Clinical trial NCT02740920
Conditions: Metastatic Melanoma
Sponsor: Canadian Cancer Trials Group
Start date: 2017-01-10; Completion date: 2019-09-30
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Studies have shown that the study drug, pembrolizumab, works by helping the immune system. In this way, pembrolizumab may help to slow the growth of melanoma or may cause cancer cells to die. Compared to standard treatments, pembrolizumab seems to lengthen the time patients lived overall and the time without their cancer getting worse.

Detailed description:
The main purpose of this study is to find out if a type of CT (computed topography) scan can help to know if pembrolizumab is working. This CT scan (called Texture Analysis) looks at the tumour in fine detail. The use of this type of CT scan has not been studied in patients with metastatic melanoma. Investigators want to see if this CT scan will show if some patients being treated with pembrolizumab respond better than others.

One of the other purposes is to compare the costs within this trial to costs of the standard of care.

Arms: arm 1: 200mg IV Day 1 every 3 weeks.
Interventions: intervention 1: Pembrolizumab intervention 2: CT Scan
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
PROTOCOL DATE: 2016-MAR-03 
 
CCTG TRIAL: IND.225 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION 
 
ADMINISTRATIVE UPDATE #1: 2016-MAY-10 
 
AMENDMENT #1: 2016-NOV-23 
 
 
AMENDMENT #2: 2017-JUL-10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE II STUDY OF THE ASSESSMENT OF RESPONSE TO PEMBROLIZUMAB IN 
METASTATIC MELANOMA: CT TEXTURE ANALYSIS AS A PREDICTIVE BIOMARKER 
 
CCTG Protocol Number: IND.225 
 
 
 
STUDY CHAIR: 
Teresa Petrella 
 
 
SENIOR INVESTIGATOR: 
Janet Dancey 
 
 
SENIOR BIOSTATISTICIAN: 
Bingshu Chen 
 
 
STUDY COORDINATOR: 
Linda Hagerman 
 
 
REGULATORY SPONSOR: 
CCTG 
 
 
SUPPORTED BY: 
Merck  
 
(For contact information of study personnel see Final Page.) 
 


 
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AMEND #1: 2016-NOV-23 
TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .................................................................................. 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 2 
 
1.0 
OBJECTIVES ......................................................................................................................................... 4 
1.1 
Primary Objective ................................................................................................................................... 4 
1.2 
Secondary Objectives .............................................................................................................................. 4 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 5 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION............................................................................ 7 
3.1 
Name ....................................................................................................................................................... 7 
3.2 
Chemical Properties ................................................................................................................................ 7 
3.3 
Mechanism of Action .............................................................................................................................. 7 
3.4 
Animal Toxicology ................................................................................................................................. 8 
3.5 
Clinical Experience ................................................................................................................................. 8 
3.6 
Pharmacokinetic Studies ......................................................................................................................... 9 
3.7 
Pharmaceutical Data ................................................................................................................................ 9 
 
4.0 
TRIAL DESIGN ................................................................................................................................... 11 
 
5.0 
STUDY POPULATION ....................................................................................................................... 12 
5.1 
Eligibility Criteria ................................................................................................................................. 12 
5.2 
Ineligibility Criteria ............................................................................................................................... 14 
 
6.0 
PRE-TREATMENT EVALUATION ................................................................................................... 16 
 
7.0 
ENTRY/REGISTRATION PROCEDURES ........................................................................................ 17 
7.1 
Entry Procedures ................................................................................................................................... 17 
7.2 
Registration ........................................................................................................................................... 17 
 
8.0 
TREATMENT PLAN ........................................................................................................................... 18 
8.1 
Chemotherapy Treatment Plan .............................................................................................................. 18 
8.2 
Dose Adjustments for Pembrolizumab.................................................................................................. 18 
8.3 
Dose Modification Guidelines for Drug-related Adverse Events ......................................................... 19 
8.4 
Duration of Protocol Treatment ............................................................................................................ 22 
8.5 
Concomitant Therapy ............................................................................................................................ 22 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT .............................................. 23 
9.1 
Evaluation During Protocol Treatment ................................................................................................. 23 
9.2 
Evaluation After Protocol Treatment .................................................................................................... 24 
 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 25 
10.1 
Definitions ............................................................................................................................................. 25 
10.2 
Response and Evaluation Endpoints ..................................................................................................... 25 
10.3 
Response Duration (RECIST 1.1 and iRECIST) .................................................................................. 30 
10.4 
Stable Disease Duration ........................................................................................................................ 30 
10.5 
Methods of Measurement ...................................................................................................................... 30 
10.6 
Time to Tumour Progression................................................................................................................. 31 
10.7 
Overall Survival .................................................................................................................................... 31 
10.8 
Censoring .............................................................................................................................................. 31 


 
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11.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 32 
11.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 32 
11.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 32 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting ................................................................... 33 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 34 
11.5 
CCTG Reporting Responsibility to Merck ............................................................................................ 34 
11.6 
Merck Reporting Responsibilities ......................................................................................................... 34 
11.7 
Reporting Safety Reports to Investigators ............................................................................................. 34 
 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 36 
12.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 36 
12.2 
Duration of Protocol Treatment ............................................................................................................ 36 
12.3 
Therapy After Protocol Treatment is Stopped ...................................................................................... 36 
12.4 
Follow-up Off Protocol Treatment ........................................................................................................ 36 
 
13.0 
CENTRAL REVIEW PROCEDURES ................................................................................................. 37 
13.1 
Central Radiology Review .................................................................................................................... 37 
13.2 
Central Pathology Review ..................................................................................................................... 37 
 
14.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 38 
14.1 
Objectives and Design ........................................................................................................................... 38 
14.2 
Sample Size and Duration of Study ...................................................................................................... 38 
14.3 
Safety Monitoring ................................................................................................................................. 38 
14.4 
Economic Analysis ................................................................................................................................ 38 
 
15.0 
PUBLICATION POLICY ..................................................................................................................... 40 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. ..................................................................................... 40 
15.2 
Responsibility for Publication ............................................................................................................... 40 
15.3 
Submission of Material for Presentation or Publication ........................................................................ 40 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 41 
16.1 
Regulatory Considerations .................................................................................................................... 41 
16.2 
Inclusivity in Research .......................................................................................................................... 41 
16.3 
Obtaining Informed Consent ................................................................................................................. 42 
16.4 
Discontinuation of the Trial .................................................................................................................. 43 
16.5 
Retention of Patient Records and Study Files ....................................................................................... 43 
16.6 
Centre Performance Monitoring ............................................................................................................ 43 
16.7 
On-Site Monitoring/Auditing ................................................................................................................ 43 
16.8 
Case Report Forms ................................................................................................................................ 44 
 
17.0 
REFERENCES ...................................................................................................................................... 45 
 
APPENDIX I -  
PATIENT EVALUATION FLOW SHEET......................................................................... 47 
APPENDIX II -  PERFORMANCE STATUS SCALES/SCORES ................................................................ 48 
APPENDIX III -  DRUG DISTRIBUTION, SUPPLY AND CONTROL ....................................................... 49 
APPENDIX IV -  DOCUMENTATION FOR STUDY .................................................................................... 50 
APPENDIX V -  NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ...................... 51 
APPENDIX VI -  CT FOR TEXTURE ANALYSIS ........................................................................................ 52 
APPENDIX VII -  HEALTH UTILITIES ASSESSMENT ............................................................................... 53 
 
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 Merck. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG and Merck 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 Merck and CCTG. The foregoing shall not apply to disclosure 
required by governmental regulations or laws; however, I will give prompt notice to Merck and CCTG of 
any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG or Merck with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
Merck and CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG IND.225 
 
