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477.  
For more information on the EQ-5D questionnaire, please go to website www.euroqol.org. 

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

 
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APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Distribution 
Pembrolizumab will be supplied by Merck & Co., Inc. to the distributor, and sent from the distributor to 
participating centres for non-Canadian sites. For Canadian sites, drug will be distributed by BARL 
 
Drug Labelling 
Pembrolizumab supplies for this study will be labelled in accordance with Health Canada Regulations and 
Italian regulations. The labels contain all information required under the drug labelling regulations.  
 
Initial Drug Supply 
Once a centre is locally activated (following receipt and review of all required documentation), CCTG will 
authorize a start-up supply of Pembrolizumab to be shipped directly to the centre. The drug will be shipped 
to the centre within 7 working days of local activation. Drug accountability and drug re-order forms will be 
included with the drug shipment and are also available on the trial website for IND.227. 
 
Only pembrolizumab is supplied. Pemetrexed and cisplatin for this protocol are commercially available and 
sourced from the Canadian market and from the markets of other participating countries. 
 
Drug Ordering (Re-supply) 
Fax a copy of the pembrolizumab drug re-order form (available on the IND.227 website) to the distributer. 
 
Please allow sufficient time for shipment of drug. 
 
Drug Accountability 
The investigational products are to be prescribed only by the investigator and co-investigators 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 of the 
investigational product and for the disposition of the product (Drug Accountability Log). 
 
Drug Destruction or Return: 
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 and confirmed with 
CCTG. Documentation of destruction must be kept on file in the site pharmacy and is subject to on site 
monitoring/audit. 
 
**PLEASE NOTE ** 
DRUG FROM THIS SUPPLY IS TO BE USED ONLY  
FOR PATIENTS REGISTERED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite 
pharmacy, provided separate drug accountability records are maintained in each pharmacy. Investigational 
agent may NOT however, be transferred to pharmacies or physicians outside the participating centre. 
 
 

 
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APPENDIX III - 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 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.227 area of the CCTG website (www.ctg.queensu.ca). 
 
Electronic Folder 
Required at 
To be 
completed/submitted 
electronically 
Supporting Documentation Required1 
Mandatory Submission 
To be uploaded immediately after the 
report they refer to has been 
submitted electronically 
Submission On Request 
To be uploaded immediately  
after request 
Eligibility Checklist 
 
Within 2 weeks of 
randomization 
Signed consent form and 
tissue banking consent2, 
surgical reports, diagnostic 
pathology reports, protocol-
mandated baseline radiology 
reports, tumour 
measurement sheet (TMS), 
PD-L1 or genomic testing 
results (if done) 
ECG, LVEF, QOL, additional 
clinical, laboratory or imaging 
reports that may impact on 
decision regarding eligibility 
Baseline Report 
 
Within 2 weeks of 
randomization 
Correlative Studies 
Report 
(Tumour and 
Blood) 
 
Within 2 weeks of 
randomization, updated 
within 4 weeks of 
collection of correlative 
bloods  
 
 
Concomitant 
Medications Report 
Continuous 
running-log 
folder 
 
 
 
Treatment Report  
Every 21 days 
Within 2 weeks of end of 
cycle 
Radiology reports for 
protocol-mandated imaging 
and non-protocol mandated 
imaging if relevant to 
disease assessment, TMS 
Radiology reports for other 
non-protocol mandated 
imaging, ECG, LVEF, QOL, 
additional clinical laboratory 
or imaging reports that may 
inform evaluation of safety 
End of Treatment 
Report 
End of treatment 
Within 2 weeks of end of 
treatment 
 
 
4 Week Follow Up 
Report 
4 weeks from end 
of last cycle 
Within 2 weeks of 4 
weeks visit 
Radiology reports for 
protocol-mandated imaging, 
TMS 
Radiology reports for other 
non-protocol mandated 
imaging . additional clinical 
laboratory or imaging reports 
that may inform evaluation of 
safety  
Follow Up Report 
Every 3 or 6 
months (see 
Sections 5.0 and 
10.4) 
Within 4 weeks of visit 
Radiology reports for 
protocol-mandated imaging, 
TMS 
Radiology reports for other 
non-protocol mandated 
imaging copies of additional 
clinical, laboratory or imaging 
reports that may inform 
evaluation of safety 
Relapse/Progression 
Report 
Upon disease 
progression  
Within 4 weeks of 
progression 
Radiology reports for 
protocol-mandated imaging 
and pathology reports 
Radiology reports for other 
non-protocol mandated 
imaging 
table continues on next page ... 
 
