A Phase II Study of CFI-400945 and Durvalumab in Patients With Advanced/Metastatic Triple Negative Breast Cancer (TNBC)
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Canadian Cancer Trials Group

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HEALTH CANADA SUBMISSION: 2019-NOV-01 
ADMINISTRATIVE UPDATE #1: 2019-NOV-14 
AMENDMENT #1: 2020-MAY-13 
AMENDMENT #2: 2020-DEC-04 
CANADIAN CANCER TRIALS GROUP (CCTG) 
A PHASE II STUDY OF CFI-400945 AND DURVALUMAB IN PATIENTS WITH 
ADVANCED/METASTATIC TRIPLE NEGATIVE BREAST CANCER (TNBC) 
CCTG Protocol Number: IND.239 
STUDY CHAIRS: 
David Cescon 
Andrew Robinson 
SENIOR INVESTIGATORS: 
Lesley Seymour 
Pierre-Olivier Gaudreau 
BIOSTATISTICIAN: 
Dongsheng Tu 
STUDY COORDINATOR: 
Caitlin Burns 
REGULATORY SPONSOR: 
CCTG 
SUPPORTED BY: 
AstraZeneca,  
University Health Network (drug only) 
(For contact information of study personnel see Final Page.) 
NCT04176848

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

 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) ................................................................................... 1 
 
TREATMENT SCHEMA....................................................................................................................................... 2 
1.0 
OBJECTIVES ........................................................................................................................................... 3 
1.1 
Primary Objective ..................................................................................................................................... 3 
1.2 
Secondary Objectives ................................................................................................................................ 3 
1.3 
Tertiary Objective ..................................................................................................................................... 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 4 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION ............................................................................. 6 
3.1 
CFI-400945 ............................................................................................................................................... 6 
3.2 
Durvalumab ............................................................................................................................................... 7 
 
4.0 
STUDY POPULATION ........................................................................................................................... 9 
4.1 
Eligibility Criteria ..................................................................................................................................... 9 
4.2 
Ineligibility Criteria ................................................................................................................................. 11 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT......................................................................................................................................... 14 
5.1 
Follow-up for Ineligible Patients ............................................................................................................ 15 
 
6.0 
ENTRY/ENROLLMENT PROCEDURES ............................................................................................ 16 
6.1 
Entry Procedures ..................................................................................................................................... 16 
6.2 
Study Enrollment .................................................................................................................................... 16 
6.3 
Inclusion of Women and Minorities ....................................................................................................... 17 
 
7.0 
TREATMENT PLAN ............................................................................................................................. 18 
7.1 
Treatment Plan ........................................................................................................................................ 18 
7.2 
Concomitant Therapy .............................................................................................................................. 23 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS .......................................................... 24 
8.1 
Definitions ............................................................................................................................................... 24 
8.2 
Response and Evaluation Endpoints ....................................................................................................... 24 
8.3 
Immune-Related Response Assessment ................................................................................................. 27 
8.4 
Response Duration (RECIST 1.1 and iRECIST) .................................................................................... 30 
8.5 
Stable Disease Duration .......................................................................................................................... 30 
8.6 
Methods of Measurement........................................................................................................................ 30 
 
9.0 
SERIOUS ADVERSE EVENT REPORTING ....................................................................................... 32 
9.1 
Definition of a Reportable Serious Adverse Event ................................................................................ 32 
9.2 
Serious Adverse Event Reporting Instructions ....................................................................................... 32 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting ............................ 33 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 35 
9.5 
CCTG Reporting Responsibility to AstraZeneca ................................................................................... 35 
9.6 
CCTG Reporting Responsibility to UHN ............................................................................................... 35 
9.7 
UHN and AstraZeneca Reporting Responsibilities ................................................................................ 35 
9.8 
Reporting Serious Adverse Events to Investigators ............................................................................... 35 
 
 

 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 37 
10.1 
Criteria for Discontinuing Protocol Treatment ....................................................................................... 37 
10.2 
Duration of Protocol Treatment .............................................................................................................. 37 
10.3 
Therapy After Protocol Treatment is Stopped ........................................................................................ 37 
10.4 
Follow-up Off Protocol Treatment ......................................................................................................... 37 
 