CENTRE: ___________________________________________ 


 
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AMEND #2: 2017-JUL-10 
TREATMENT SCHEMA 
 
Eligibility Criteria 
• 
Histologically confirmed melanoma that is recurrent/metastatic and not amenable to potentially 
curative surgery; 
• 
Clinically and/or radiologically documented disease with at least one site of disease unidimensionally 
measurable by contrast-enhanced CT scan; 
• 
Radiology must be performed within 28 days prior to registration (35 days if negative); 
• 
Age > 18 years; 
• 
ECOG 0 to 1; 
• 
Previous surgery permitted as long as 21 days prior to patient registration and wound healing has 
occurred; 
• 
Palliative radiation permitted as long as >7 days between last dose and enrolment on trial; 
• 
Neutrophils ≥ 1.5 x 109/L; 
• 
Platelets ≥ 100 x 109/L; 
• 
Hemoglobin ≥ 90 g/L or ≥ 5.6 mmol/L (without transfusion or EPO dependency); 
• 
Serum creatinine ≤ 1.5 x ULN OR measured or calculated creatinine clearance ≥ 60 mL/min for subject 
with creatinine levels > 1.5 x ULN; 
• 
Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels 
> 1.5 x ULN; 
• 
AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver mets); 
• 
Albumin ≥ 25 g/L; 
• 
Negative serum or urine pregnancy test within 7 days prior to registration (if applicable); 
• 
Men and women of child-bearing potential must use adequate contraception as described in Section 
5.1.7. 
 
Ineligibility Criteria 
• 
Prior systemic therapy for metastatic melanoma; 
• 
Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies); 
• 
Known history of or known positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA 
[qualitative] is detected). Patients with unknown history of HBV or HCV will require screening; 
• 
Patients with previously treated brain metastases may participate provided they are stable with no 
evidence of enlargement following radiation treatment and no acute radiation toxicity OR no evidence 
of enlargement at least 4 weeks prior to the first dose of study drug if untreated and are off systemic 
steroids for at least two weeks;  
• 
Patients who are pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study; 


 
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AMEND #1: 2016-NOV-23; AMEND #2: 2017-JUL-10 
• 
Patients who previously had a severe hypersensitivity reaction to treatment with another mAb; 
• 
Patients with an active autoimmune disease or a documented history of autoimmune disease or 
syndrome that requires systemic steroids or immunosuppressive agents; 
• 
Patients with a history of a malignancy (other than the disease under treatment in the study) within 5 
years prior to first study drug administration; 
• 
Patients on any systemic corticosteroid therapy within one week before the planned date for first dose 
of treatment or on any other form of immunosuppressive medication; 
• 
Patients with an allergy to iodinated contrast media used for CT; 
• 
Patients with a known history of active TB (Bacillus Tuberculosis); 
• 
Patients with evidence of interstitial lung disease; 
• 
Patients with known history of, or any evidence of active, non-infectious pneumonitis. 
 
Pre-Treatment Evaluations 
• 
History, physical exam, ECOG performance status, vital signs, toxicity/baseline symptoms (within 14 
days prior to registration); 
• 
Hematology and biochemistry (within 7 days prior to registration); 
• 
Pregnancy test (within 7 days prior to registration, if applicable); 
• 
ECG (within 7 days prior to registration if not done within 6 months); 
• 
Health Utilities Index (EQ-5D) (within 7 days prior to registration); 
• 
CT scan with contrast of chest, abdomen/pelvis (within 28 days prior to registration; 35 days if 
negative). 
 
Treatment 
• 
Pembrolizumab will be given intravenously day 1 every 3 weeks 
 
On-Treatment Evaluations 
• 
History and physical exam, ECOG (Day 1 each cycle) 
• 
Vital signs (blood pressure and pulse) (Day 1 each cycle) 
• 
Hematology and Biochemistry (Day 1 each cycle) 
• 
TSH, FT3, FT4 (every other cycle) 
• 
CT scan with contrast of chest, abdomen/pelvis (4 weeks, 12 weeks, then every 12 weeks) 
• 
ECG (as clinically indicated) 
• 
Health Utilities Index (EQ-5D) and Resource Utilization Assessment (each 12 weekly visit until 
progression OR maximum 1 year from registration) 
• 
Adverse events – patients to be evaluated continuously for adverse events. 
 
Duration of Treatment 
 
See Section 12. 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To assess whether tumour texture parameters from a CT scan can differentiate patients who do and 
who do not respond to treatment with pembrolizumab. 
 
1.2 
Secondary Objectives 
• 
To assess whether tumour texture parameters from a CT scan can correlate with time to disease 
progression in patients with metastatic melanoma being treated with pembrolizumab.  
• 
To assess duration of response (DoR). 
• 
To assess overall response rate (ORR, PR, CR). 
• 
To assess overall survival (OS). 
• 
To compare cost per quality adjusted life years (QALY) between pembrolizumab and 
dacarbazine. 
• 
To compare cost per quality adjusted life years (QALY) between pembrolizumab and 
ipilimumab. 
• 
Toxicity using the CTCAE v.4. 
 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Metastatic melanoma historically has had a very poor survival. Thankfully this is now changing 
due to advent of new targeted drugs and breakthroughs in immunotherapy. Programmed cell death 
1 (PD-1) receptor is an inhibitory receptor expressed by T cells. Its ligand, PD-L1 is frequently 
expressed within the tumour microenvironment including tumour cells. Tumour models have 
shown that PD-1 negatively regulates the effector phase of T-cell responses after ligation of PD-
L1 expressed within the tumour [Blank 2004]. Several drugs have been developed that block PD-1 
and hence augment the T cell response. The most mature results have been obtained in advanced 
melanoma patients and indicate high response rates, high quality responses and prolonged duration 
of response and prolonged survival. 
 
Pembrolizumab is a highly selective, humanized monoclonal IgG4-kappa isotype antibody against 
PD-1 that is designed to block the negative immune regulatory signalling of the PD-1 receptor 
expressed by T cells [Hamid 2013]. Pembrolizumab has shown improved response rates, response 
duration and survival compared to standard treatments for melanoma [Ribas 2015; Patnaik 2014]. 
Patients receiving pembrolizumab had an overall RR of 38% with durable responses and 
approximately a further 30% of patients with disease control. The 1 year survival in this trial was 
67% and 50% at 2 years in patients with metastatic melanoma [Daud 2015]. Pembrolizumab was also 
compared to ipilimumab in first line therapy for metastatic melanoma and showed a better RR and 
OS rate compared to ipilimumab with a RR of 34% compared to 12% and OS at 12 months of 74% 
compared to 58% for ipilimumab [Robert 2015]. In this study and subsequent phase III studies, 
pembrolizumab is administered intravenously at 2 mg/kg every 2 weeks for a total of 2 years. 
Recent results from pharmacokinetic studies indicate that a flat dose of 200 mg IV is sufficient for 
exposure and that there is no additional advantage to weight-based dosing. In addition, responses 
occur early within the first 8 weeks and it is possible that 2 years of consecutive therapy may not 
be needed given the durable responses seen with ipilimumab short courses.  
 