 

 
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Electronic Folder 
Required at 
To be 
completed/submitted 
electronically 
Supporting Documentation Required1 
Mandatory Submission 
To be uploaded immediately after the 
report they refer to has been 
submitted electronically 
Submission On Request 
To be uploaded immediately  
after request 
Death Report 
When patient 
dies 
Within 4 weeks of 
patient’s death 
Autopsy report if performed 
Additional clinical, laboratory 
or imaging reports that may 
inform evaluation of cause of 
death 
SAE Report3 
At the time of 
event and 
reported to 
CCTG 
Within 1 working day 
 
Additional clinical, laboratory 
or imaging reports that may 
inform evaluation of safety 
including, admission and 
discharge summaries/notes 
1 
Scan and upload into the EDC Supporting Document Upload Tool - please refer to the slide set on the IND.227 website for guidance. Source 
documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, and/or serious adverse events. EDC 
forms submitted without supporting documentation are not considered submitted and will be reflected in the Centre Performance Index (CPI) 
as not submitted. All relevant patient identifiers, other than the CCTG patient ID assigned at enrolment,  and any other prohibited personal 
information must be fully and completely redacted (blacked-out) on all source documentation, per national and local privacy protection 
regulations and requirements. Acceptable methods include: 
• 
fully opaque sticker/tab placed over the identifiers prior to scanning 
• 
fully opaque black marker; prior to upload please ensure that the information is no longer visible on the scanned document  
• 
electronic black box placed over identifiers in PDF document that is subsequently printed and then scanned. (NOTE: do not send the 
unprotected PDF file with black boxes included as those can be moved / removed easily after opening) 
• 
electronic stripping of identifiers prior to upload (typically only possible for DICOM images) 
Note that supporting documents must include the participant’s trial code, CCTG patient serial number, and participant initials (or a two/three 
masking letter code assigned by your centre) 
2 
For Canadian centres: it is acceptable to submit only the signature page(s) of the main consent and only the check box page(s)/signature page(s) 
of the optional consent provided that the version date of the consent form is indicated. Centres are expected to redact the participant’s name and 
signature on the submitted copy, leaving only a portion visible (e.g. initials or loops) to confirm that a person has signed but that cannot 
identify that individual. For all other centres: submission of consent forms is not required but they will be reviewed on site. 
3 
See Section 9.0 Serious Adverse Event Reporting for details. 

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

 
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APPENDIX VI - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
Electronic copies of the Quality of Life Questionnaires are  available on the IND.227 website in English, 
French (for Canada), and other required languages (for other participating countries). 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
1. additional and useful information may be obtained from quality of life measurements 
2. a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
1. to try to achieve the best possible outcome for patients 
2. to evaluate the extent of change in the quality of life of an individual or group across time 
3. to evaluate new treatments and technologies 
4. to support approval of new drug applications 
5. to try to provide the best value for health care dollars 
6. to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
1. pre-randomization or pre-registration (baseline) 
2. during treatment 
3. during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
 

 
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If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment, as required by the schedule in the protocol (up to 3 days prior to treatment is 
acceptable). If the patient does not have a doctor visit scheduled, or if it was not possible for the patient 
to complete the questionnaire before being seen by the doctor, s/he should still complete the 
questionnaire prior to treatment. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. In that 
case, you may express sympathy that things are below par, but state that this is exactly the information 
we require if we are to understand more about how quality of life is affected. You may also remind 
them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
5. What If . . .  
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient.  
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 

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

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

 
 
Quality of Life Questionnaire – ENGLISH  
 
CCTG Trial: IND.227 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization 
During Treatment: 
 Day 1 cycle _____  
Off Treatment: 
 4 weeks post end of protocol therapy 
 Follow-up visit # ______ 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy            mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial IND.227 
Page 1 of 4 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (IND.227) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial IND.227 EORTC QLQ-C30 
Page 2 of 4 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial IND.227. EORTC QLQ-C30 
Page 3 of 4 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial IND.227 - EORTC QLQ-C30-LC13  
Page 4 of 4 
 
 Copyright 1994 EORTC Quality of life Group. All rights reserved 
Patients sometimes report that they have the following symptoms. Please indicate the extent to which 
you have experienced these symptoms during the past week. Please answer by circling the number 
that best applies to you. 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. How much did you cough? 
1 
2 
3 
4 
 
 
 
 
 
32. Did you cough up blood? 
1 
2 
3 
4 
 
 
 
 
 
33. Were you short of breath when you rested? 
1 
2 
3 
4 
 
 
 
 
 
34. Were you short of breath when you walked? 
1 
2 
3 
4 
 
 
 
 
 
35. Were you short of breath when you climbed stairs? 
1 
2 
3 
4 
 
 
 