11.0 
CENTRAL REVIEW PROCEDURES .................................................................................................. 39 
11.1 
Central Data Review ............................................................................................................................... 39 
11.2 
Central Radiology Review ...................................................................................................................... 39 
11.3 
Central Pathology Review ...................................................................................................................... 39 
 
12.0 
CORRELATIVE STUDIES ................................................................................................................... 40 
12.1 
Protocol-Mandated Correlative Studies .................................................................................................. 40 
 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................... 42 
13.1 
Primary Endpoints and Analysis ............................................................................................................. 42 
13.2 
Sample Size and Duration of Study ........................................................................................................ 42 
13.3 
Safety Monitoring ................................................................................................................................... 42 
 
14.0 
PUBLICATION POLICY ...................................................................................................................... 43 
14.1 
Authorship of Papers, Meeting Abstracts, Etc........................................................................................ 43 
14.2 
Responsibility for Publication................................................................................................................. 43 
14.3 
Submission of Material for Presentation or Publication ......................................................................... 43 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES....................................................... 44 
15.1 
Regulatory Considerations ...................................................................................................................... 44 
15.2 
Inclusivity in Research ............................................................................................................................ 44 
15.3 
Obtaining Informed Consent................................................................................................................... 45 
 
16.0 
REFERENCES ........................................................................................................................................ 48 
 
APPENDIX I -  
PERFORMANCE STATUS SCALES/SCORES ................................................................. 49 
APPENDIX II - 
DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED 
REACTIONS ......................................................................................................................... 50 
APPENDIX III -  DRUG DISTRIBUTION, SUPPLY AND CONTROL ........................................................ 51 
APPENDIX IV -  DOCUMENTATION FOR STUDY ..................................................................................... 53 
APPENDIX V -  NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ...................... 55 
APPENDIX VI -  PROHIBITED MEDICATIONS ........................................................................................... 56 
APPENDIX VII -  EMERGENCY SITUATIONS AND COMPLIANCE ......................................................... 57 
 
 
LIST OF CONTACTS ............................................................................................................................. Final Page 
 

 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol and any supplementary information that may be added to this document, 
contains information that is confidential and proprietary and must be kept in confidence. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, in accordance with any modifications that may 
occur over the duration of the study, and according to Good Clinical Practice and any applicable local 
regulations. I will make a reasonable effort to complete the study within the time designated. I confirm that 
I and study personnel participating under my supervision have adequate resource to fulfill their 
responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG 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 UHN, AstraZeneca and CCTG. The foregoing shall not apply 
to disclosure required by governmental regulations or laws; however, I will give prompt notice to UHN, 
AstraZeneca and CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrollment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG, UHN or AstraZeneca with or without cause. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG IND.239 
 
CENTRE: ___________________________________________ 

 
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TREATMENT SCHEMA 
 
This is a multicentre, open-label phase II study of CFI-400945 and durvalumab in patients with advanced 
or metastatic triple negative breast cancer. Up to 28 patients will be enrolled. This study is being conducted 
by the Canadian Cancer Trials Group (CCTG) and supported by AstraZeneca and University Health 
Network (provision of CFI-400945 only). 
 
Patient with unresectable 
locally recurrent or metastatic 
triple negative breast cancer 
 
Cycle 1 
CFI-400945 orally  
 
Cycle 2 on: 
CFI-400945 orally once daily x 28 days 
and  
Durvalumab 1500 mg IV on Day 1 q28d 
 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate the objective response rate (RECIST 1.1) of CFI-400945 given with durvalumab. 
 
1.2 
Secondary Objectives 
• 
To evaluate Disease Control Rate (DCR, defined as CR or PR or stable disease (SD) > 16 
weeks in duration) of CFI-400945 given with durvalumab. 
• 
To evaluate the immune-related response rate (iRECIST) of CFI-400945 given with 
durvalumab. 
• 
To establish the safety and tolerability of CFI-400945 given orally in combination with 
durvalumab in a q4w schedule and to confirm the recommended phase II dose (RP2D) in 
patients with metastatic triple negative breast cancer (TNBC). 
 