Imaging is widely used in oncology for confirmation of diagnosis, staging and assessing treatment 
response. Tumour heterogeneity, such as heterogeneity of the tumour blood supply is a well-
recognized feature of malignancy. Computed tomographic (CT) texture analysis is a form of 
quantitative feature analysis that focuses on the heterogeneity of attenuation within tumours [Goh 
2011]. Evidence suggests that texture analysis has the potential to augment diagnosis by 
differentiating between benign and malignant neoplasms, tumour staging by differentiating 
between invasive and non-invasive disease and malignant/non-malignant lymph nodes, and therapy 
response assessment in oncological practice [De Ruysscher 2013; Bayanati 2014]. Characteristics such 
as textural heterogeneity on a CT scan have been used to predict response and time to progression 
in renal cell carcinoma (RCC) and non-small cell lung carcinoma (NSCLC) patients [Goh 2011; Win 
2013]. In metastatic renal cell cancer patients on TKIs, texture analysis was shown to be an 
independent factor associated with time to progression [Goh 2011].  
 


 
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AMEND #1: 2016-NOV-23 
Our investigators have previously evaluated and confirmed the prognostic value of texture analysis 
in RCC. To our knowledge the potential of texture analysis has not been explored in patients with 
metastatic melanoma. However, its application in patients with advanced melanoma who are 
candidates for immunotherapy is reasonable and may be quite valuable. We hypothesize that 
texture analysis will differentiate responders/non-responders to pembrolizumab and differentiate 
between pseudoprogression from true disease progression. The benefits of imaging biomarker 
would be several: identification of patients for treatment, early discontinuation for failure of 
response, and appropriate continuation of treatment in patients with pseudoprogression. By limiting 
the numbers of patients receiving treatment that are not benefiting, the overall cost effectiveness of 
treatment and overall benefit to Canadian patients and the Canadian health care system is increased. 
 
We are proposing a phase II study in metastatic melanoma patients treated with pembrolizumab 
200 mg IV q 3 weeks to assess whether tumour texture parameters from a CT scan can differentiate 
time to progression and response. Patients will be followed on study for a maximum of 12 months. 
The trial will be sponsored and conducted by the Canadian Cancer Trials Group, Canada’s largest 
adult cooperative cancer clinical trials group. The group has conducted more than 400 phase I-III 
trials in all cancer settings and all modalities of treatment. The Melanoma Disease Site Committee 
of the CCTG has successfully conducted several early phase clinical trials testing novel treatments 
in melanoma at cancer centres across the country. The group will collaborate with experienced 
imaging researchers at Sunnybrook and OICR to ensure quality of acquisition and interpretation of 
CT images. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the 
exposure range established in melanoma as associated with maximal efficacy response and 3) will 
maintain individual patients exposure in the exposure range established in melanoma that are well 
tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4.0 
TRIAL DESIGN 
 
This is an open-label, multicentre, phase II trial of pembrolizumab in first line therapy of metastatic 
melanoma. This trial is being conducted by the Canadian Cancer Trials Group with the support of 
Merck. 


 
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AMEND #1: 2016-NOV-23 
5.0 
STUDY POPULATION 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of registration. Questions 
about eligibility criteria should be addressed prior to registration. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Histologically confirmed melanoma that is recurrent/metastatic and not amenable to potentially 
curative surgery. 
 
5.1.2 
Presence of clinically and/or radiologically documented disease based on RECIST 1.1. At least one 
site of disease must be unidimensionally measurable by contrast-enhanced CT scan as follows: 
 
CT scan (with slice thickness of < 5 mm) 
> 10 mm 
 longest diameter 
Lymph nodes by CT scan 
> 15 mm 
 measured in short axis 
 
All radiology studies must be performed within 28 days prior to registration and meet the criteria 
outlined in Appendix VI (exception: within 35 days if negative). 
 
5.1.3 
Age > 18 years.  
 
5.1.4 
ECOG Performance Status of 0 to 1. 
 
5.1.5 
Previous Therapy 
 
Surgery: 
Previous surgery is permitted provided that it has been at least 21 days prior to patient registration 
and that wound healing has occurred. 
 
Systemic Therapy: 
Patients may not have received any prior systemic therapy for metastatic melanoma. 
 
Radiation: 
Palliative radiation is permitted provided > 7 days has elapsed between last dose and enrollment on 
the trial. 


 
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Admin Update #1: 2016-MAY-10; AMEND #2: 2017-JUL-10 
5.1.6 
Laboratory Requirements (must be done within 7 days prior to registration) 
 
Hematology: Absolute neutrophils (ANC) 
> 1.5 x 109/L 
 
Platelets 
> 100 x 109/L 
 
Hemoglobin 
> 90 g/L or > 5.6 mmol/L (without transfusion 
or EPO dependency)  
 
Chemistry: 
Serum creatinine  
< 1.5 x ULN 
 
OR 
OR  
 
Measured or calculated creatinine > 60 mL/min for subject with creatinine 
 
clearance  
levels > 1.5 x ULN 
 
 
Serum Total Bilirubin 
< 1.5 x ULN 
 
OR 
 
Direct bilirubin  
< ULN for subjects with total bilirubin levels 
> 1.5 x ULN 
 
 
AST and ALT 
< 2.5 x ULN (< 5 x ULN for subjects with 
liver mets) 
 
 
Albumin 
> 25 g/L 
 
5.1.7 
Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method. A woman is considered to be of "childbearing potential" if she has had menses at any time 
in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or 
with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
5.1.8 
Women of childbearing potential will have a serum or urine pregnancy test within 7 days prior to 
registration to determine eligibility. If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required. This may also include an ultrasound to rule-out pregnancy 
if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 


 
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5.1.9 
Patient consent must be obtained according to local Institutional and/or University Human 
Experimental Committee requirements. It will be the responsibility of the local participating 
investigators to obtain the necessary local clearance, and to indicate in writing to the CCTG Study 
Coordinator that such clearance has been obtained, before the trial can commence in that centre. 
Because of differing requirements, a standard consent form for the trial will not be provided but a 
sample form is provided on the IND.225 webpage. A copy of the initial REB approval and approved 
consent form must be sent to the central office. The patient must sign the consent form prior to 
registration and prior to tests which are considered to be study specific (see Section 6). Please note 
that the consent form for this study must contain a statement which gives permission for the CCTG 
and monitoring agencies to review patient records.  
 
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.  
 
5.1.10 Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 
(Call the CCTG office (613-533-6430) if questions arise regarding the interpretation of this 
criterion.) Investigators must assure themselves the patients registered on this trial will be available 
for complete documentation of the treatment, adverse events, and follow-up. 
 
5.1.11 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
registration. 
 
5.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Patients who have received prior systemic treatment for metastatic melanoma.  
 
5.2.2 
Patients with known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
5.2.3 
Patients with a known history of or known positive for Hepatitis B (HBsAg reactive) or Hepatitis 
C (HCV RNA [qualitative] is detected). Patients with unknown history of HBV or HCV will require 
screening. 
 
5.2.4 
Patients with previously treated brain metastases may participate provided they are stable with no 
evidence of enlargement following radiation treatment and no acute radiation toxicity OR no 
evidence of enlargement at least 4 weeks prior to the first dose of study drug if untreated and are 
off systemic steroids for at least two weeks. 
 
5.2.5 
Patients who are pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the pre-screening or screening visit through 4 months 
after the last dose of trial treatment. 
 
5.2.6 
Patients who previously had a severe hypersensitivity reaction to treatment with another mAb. 


 
PROTOCOL DATE: 2016-MAR-03 
 
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AMEND #1: 2016-NOV-23 
5.2.7 
Patients with an active autoimmune disease or a documented history of autoimmune disease or 
syndrome that requires systemic steroids or immunosuppressive agents. (Only patients on active 
treatment are ineligible). 
 
5.2.8 
Patients with a history of a malignancy (other than the disease under treatment in the study) within 
5 years prior to first study drug administration. 
 
5.2.9 
Patients on any systemic corticosteroid therapy within one week before the planned date for first 
dose of treatment or on any other form of immunosuppressive medication. 
 