 
 
36. Have you had a sore mouth or tongue? 
1 
2 
3 
4 
 
 
 
 
 
37. Have you had trouble swallowing? 
1 
2 
3 
4 
 
 
 
 
 
38. Have you had tingling hands or feet? 
1 
2 
3 
4 
 
 
 
 
 
39. Have you had hair loss? 
1 
2 
3 
4 
 
 
 
 
 
40. Have you had pain in your chest? 
1 
2 
3 
4 
 
 
 
 
 
41. Have you had pain in your arm or shoulder? 
1 
2 
3 
4 
 
 
 
 
 
42. Have you had pain in other parts of your body? 
1 
2 
3 
4 
 
If yes, where_____________________________ 
 
 
 
 
 
 
 
 
 
43. Did you take any medicine for pain? 
 
 
 
 
 
1   No  
2   Yes 
 
 
 
 
 
If yes, how much did it help? 
1 
2 
3 
4 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 

 
PROTOCOL AMENDMENT #4: 2020-APR-14 
 
CCTG TRIAL: IND.227 
 
 
CONFIDENTIAL 
74 
CONFIDENTIAL 
APPENDIX VII - HEALTH UTILITIES ASSESSMENT  
 
Introduction  
 
The assessment of overall health benefits is complicated by the need for a measure that can combine various 
benefits, such as overall survival and disease free survival into a single measure of benefit. Patients may 
value particular benefits differently. There is no obvious way to add together independently collected 
benefits for an individual or for a trial to yield a measure of overall benefit. Health utilities are a measure 
of how people value particular health outcomes. They provide a common denominator that can be combined 
with survival to form a measure of overall health benefits.  
 
Such a measure of overall health benefit can then be used as part of a health economic analysis. Health 
economic analyses assess the benefits and costs of an intervention, for consideration whether the 
intervention may be worth its “costs” – including financial, toxicity, and social costs. 
 
The collection of information about health utilities is becoming more common in clinical protocols. In 
clinical trials, health utilities are most often collected using a patient self-reported questionnaire.  
 
Health utilities data can be used in a variety of ways: 
• 
to try and achieve the best possible outcome for patients and populations; 
• 
to evaluate the extent of change in health benefits of an individual, group, or population across time; 
• 
to evaluate new treatments, technologies, and patient management strategies; 
• 
to support approval of new drug applications or patient management strategies; 
• 
to try to provide the best value for health care dollars within and across diseases and health; 
• 
to compare costs and benefits of various financial and organization aspects of health care services. 
 
In the future, approval of new therapies or patient management strategies will most likely be based on a 
combination of health benefit and cost data. This may be formally done using health utilities as part of a 
health economic analysis.  
 
Instructions for Administration of a Health Utilities Questionnaire 
(see IND.227 webpage for questionnaire)  
 
The instructions below are intended as a guide for the administration of the Health Utilities Questionnaire  
 
1. Preamble  
 
Health utilities data are collected for research purposes, and will not be used for the patient’s individual 
medical care. The assessment is in the form of a self report questionnaire. Therefore, it must be 
completed by the patient only, without translation, coaching or suggestions as to the “correct” answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
Pre-registration (for this study, within 7 days prior to registration)  
• 
During treatment (day 1 each cycle ) 
• 
During Follow up 
 
 

 
PROTOCOL AMENDMENT #4: 2020-APR-14 
 
CCTG TRIAL: IND.227 
 
 
CONFIDENTIAL 
75 
CONFIDENTIAL 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient.  
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pre-treatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient’s life, e.g. psychological distress, social disruption, 
symptoms, side effects, etc. 
 
The Clinical Research Associate (CRA) should collect the questionnaire as soon as it has been 
completed, check to see that each question has been answered and gently remind the patient to answer 
any inadvertently omitted questions. If a patient states that s/he prefers not to answer some questions 
and gives a reason(s), the reason(s) should be noted on the questionnaire. If a specific reason is not 
given, this also should be noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The health utilities questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to 
treatment.  
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. In that 
case, you may express sympathy that things are below par, but state that this is exactly the information we 
require if we are to understand more about how overall health is affected. You may also remind them that 
it takes only a few minutes to complete.  
 
4. What If…  
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled.  
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. A couple of situations are described below. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient.  
 
Contact the patient by phone informing him or her that the questionnaire was not completed. As 
the patient is s/he is willing to complete one:  
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire.  
 
 

 
PROTOCOL AMENDMENT #4: 2020-APR-14 
 
CCTG TRIAL: IND.227 
 
 
CONFIDENTIAL 
76 
CONFIDENTIAL 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the 
phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone.  
 