1.3 
Tertiary Objective 
• 
To assess the pharmacodynamic and immune effects of CFI-400945+durvalumab. 
 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Recent advancements in the treatment of breast cancer have led to higher rates of cure for early 
stage disease, and longer survival for those living with metastatic disease. However, there remains 
a critical need for new and effective therapies for those whose disease is resistant or becomes 
resistant to currently available options. This need is especially urgent for triple negative breast 
cancer (TNBC), an aggressive subtype associated with early lethality, for which chemotherapy is 
the only approved treatment (apart from PARP inhibitors in patients with germline BRCA1/2 
mutations). 
 
Studies of anti-PD-1/PD-L1 immune checkpoint inhibitors have shown some monotherapy activity 
in TNBC, but this is very limited in patients with features of aggressive disease (liver metastases, 
elevated LDH), and response rates observed in the second line or later setting are ~ 5%. [Adams 
2017(a); Adams 2017(b); Emens 2018]. 
 
More recently, multiple clinical trials in the neoadjuvant and metastatic settings have evaluated 
anti-PD-1/PD-L1 antibodies in combination with cytotoxic chemotherapy in TNBC. The first of 
these to be reported has shown an improvement in progression free survival with the addition of the 
anti- PD-L1 antibody atezolizumab to nab-paclitaxel chemotherapy. However, since the majority 
of patients developing metastatic TNBC have received anthracyclines and taxanes in the 
neo/adjuvant setting, chemoresistance is a major challenge. Thus, non-chemotherapy options could 
have significant advantages, both in terms of efficacy and treatment-associated toxicity. This study 
seeks to augment the efficacy of PD-L1 blockade in TNBC by developing a combination of 
durvalumab with a first in class inhibitor of Polo-like Kinase 4 (PLK4), a cytotoxic small molecule 
oral therapy with potent pre-clinical activity in TNBC models which can be safely administered to 
patients with advanced solid tumours [Mason 2014]. 
 
PLK4 is an atypical member of the Polo-like serine/threonine kinases and differs from other PLK 
enzymes in structure and function. PLK4 controls centriole duplication and mitotic progression, 
and was identified as a drug target based on functional screening to identify vulnerabilities of 
genomically unstable breast cancers [Mason 2014; Dominguez-Brauer 2015]. CFI-400945 was generated 
as a potent, selective and orally bioavailable inhibitor of PLK4 (PLK4 Ki=0.26 nM) [Mason 2014; Yu 
2015], and was advanced into clinical development based on desirable pharmacologic properties 
and pre-clinical antitumour activity. In vitro, CFI-400945 exhibits potent anti-proliferative effects 
in cancer cell lines via induction of apoptosis and cell cycle arrest with induction of aneuploidy. In 
vivo testing of diverse models, including cell line and patient-derived xenografts of breast and 
ovarian cancer confirmed potent anti-tumour effects at tolerable doses [Mason 2014]. 
 
A first-in-human phase I dose escalation study of CFI-400945 evaluated dose levels from 3 to 96 
mg/day [NCT01954316]. CFI-400945 was generally well-tolerated, with dose limiting toxicities of 
neutropenia and asymptomatic lipase elevation (n=1) observed at doses ≥ 72 mg/day. No 
significant treatment-emergent/dose-dependent toxicities other than neutropenia were observed. 
Evidence of anti-tumour activity was observed in a patient with KRAS mutant colorectal cancer 
who remained on study for 12 cycles at 48 mg/day (best response -24%), and a patient with AKT1- 
mutated endometrioid endometrial cancer (best response to any prior therapy had been progressive 
disease) had a minor response (19% shrinkage of target lesion) for 6 cycles. Long term tolerability 
has been confirmed, including a patient who remained on trial for over 24 months (48 mg/day). 
Please refer to the most recent version of the Investigator Brochure for more details. 
 
 

 
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Unexpected responses to immune checkpoint blockade were observed in 2 patients (KRAS-mut 
CRC and AKT1-mut MSS endometrial cancer) who had experienced prior tumor shrinkage with 
CFI-400945. Based on hypotheses that the induction of aneuploidy caused by treatment with CFI-
400945 could create an immunogenic stimulus [Davoli 2017], and supported by these clinical 
anecdotes, where patients pre-treated with CFI-400945 experienced unexpected responses to ICB, 
the combination of CFI- 400945 and PD-1 inhibition was evaluated in transplantable murine cancer 
models (MC38 and CT26). In both models, the combination of CFI-400945 and PD-1 blockade 
resulted in increased antitumour activity compared to either agent alone, as evidenced by an 
increased rate of tumour regressions. Importantly, specific antitumour immunity was also observed, 
as demonstrated by resistance to reinoculation of the same cell line. 
 