5.2.10 Patients with an allergy to iodinated contrast media used for CT. 
 
5.2.11 Patients with a known history of active TB (Bacillus Tuberculosis).  
 
5.2.12 Patients with evidence of interstitial lung disease. 
 
5.2.13 Patients with known history of, or any evidence of active, non-infectious pneumonitis. 


 
PROTOCOL DATE: 2016-MAR-03 
 
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CONFIDENTIAL 
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AMEND #1: 2016-NOV-23; AMEND #2: 2017-JUL-10 
6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations 
Timing 
History and Physical 
Exam including: 
 history 
 height/weight 
 vital signs (blood pressure and pulse) 
 ECOG performance status 
 documentation of all measurable and non-
measurable disease 
 clinical tumour measurements (if applicable) 
Within 14 days prior to 
registration 
Hematology 
 CBC, differential, platelets 
Within 7 days prior to registration 
Biochemistry 
 serum creatinine (or measured or calculated 
creatinine clearance) 
 electrolytes (sodium, potassium, chloride, 
bicarbonate) 
 bilirubin 
 alkaline phosphatase 
 AST, ALT 
 LDH 
 phosphorous 
 calcium 
 magnesium 
 albumin 
 TSH, FT3, FT4 
 HCV, HBV screening serology (if unknown) 
Within 7 days prior to registration 
Radiology1 
 CT scan with contrast of chest, abdomen/pelvis 
 other sites as clinically indicated 
Within 28 days2 prior to 
registration 
Other Investigations 
 pregnancy test* (if applicable) 
Within 7 days prior to registration 
 ECG (if not done within 6 months) 
Economics 
 Health Utilities Index (EQ-5D) 
Adverse Event3 
 baseline adverse event evaluation (to document 
residual adverse event from previous therapy 
and baseline symptoms) 
1 
To ensure comparability, baseline and subsequent CT scans to assess response must be performed using identical 
techniques (i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, 
the identical contrast agent, and preferably the same scanner – see Appendix VII). 
2 
Thirty-five days if negative 
3 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). 
* 
These tests are considered study-specific and must be performed AFTER the informed consent form has been signed. 


 
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7.0 
ENTRY/REGISTRATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All registrations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
registering patients will be provided at the time of study activation and will also be included in the 
“EDC Data Management Guidebook”, posted on the IND.225 trial specific web-site. If sites 
experience difficulties accessing the system and/or registering patients please contact the help desk 
(link in EDC) or the IND.225 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.225) 
• 
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 5.0, including dates of essential tests and 
actual laboratory values 
• 
height and weight  
 
7.2 
Registration 
 
Registrations will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting registration. 
 
All patients are to be followed until death or until sites are informed by CCTG that further follow-
up is no longer required.  


 
PROTOCOL DATE: 2016-MAR-03 
 
CCTG TRIAL: IND.225 
 
 
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Admin Update #1: 2016-MAY-10 
8.0 
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. 
 
8.1 
Chemotherapy Treatment Plan 
 
8.1.1 
Drug Administration 
 
Agent 
Route 
Starting Dose 
Schedule 
Pembrolizumab 
IV 
200 mg 
Day 1 every 3 weeks 
 
8.2 
Dose Adjustments for Pembrolizumab 
 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life threatening 
AEs as per Table below. 
 
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.  
 
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.  
• 
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.  


 
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Admin Update #1: 2016-MAY-10 
• 
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. 
 
8.3 
Dose Modification Guidelines for Drug-related Adverse Events 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure. Insulin 
replacement therapy is 
recommended for Type I 
diabetes mellitus and for grade 
3-4 hyperglycemia associated 
with metabolic acidosis or 
ketonuria. 
Resume pembrolizumab when patients are 
clinically and metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab 
can be continued while 
endocrine replacement therapy 
is instituted. When symptoms 
improve to grade 1 or less, 
steroid taper should be started 
and continued over no less than 
4 weeks. 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
table continued on next page … 


 
PROTOCOL DATE: 2016-MAR-03 
 
CCTG TRIAL: IND.225 
 
 
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Admin Update #1: 2016-MAY-10 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can be continued 
while thyroid replacement therapy is instituted 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  Permanently discontinue if toxicity develops 
despite adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1. 
For grade 2 events treat with 
systemic corticosteroids. When 
symptoms improve to grade 1 
or less, steroid taper should be 
started and continued over no 
less than 4 weeks.  
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or 
equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one 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 subject should be 
premedicated for the next scheduled dose; Refer to Section 8.3.1, Infusion Related Reactions Table for further management 
details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose. 
 
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. 


 
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CCTG TRIAL: IND.225 
 
 
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8.3.1 
Infusion Related Reactions 
 
NCI CTCAE 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 subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g. 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hrs 
Stop Infusion and monitor symptoms. 
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 subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one 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 subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., 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: 
− IV fluids 
− Antihistamines 
− NSAIDS 
− Acetaminophen 
− Narcotics 
− Oxygen 
− Pressors 
− Corticosteroids 
− Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 


 
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8.4 
Duration of Protocol Treatment 
 
Treatment will continue until the criteria for removal from protocol treatment have been met (see 
Section 12.0). 
 
8.5 
Concomitant Therapy 
 
8.5.1 
Permitted 
 
Patients may receive ongoing supportive and palliative care (e.g. pain control) as clinically 
indicated throughout the study. Physiological doses of systemic corticosteroids are allowed, as well 
as inhaled, topical and prophylaxis use for allergic reactions, such as IV contrast dye. All supportive 
medications must be recorded on the electronic case report form as appropriate. 
 
8.5.2 
Not Permitted 
• 
Antineoplastic systemic chemotherapy or biological therapy. 
• 
Immunotherapy including corticosteroids (see Section 8.5.1), except for treatment of potential 
immune-related AEs during the study. 
• 
Investigational agents other than pembrolizumab. 
• 
Radiation therapy (Note: radiation therapy to a symptomatic solitary lesion may be allowed 
after consultation with CCTG). Radiation to target lesions should be avoided and if required, 
patient would be considered to have progressive disease. 
• 
Live vaccines within 30 days prior to the first dose of study therapy and while on study. 
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine. 


 
PROTOCOL DATE: 2016-MAR-03 
 
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AMEND #2: 2017-JUL-10 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
9.1 
Evaluation During Protocol Treatment 
 
Investigations 
Timing 
History and Physical 
Exam including: 
 history 
 weight 
 ECOG Performance status 
 vital signs (blood pressure and pulse) 
 clinical tumour measurements (if 
applicable) 
Day 1 each cycle 
Hematology* 
 CBC, differential, platelets 
Day 1 each cycle 
Biochemistry* 
 electrolytes (sodium, potassium, 
chloride, bicarbonate) 
 alkaline phosphatase 
 AST, ALT 
 serum creatinine 
 bilirubin 
Day 1 each cycle 
 phosphorous 
 calcium 
 magnesium 
 albumin 
As clinically indicated 
 TSH, FT3, FT4 
Every other cycle 
Radiology** 
 CT scan with contrast of chest, 
abdomen/pelvis 
 Other sites as clinically indicated 
4 weeks, 12 weeks, then every 12 
weeks  
Other Investigations 
 ECG 
As clinically indicated 
Economics 
 Health Utilities Index (EQ-5D) 
 Resource Utilization Assessment 
To be completed at each 12 weekly 
visit until progression OR 
maximum 1 year from registration 
Adverse Events*** 
Patients must be evaluated after each cycle for adverse events  
* 
Bloodwork Timing: Pre-treatment blood draws should be done within 72 hours (maximum) prior to treatment.  
** 
Patients with a CR or PR should have scans repeated after minimum 4 weeks to confirm response. See Appendix VII for CT 
requirements. 
*** Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). 