If no, note the reason why the questionnaire was not completed on the appropriate case report form.  
 
B. The patient does not want to complete the questionnaire in clinic.  
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, 
and failing to comply with the patient’s wishes is likely to result in the questionnaire not being 
completed at all, then the patient may take the questionnaire home with instructions that it is to be 
completed the same day. When the questionnaire is returned, the date on which the questionnaire 
was completed should be noted and a comment made on the questionnaire as to why the patient 
took it away from the clinic for completion.  
 
5. Inability to Complete Health Utilities Questionnaire (for reason other than illiteracy in English or 
French or relevant language)  
 
An eligible patient may be willing but physically unable to complete the questionnaire, because of 
blindness, paralysis, etc. If the patient is completing the EQ-5D assessment in the clinic, the 
questionnaire should be read to them and the answers recorded by the health care professional (e.g. 
preferably the clinical research associate assigned to the trial, but another clinic nurse, a doctor or social 
worker who is familiar with the instructions for administering the questionnaires would be acceptable). 
If the patient is completing the questionnaire at home, and a telephone interview by the clinical research 
associate is not possible, then a spouse or friend may read the questions to the patient and record the 
answers. However, this method should be a last resort, and the spouse or friend should be instructed to 
not coach or suggest answers to the patient. Whichever method is used, it should be recorded on the 
questionnaire.  
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 

 
 
Health Utilities Index – ENGLISH  
 
CCTG Trial: IND.227 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization 
During Treatment: 
 Day 1 cycle _____  
Off Treatment: 
 4 weeks post end of protocol therapy 
 Follow-up visit # ______ 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy            mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 

This box to be completed by the clinical research associate:        Pt. Serial #: _____________ Pt. Initials: ___ ___ ___ 
 
CCTG Trial IND.227 
 
Canada (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
Under each heading, please tick the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems in walking about  
 
I have slight problems in walking about  
 
I have moderate problems in walking about  
 
I have severe problems in walking about  
 
I am unable to walk about  
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
I have slight problems washing or dressing myself  
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself  
 
I am unable to wash or dress myself  
 
 
USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities) 
I have no problems doing my usual activities  
 
I have slight problems doing my usual activities  
 
I have moderate problems doing my usual activities  
 
I have severe problems doing my usual activities  
 
I am unable to do my usual activities  
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort  
 
I have slight pain or discomfort  
 
I have moderate pain or discomfort  
 
I have severe pain or discomfort  
 
I have extreme pain or discomfort  
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
I am slightly anxious or depressed  
 
I am moderately anxious or depressed  
 
I am severely anxious or depressed  
 
I am extremely anxious or depressed  
 
 

 
CCTG Trial IND.227 
 
Canada (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your  
health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below. 
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 
10 
0
20 
30 
40 
50 
60 
80 
70 
90 
100
5
15 
25 
35 
45 
55 
75 
65 
85 
95 
The best health     
 you can imagine 
The worst health   
 you can imagine 

 
PROTOCOL AMENDMENT #4: 2020-APR-14 
 
CCTG TRIAL: IND.227 
 
 
CONFIDENTIAL 
80 
CONFIDENTIAL 
APPENDIX VIII - EMERGENCY SITUATIONS AND COMPLIANCE 
 
1.0 
Management of Protocol Variances in Emergency Situations 
 
Compliance with the trial protocol 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.  
 

 
PROTOCOL AMENDMENT #4: 2020-APR-14 
 
CCTG TRIAL: IND.227 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
PATIENT REGISTRATION 
All patients must be registered with CCTG before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Joana Sederias or Kelsey Curran 
Study Coordinators, CCTG 
Emails:  
jsederias@ctg.queensu.ca 
kcurran@ctg.queensu.ca 
 
or 
 
Lesley Seymour 
Senior Investigator, CCTG 
Email: lseymour@ctg.queensu.ca 
613-533-6430 
613-533-2411 
STUDY CHAIRS 
Canada: 
Dr. Quincy Chu 
Study Chair 
Email: 
Quincy.Chu@albertahealthservices.ca 
 
 
Italy: 
Dr. Francesco Perrone 
Email: 
f.perrone@istitutotumori.na.it 
 
 
France: 
Dr. Laurent Greillier 
Email: 
laurent.greillier@ap-hm.fr 
 
 
 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for details 
of reportable events. 
Lesley Seymour 
Senior Investigator, CCTG 
 
or 
 
Joana Sederias or Kelsey Curran 
Study Coordinators, CCTG 
613-533-6430 
613-533-2411 
DRUG ORDERING 
See Appendix II for full details. 
See Appendix II and IND.227 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