 
PROTOCOL DATE: 2016-MAR-03 
 
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AMEND #2: 2017-JUL-10 
9.2 
Evaluation After Protocol Treatment 
 
All patients will be seen at 4 weeks after the end of the last cycle date. Thereafter, continued follow-
up is not required for patients who go off protocol treatment with progressive disease, except to 
document ongoing toxicities (until resolved to < grade 2) and late toxicities (including second 
malignancies). Patients who go off protocol therapy before progression is documented or have 
objective CR, PR or SD ongoing, follow-up and a Follow-up Report will be required at least every 
3 months for a maximum of 1 year, (See Appendix I for investigations to be performed). Death 
Report will be required for all patients. Due within 2 weeks of knowledge of death (see 
Appendix IV - Documentation for Study). 
 
Investigations 
Timing 
History and Physical 
Exam including: 
 history 
 weight 
 ECOG Performance status 
 vital signs (blood pressure and pulse) 
 clinical tumour measurements (if 
applicable) 
4 weeks post end of last cycle 
Hematology 
 CBC, differential, platelets 
4 weeks post end of last cycle 
Biochemistry 
 electrolytes (sodium, potassium, chloride, 
bicarbonate)  
 alkaline phosphatase 
 AST, ALT 
 serum creatinine 
 bilirubin 
4 weeks post end of last cycle 
 phosphorous 
 calcium 
 magnesium 
 albumin 
As clinically indicated 
Radiology* 
 CT with contrast of chest, abdomen and 
pelvis 
As per standard of care (at least 
every 3 months) until 
progression or a maximum of 
1 year 
Other Investigations 
 ECG 
As clinically indicated 
Adverse Events 
Adverse events will be recorded and graded 
according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) 
(Appendix V). 
4 weeks post end of last cycle 
* Patients with a CR or PR should have scans repeated after minimum 4 weeks to confirm response. 
 
 


 
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AMEND #1: 2016-NOV-23 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions 
 
10.1.1 Evaluable for adverse events. All patients will be evaluable for adverse event evaluation from the 
time of their first treatment. 
 
10.1.2 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 2016]. 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee as well 
as the modified iRECIST guidelines [Seymour 2016]. Investigators should note the different 
requirements for confirmatory scans as well as follow up for the two criteria. 
 
10.2 
Response and Evaluation Endpoints 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee. 
 
10.2.1 Measurable Disease. Measurable tumour lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as > 20 mm with chest x-ray 
and as > 10 mm with CT scan or clinical examination. Bone lesions are considered measurable only 
if assessed by CT scan and have an identifiable soft tissue component that meets these requirements 
(soft tissue component > 10 mm by CT scan). Malignant lymph nodes must be ≥ 15mm in the short 
axis to be considered measurable; only the short axis will be measured and followed. All tumour 
measurements must be recorded in millimetres (or decimal fractions of centimetres). Previously 
irradiated lesions are not considered measurable unless progression has been documented in the 
lesion. 
 
10.2.2 Non-measurable Disease. All other lesions (or sites of disease), including small lesions are 
considered non-measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, lymphangitic involvement of lung or skin and abdominal masses 
followed by clinical examination are all non-measurable. Lesions in previously irradiated areas are 
non-measurable, unless progression has been demonstrated. 
 
10.2.3 Target Lesions. When more than one measurable tumour lesion is present at baseline all lesions up 
to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. Note that pathological nodes must meet the criterion of a 
short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed (see 10.2.4). At baseline, the sum of the target 
lesions (longest diameter of tumour lesions plus short axis of lymph nodes: overall maximum of 5) 
is to be recorded. Note: For this study, skin lesions will be considered as non-target lesions. 


 
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AMEND #1: 2016-NOV-23 
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 can not 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. 
 
10.2.4 Non-target Lesions. All non-measurable lesions (or sites of disease) plus any measurable lesions 
over and above those listed as target lesions are considered non-target lesions. Measurements are 
not required but these lesions should be noted at baseline and should be followed as “present” or 
“absent”. Note: For this study, skin lesions will be considered as non-target lesions. 
 
10.2.5 Response. 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and normalization of 
tumour markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: continue 
to record the measurement even if < 10mm and considered CR). Residual lesions (other than nodes 
< 10 mm) thought to be non-malignant should be further investigated (by cytology specialized 
imaging or other techniques as appropriate for individual cases [Eisenhauer 2009] before CR can be 
accepted. Confirmation of response is 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. If the evidence of 
PD is equivocal (target or non-target), treatment may continue until the next assessment, but if 
confirmed, the earlier date must be used. 
 
Patients that are clinically well may continue on therapy following RECIST progression with 
new lesions or increase in target lesions if the increase in disease burden does not meet the 
definition of PD by immune response criteria [Seymour 2016]. In this situation, patients do not 
have unequivocal progression until immune response criteria are met (see Table 2 below). 


 
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AMEND #1: 2016-NOV-23 
Table 1: Integration of Target, non-Target and New Lesions into Response Assessment: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes <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. 
 
Immune-Related Response Assessment 
 
Overall response will also be assessed using  iRECIST [Seymour 2016]. 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. 


 
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AMEND #1: 2016-NOV-23 
Confirming Progression 
 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen as 
evidenced by one or more of the following: 
• 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
- 
Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum 
- 
Continued unequivocal progression in non-target disease with an increase in tumour burden 
- 
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions. 
• 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in table 2, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. 
 
New Lesions 
 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow 
clear differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of NLT should NOT be included in the sum of measures of original target lesions 
identified at baseline. Rather, these measurements will be collected on a separate table in the case 
record form. 
 
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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AMEND #1: 2016-NOV-23 
Table 2: 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 3: iRECIST Best Overall Response (iBOR) 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
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. 
 
10.3 
Response Duration (RECIST 1.1 and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(whichever is first recorded) are first met until the first date that recurrent or progressive disease is 
objectively documented, taking as reference the smallest measurements recorded on study 
(including baseline). 
 
10.4 
Stable Disease Duration 
 
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
 
10.5 
Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
 


 
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10.5.1 Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm 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. 
 
10.5.2 Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions > 20 mm on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.  
 
10.5.3 CT, MRI. For this protocol the baseline CT scans within the first 12 weeks must conform to the 
requirements outlined in Appendix VII. For assessment of response using RECIST 1.1, 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. Other specialized imaging or other techniques 
may also be appropriate for individual case [ref RECIST 1.1]. For example, while PET scans are 
not considered adequate to measure lesions, PET-CT scans may be used providing that the CT 
conforms to Appendix VII. 
 
10.5.4 Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
 
10.5.5 Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
 
10.5.6 Tumour Markers. Tumour markers alone cannot be used to assess objective tumour response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response.  
 
10.5.7 Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare cases 
if required by protocol (for example, residual lesions in tumour types such as germ cell tumours, 
where known residual benign tumours can remain). When effusions are known to be a potential 
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumour has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease. 
 
10.6 
Time to Tumour Progression 
 
Time to tumour progression will be measured from date of registration until documented 
progression or death. 
 
10.7 
Overall Survival 
 
Overall survival will be calculated from date of registration until death. 
 
10.8 
Censoring 
 
Patients alive without progression at end of study will be censored at last visit/known to be alive 
and progression free.  


 
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11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events, regardless of whether they are unexpected or related to protocol 
treatment, occurring during the treatment period and within 30 days after the last protocol 
treatment administration, must be reported in an expedited manner. Any late deaths related to 
protocol treatment or other serious adverse event occurring after this 30-day period which is 
unexpected and related to protocol treatment must also be reported in an expedited manner (see 
Section 11.2 for reporting instructions).  
• 
Known drug related events are excluded from expedited reporting unless they cause 
hospitalization, death or are life threatening 
• 
SAE’s that are considered definitely related to disease are excluded from expedited reporting 
but must be reported as adverse events 
• 
 A serious adverse event (SAE) is any adverse event that at any dose:  
− 
results in death  
− 
is life-threatening  
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care)  
− 
results in persistent or significant disability or incapacity  
− 
is a congenital anomaly/birth defect  
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
11.2 
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.225 section of the CCTG website (www.ctg.queensu.ca). 


 
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Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG via 
EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit report 
to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
Linda Hagerman, 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. 225 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).  
 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting 
 
11.3.1 Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 5.1.7. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy.  
 
11.3.2 Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants, and 
female partners of male participants. Pregnancies occurring up to 4 months after the completion of 
study treatment must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage. 


 
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Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca).  
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which a causal relationship with protocol treatment cannot be ruled out). 
 
11.5 
CCTG Reporting Responsibility to Merck 
 
Merck will be notified of all protocol reportable serious adverse events (as defined in Section 11.1), 
via CIOMS report within 2 working days of receipt of report at CCTG. CCTG, as sponsor, will 
determine regulatory reportability in Canada.  
 
11.6 
Merck Reporting Responsibilities 
 
Merck will report all regulatory reportable serious adverse events from non-CCTG trials (Safety 
Updates) with pembrolizumab to CCTG within the timelines outlined in the contract. CCTG will 
review these events to determine which meet the criteria (serious, unexpected, drug related) for 
reporting to IND.225 investigators. Merck will report these events to Health Canada. 
 
11.7 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to the CCTG. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. The reports will be posted to the CCTG 
trial IND.225 web-based safety monitoring utility. 


 
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Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
IND.225 web based safety monitoring utility and documentation of REB submission must be 
retained in the study binder on site. The REB submission template provided by CCTG can be used 
to assist with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 


 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 8.0. 
• 
Tumour progression or disease recurrence as defined in Section 10.0. 
• 
Request by the patient. 
• 
Completion of therapy as outlined in Section 8.0. 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. 
 
12.2 
Duration of Protocol Treatment  
 
Maximum 1 year or until one or more criteria in Section 12.1 are met. After 1 year, patients may 
continue on pembrolizumab but will transition to standard of care management. 
 
12.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
12.4 
Follow-up Off Protocol Treatment 
 
See Section 9.2. 


 
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13.0 
CENTRAL REVIEW PROCEDURES 
 
13.1 
Central Radiology Review 
 
At the conclusion of the trial, a central review of x-rays and/or scans will be carried out for response. 
CT scans will be reviewed and analyzed for texture analysis. For purposes of reporting, the results 
of both local and central radiology reviews will be included. 
 
13.2 
Central Pathology Review 
 
There will be no central pathology review for this study. 


 
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AMEND #1: 2016-NOV-23 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
This is an open-label, multicentre, phase II trial of pembrolizumab in first line therapy of metastatic 
melanoma. The primary objective is to assess whether tumour texture parameters from a CT scan 
correlates with response in metastatic melanoma patients treated with pembrolizumab. Secondary 
end points include duration of response, overall response rate and survival. 
 
14.2 
Sample Size and Duration of Study 
 
This is the first trial to evaluate tumour texture parameters to correlate them with tumour response 
to pembrolizumab. 
 
Without knowing the true fraction of patients with CT features that are considered “positive” or 
“negative” it is not possible to do a true power calculation and the trial should be viewed as 
exploratory assessment of the potential of texture parameters to correlate with response.  However, 
assuming the response rate to pembrolizumab is 35%, then a sample size of 80 patients will allow 
analysis of CT texture analysis parameters among 20-25 responding patients versus 55-60 non-
responding patients. We propose to recruit 84 patients to identify 80 evaluable patients to assess 
for texture parameters in responders and non-responders which may support further evaluation in 
definitive trials. Sensitivity, specificity, positive and negative predictive values will be assessed. 
 
Accrual rate is anticipated to be approximately 5-10 patients/month for total duration of accrual of 
6-12 months. 
 
Patients will be followed on study for the duration as indicated in Section 12. 
 
14.3 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators' meetings. Adverse events will be categorized using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE). The worst event for each patient in 
each category or subcategory will be described. Both events related and unrelated to treatment will 
be captured.  
 
Clinical and laboratory data will be tabulated and compared to normal ranges for the institution. 
 
14.4 
Economic Analysis 
 
The purpose of the CCTG economic evaluation in this phase II study is to determine the incremental 
cost-effectiveness and cost-utility of pembrolizumab from a universal access government payer 
perspective, over a lifetime time horizon by prospectively collecting resource utilization 
information during this clinical trial and comparing to data collected from public databases. 


 
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In this study, a cost-utility analysis will be conducted to compare the overall cost per quality-
adjusted-life-year (QALY) for pembrolizumab individually with dacarbazine and ipilimumab. Case 
report forms will be used in this study to document non-protocol based health care resource 
utilization 
over 
the 
course 
of 
treatment 
and 
follow-up, 
including 
outpatient 
consultations/visits/investigations, inpatient admissions, emergency room visits, supportive care 
medication for management of toxicity, and investigations/admissions/treatment of adverse events 
and disease progression. Forms will be ascertained at 12-week intervals while on treatment until 
disease progression or a maximum period of 12 months. Unit costs for drugs, hospitalizations, and 
treatments will be ascertained using publically available sources and reported in adjusted Canadian 
dollars.  
 
Patient preferences while on pembrolizumab, or utilities, will be derived from the EQ-5D 
questionnaire [Brooks 1996; Drummond 1997; www.euroqol.org]. The EQ-5D self-administered questionnaire 
consists of two pages comprising the EQ-5D descriptive system and the EQ VAS. The EQ-5D 
descriptive system comprises five dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) and each dimension comprises three levels (no problems, 
some/moderate problems, extreme problems). The five level score may also be used. A unique EQ-
5D health state is defined by combining one level from each of the five dimensions. The EQ 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. EQ-5D will be obtained at prescribed intervals. Utilities for patients on dacarbazine 
and ipilimumab will be obtained from published literature [Tomme 2014]. 
 
A decision analytic Markov model will be used to extrapolate the costs and survival estimates from 
the current study (for pembrolizumab) and dacabazine/ipilimumab in order to generate cost/life-
year estimates over clinically plausible scenarios. Survival estimates for dacarbazine and 
ipilimumab will be obtained from previously published randomized controlled trials [Robert 2011]. 
Life-year estimates will be multiplied by time-weighted utility values to generate QALYs. Use of 
pembrolizumab will be individually compared with dacarbazine and ipilimumab to generate 
incremental cost effectiveness ratios (ICERs) expressed as cost/QALY.  
 
Deterministic and probabilistic sensitivity analyses using Monte Carlo simulations will be used to 
explore the robustness of the model to clinically plausible variations in key assumptions and 
variations in the analytical methods used. Major drivers of medical care costs, including 
hospitalizations, drug costs, and survival, will be varied +/- 20% and based on reported estimates 
provided in the literature. Cost effectiveness acceptability curves will be used to understand the 
impact of different thresholds of cost effectiveness and increase generalizability of results.  
 


 
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15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group and Merck, 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. 
 
15.1.2 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)." 
 
15.2 
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). 
 
15.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by Merck, 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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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
16.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion.  
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs.  
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately.  
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs.  
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable).  
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation.  


 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in a CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject.  
 
16.3.1 Obtaining Consent for Pregnancy Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner) should not be collected about or from them unless or until they are a willing participant in 
the research. The rights and protections offered to participants in research apply and consent must 
be obtained prior to collecting any information about or from them. If the main consent form 
adequately addresses the collection of information regarding the outcome of a pregnancy of a trial 
participant, a “Pregnancy Follow-up consent form will not be required by CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” can be found on the trial webpage. The 
appropriate consent form must be used to obtain consent from any non-trial participant (such as the 
pregnant partner). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy. Similarly, male participants will not be 
withdrawn from the main study should their partner refuse/withdraw permission. 


 
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Obtaining Consent for Research on Children  
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner), consent must be obtained from the parent/guardian.  
 
16.4 
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. 
 
16.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP.  
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site.  
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI). 
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 


 
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As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For 
details of accessing the EDC system and completing the on-line Case Report Forms please refer to 
the “Registration/Randomization and Data Management Guidebook” posted on the IND.225 area 
of the CCTG web-site: www.ctg.queensu.ca. 
 


 
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AMEND #1: 2016-NOV-23 
17.0 
REFERENCES 
Bayanati H, E Thornhill R, Souza CA, Sethi-Virmani V, Gupta A, Maziak D, Amjadi K, Dennie C. Quantitative 
CT texture and shape analysis: Can it differentiate benign and malignant mediastinal lymph nodes in patients 
with primary lung cancer? Eur Radiol. 2014 Sep 13. [Epub ahead of print] PubMed PMID: 25216770. 
Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell 
receptor (TCR) transgenic CD8+ T cells. Cancer Res 2004; 64: 1140-5. 
Brooks R (1996).  EuroQol: the current state of play. Health Policy 37(1):53-72.  
Daud A, Ribas A, Robert C, et al. Keynote-001: Findings support pembrolizumab in melanoma. 2015 ASCO 
Annual Meeting. J Clin Oncol 33, 2015 (suppl;abstr 9005). 
De Ruysscher D. Predicting outcome by images. Clin Cancer Res. 2013. 
Drummond M et al  (1997).  Methods for the economic evaluation of health care programmes.  2nd ed. 
Oxford.  Oxford University Press. 
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney 
M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in 
solid tumors: Revised RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009. 
Goh V, et al. Assessment of response to Tyrosine Kinase Inhibitors in metastatic renal cell cancer: CT texture 
as a predictive biomarker. Radiology. 2011. 61;1: 165-171. 
Hamid O, et al. Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. NEJM 2013; 369; 
2: 134-144. 
Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith 
LS, Espino G, Gergich K, Delgado LM, Daud AI, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, 
Lehnert M, Iannone R, Tolcher AW. Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal 
Antibody) in Patients With Advanced Solid Tumors. Clin Cancer Res. 2015 May 14. pii:clincanres.2607.2014. 
[Epub ahead of print] PubMed PMID: 25977344. 
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis 
KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, 
Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, 
Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, 
Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory 
melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Jun 23. pii: S1470-
2045(15)00083-2. doi: 10.1016/S1470-2045(15)00083-2. [Epub ahead of print] PubMed PMID: 26115796. 
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, 
Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim 
N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced 
Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 
19.PubMed PMID: 25891173. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic 
melanoma. N Engl J Med 2011, 364:2517-2526. 
Seymour L, Bogaerts J, Perrone A et al. iRECIST: Guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2016; in press. 
Tomme I, Devleesschauwer B, Beutels P et al. Health-related quality of life in patients with melanoma expressed 
as utilities and disability weights. Br J Dermatol. 2014 Dec;171(6):1443-50.  
 
 


 
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Win T et al. Tumour heterogeneity as measured on the CT component of PET/CT predicts survival in patients 
with potentially curable non small cell lung cancer. Clin Cancer Res. 2013 Jul 1;19(13):3591-9. doi: 
10.1158/1078-0432. CCR-12-1307. Epub 2013 May 9. PubMed PMID: 23659970. 
Wolchok et al. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related 
Response Criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-20. doi: 10.1158/1078-0432. CCR-09-1624. Epub 
2009 Nov 24. PubMed PMID: 19934295.  
For more information on the EQ-5D questionnaire, please go to website www.euroqol.org. 


 
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AMEND #1: 2016-NOV-23; AMEND #2: 2017-JUL-10 
APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Pre-study 
(within 7 days prior 
to registration, or as 
noted) 
Day 1 
each 
cycle 
As 
clinically 
indicated  
Every 12 
weekly 
visit 
4 wks,  
12 wks then 
every 12 weeks 
4 Weeks post 
treatment  
History & Physical Exam 
 
 
 
 
 
 
Height and Weight 
X1 
X 
 
 
 
X 
ECOG Performance Status 
X1 
X 
 
 
 
X 
Vital signs (blood pressure and 
pulse) 
X1 
X 
 
 
 
X 
Documentation of all measurable 
and non-measurable disease 
X1 
 
 
 
X 
X  
(if applicable) 
Clinical tumour measurements (if 
applicable) 
X1 
X 
 
 
X 
X 
(if applicable) 
Hematology & Biochemistry2 
 
 
 
 
 
 
CBC, differential, platelets 
X 
X 
 
 
 
X 
Serum creatinine, sodium, 
potassium, chloride, bicarbonate, 
bilirubin, ALP, AST, ALT, LDH3,  
X 
X 
 
 
 
X 
Phosphorous, calcium, magnesium, 
albumin 
X 
 
X 
 
 
 
TSH, FT3, FT4 
X 
X4 
 
 
 
 
HCV, HBV screening serology (if 
unknown) 
X 
 
 
 
 
 
Other Investigations 
 
 
 
 
 
 
Pregnancy test, in women of 
childbearing potential only 
X 
 
 
 
 
 
ECG 
X5 
 
X 
 
 
 
Economics 
 
 
 
 
 
 
Health Utilities Index (EQ-5D) 
X 
 
 
X6 
 
 
Resource Utilization Assessment 
 
 
 
X6 
 
 
Radiology 
 
 
 
 
 
 
CT scan with contrast of chest, 
abdomen/pelvis 
Other sites as clinically indicated 
X 
(within 28 days prior to 
registration; 35 if 
negative) 
 
 
 
X7 
X8 
Adverse Events 
 
 
 
 
 
 
Adverse Events/ Baseline Symptoms9 
X 
Continuously each visit 
X 
1 Within 14 days prior to registration. 
2 Bloodwork Timing: Pre-treatment blood draws should be done within 72 hours (maximum) prior to treatment.  
3 LDH is not required after baseline. 
4 Every other cycle 
5 Only required if not done within 6 months prior to registration 
6 Each 12 weekly visit until progression OR maximum 1 year from registration 
7 Patients with a CR or PR should have scans repeated after minimum 4 weeks to confirm response 
8 All patients will be seen at 4 weeks after the end of last cycle date. Thereafter, continued follow-up is not required for patients who go off 
protocol treatment with progressive disease, except to document ongoing toxicities (until resolved to < grade 2) and late toxicities (including 
second malignancies). For patients who go off protocol therapy before progression is documented or have objective CR, PR or SD ongoing, 
follow-up and a Follow-up Report will be required at least every 3 months for a maximum of 1 year. A Death Report will be required for all 
patients.  
9 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
(Appendix V).  


 
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APPENDIX II - 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 III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Drug Distribution 
Full details on Drug Distribution will be posted on the IND.225 webpage. 
 
Pembrolizumab will be supplied by Merck to the distributor, and sent from the distributor to the 
participating centres. 
 
Drug Labelling 
Drug for this study has been labelled in accordance with Health Canada regulations.  
 
Initial Drug Supply 
Once a centre is locally activated (following receipt and review of all required documentation), the 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 5 working days of local activation. Note: Shipment will not be made on Fridays 
and weekends. 
 
Drug accountability forms will be posted on the trial website. 
 
Drug Ordering (Re-Supply) 
Subsequent requests for more drug should be made by authorized personnel at each centre as directed on 
the supplied CCTG Request for Drug Shipment form. The drug re-order form can be found on the IND.225 
website. 
 
Please allow sufficient time for shipment of drug. 
 
Note: Shipment will not be made on Fridays and weekends. Drug accountability and drug re-order forms 
will be posted on the trial website for pharmacists to download. 
 
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 
Expired/used study drug may be destroyed as per local standard operating procedures. Destruction of 
expired/used drug must be documented on the Drug Accountability Log and a copy of the destruction 
certificate kept on file in the pharmacy. Instructions for return or destruction of unused drug will be supplied 
at the time of expiry and at trial closure. 
 
** 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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AMEND #1: 2016-NOV-23 
APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of registration and will apply to all eligible and ineligible 
patients. This trial will use a web-based Electronic Data Capture (EDC) system for all data collection 
including SAE reporting (see section 11.0 for details regarding SAE reporting). For details about accessing 
the EDC system and completing the on-line Case Report Forms, please refer to the Data Management 
Guidebook posted on the IND.225 area of the CCTG web-site (www.ctg.queensu.ca). 
 
Form 
To be Completed/Submitted Electronically: 
Supporting Documentation to be 
sent using Supporting Document 
Upload Tool2 
PATIENT 
ENROLLMENT 
FOLDER 
Must be completed at time of registration to confirm eligibility. 
 
BASELINE 
REPORT  
Due within 2 weeks of patient registration. 
Copies of signed consent 
signature page(s); relevant 
pathology and radiology 
reports; ECG reports 
TREATMENT 
REPORT 
To be completed every 3 weeks (i.e. after each cycle). Due within 
2 weeks of end of cycle. This form documents treatment, adverse 
events, investigations and response assessment for each cycle. 
Relevant radiology reports.  
HEALTH 
UTILITIES INDEX 
(EQ-5D)  
To be completed within 7 days prior to registration and at each 
12 weekly visit until progression OR maximum 1 year from 
registration 
Relevant radiology reports. 
RESOURCE 
UTILIZATION 
ASSESSMENT 
To be completed at each 12 weekly visit until progression OR 
maximum 1 year from registration.  
Relevant radiology reports. 
END OF 
TREATMENT 
REPORT 
To be completed when patient goes off protocol treatment. Due 
within 2 weeks of end of protocol treatment. 
 
4 WEEK POST 
TREATMENT 
REPORT 
To be completed once on all patients, 4 weeks after going off 
protocol treatment. Due within 2 weeks after contact with patient. 
 
FOLLOW-UP 
REPORT 
Continued follow-up is not required for patients who go off 
protocol treatment with progressive disease, except to document 
ongoing toxicities (until resolved to < grade 2) and late toxicities 
(including second malignancies). For patients who go off protocol 
therapy before progression is documented or have objective CR, 
PR or SD ongoing, follow-up and a Follow-up Report will be 
required every 3 months for a maximum of 1 year. Due within 
2 weeks after contact with patient. 
Relevant radiology reports. 
RELAPSE/ 
PROGRESSION 
REPORT 
To be completed at the time of disease relapse or progression. Due 
within 2 weeks after contact with patient. 
Relevant radiology reports. 
DEATH REPORT 
Required for all patients1. Due within 2 weeks of knowledge of 
death. 
Autopsy report, if done. 
SERIOUS 
ADVERSE EVENT 
REPORT FORM 
All reportable serious adverse events must be reported as 
described in Section 11.0. All reportable serious adverse events 
must be reported as described in Section 11.0. Preliminary CCTG 
Serious Adverse Event Report due within 24 hours. Updated 
CCTG Serious Adverse Event Report due within 7 days.  
All relevant test reports; 
admission, discharge 
summaries/notes. 
1 
It is the investigator's responsibility to investigate and report the date/cause of death of any patient. Any death that is thought to be treatment 
related must also be reported as a Serious Adverse Event as described in section 11. 
2 
Supporting documents should be submitted using the Supporting Document Upload Tool. For instructions on this tool, see Power 
Point Presentation available on the IND.225 webpage. 


 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


 
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APPENDIX VI - CT FOR TEXTURE ANALYSIS 
 
CT for Texture Analysis (Baseline, 4 weeks, 12 weeks then every 12 weeks) 
 
CT Platform: CT exam should be performed on the same multi-slice CT scanner model within the same 
institution. 
 
Intravenous contrast: Patients must undergo CT with intravenous contrast unless there is a contrast allergy 
that has developed after the baseline scan, in which case, the subsequent scans will be performed without 
intravenous contrast. 
 
Coverage: Chest, abdomen and pelvis 
 
Scan parameters for baseline, 4 weeks, 12 weeks then every 12 weeks: 
 
Coverage: 
1. Arterial and portal phase abdomen as per local protocol 
2. Pelvis post contrast 
3. Chest post contrast 
 
Contrast: Administered as per local protocol with a single bolus 
 
Other Parameters: 
 
Slice thickness: 5 mm, reconstruction 2.5 mm 
 
CT Radiation Dose and Dose Reduction Method: 
If the CT scanner utilized has dose reduction capabilities (i.e. Auto-mA) these should be set for minimal 
dose reduction to help minimize noise related artifacts. Radiation dose saving approaches which may be in 
use such as those for renal colic or young adults or pediatric patients should not be used. 
 
Central Review 
All CT scans performed on trial at baseline, 4 weeks, 12 weeks then every 12 weeks should be saved to 
DVD/CD and sent for central review with an imaging CT form (posted on the IND 225 webpage) to: 
 
Masoom Haider, MD 
Sunnybrook Health Sciences Centre 
Dept. of Medical Imaging AG-46 
2075 Bayview Ave 
Toronto, Ontario M4N 3M5 


 
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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.225 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 (for this study, at each 12 weekly visit until progression OR maximum 
1 year from registration) 
 
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. 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, eg: psychological distress, social disruption, 
symptoms, side effects, et cetera.  
 
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. 
 
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. 


 
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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) 
 
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.  
 
 


 
PROTOCOL DATE: 2016-MAR-03 
 
CCTG TRIAL: IND.225 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
PATIENT REGISTRATION 
All patients must be registered with CCTG before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Data Management Guidebook, 
Protocol, Safety Information, 
Electronic Case Report Forms, 
Available on CCTG Website 
Available on CCTG Website: 
http://www.ctg.queensu.ca  
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Linda Hagerman 
Study Coordinator. CCTG 
Email: lhagerman@ctg.queensu.ca 
 
or: 
 
Dr. Janet Dancey 
Senior Investigator, CCTG 
Investigational New Drug Program 
Email: jdancey@ctg.queensu.ca 
613-533-6430 
613-533-2411 
STUDY CHAIR 
Dr. Teresa Petrella 
Study Chair 
Email: teresa.petrella@sunnybrook.ca 
416-480-5248 
416-480-7802 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for details 
of reportable events. 
Dr. Janet Dancey 
Senior Investigator, CCTG 
Investigational New Drug Program 
 
or 
 
Linda Hagerman 
Study Coordinator, CCTG 
613-533-6430 
613-533-2411 
DRUG ORDERING 
See Appendix III for full details.