Durvalumab is a FDA-approved immunotherapy that blocks PD-L1/PD-1 interaction. Its 
antitumour activity has been observed in many solid tumours [Massard 2016]. Development in breast 
cancer has focused on combinations, including with chemotherapy, targeted therapy (olaparib), and 
with other immune checkpoint inhibitors (tremelimumab). While no large study of durvalumab in 
breast cancer has been reported, the largest studies of PD-1 and PD-L1 inhibitors in chemotherapy-
pretreated patients with metastatic TNBC have shown response rates in the ~5% range [Adams 
2017(b); Emens 2018]. The safety and tolerability of durvalumab is well-established, making it an 
excellent potential combination partner for CFI-400945 for which overlapping toxicities are not 
expected. 
 
Given the robust preclinical activity of CFI-400945 in TNBC [Mason 2014], the clinical activity of 
CFI-400945 in advanced solid tumours (with a tolerable and convenient oral dosing schedule), and 
non-overlapping toxicity with durvalumab, we propose the clinical evaluation of the combination 
of CFI-400945 plus durvalumab in patients with chemotherapy-resistant TNBC whose tumours are 
unlikely to benefit from single agent immune checkpoint inhibitor. 
 
 

 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
CFI-400945 
 
Consult the most recent version of the investigator brochure for current information. 
 
3.1.1 
Mechanism of Action 
 
In pre-clinical studies, CFI-400945 was shown to be a selective and potent inhibitor of Polo-like 
Kinase 4 (PLK4), which regulates centriole duplication. CFI-400945 does not inhibit PLK 1-3 at 
relevant doses. PLK4 is overexpressed in a variety of solid tumours, and elevated expression is 
associated with poor clinical outcomes [Hu 2006; Miller 2005; Van de Vijver 2002]. Depletion of 
PLK4 expression in cancer cells by RNA interference leads to mitotic defects and cell death [Mason 
2014]. Thus, pharmacologic inhibition of this target is expected to produce antiproliferative and 
cytotoxic effects against cancer cells, as has been observed in mechanistic studies with CFI-400945. 
 
3.1.2 
Experimental Antitumour Activity 
 
CFI-400945 induces apoptosis and inhibits proliferation of human breast cancer cell lines at 
nanomolar concentrations. In vivo anti-tumour activity of CFI-400945 has been shown in mice 
bearing human cancer xenografts of multiple histologies, including robust tumour growth inhibition 
and durable tumour regression in primary tumour xenografts of breast and ovarian cancer [Mason 
2014]. 
 
3.1.3 
Clinical Trials 
 
Human experience with CFI-400945 consists of a dose-finding phase I study (CFI-400945-CL-
001) in which subjects with treatment refractory advanced solid tumours were evaluated. As of 
December 20, 2017, interim safety data are available for a total of 50 subjects treated in 10 cohorts 
dosed over the range of 3 – 96 mg/day in 28-day continuous cycles. A RP2D of 64 mg/day for the 
continuous dosing schedule has been established. DLTs in the 72 mg and 96 mg cohorts included 
G3 neutropenia in both cohorts, G4 febrile neutropenia in the 64 mg and 96 mg cohorts, and 
asymptomatic G4 lipase elevation in the 72 mg cohort. The common related AEs (≥ 10%) were 
fatigue, nausea, decreased appetite, diarrhea, neutrophil count decreased and neutropenia. Two 
possibly related AEs led to study discontinuation; serum amylase/lipase increase (72 mg/day) and 
febrile neutropenia (64 mg/day). Dose-limiting toxicity (DLT) occurred in four subjects; these were 
serum amylase/lipase increase and neutropenia (72 mg/day), and two cases of febrile neutropenia 
(64 mg/day and 96 mg/day). To add an additional safety margin to mitigate risk of early onset 
myelosuppression seen in a minority of patients, more intensive hematologic monitoring was added 
to this period, and a 14 day run in (Cycle 0), consisting of 7 days of CFI-400945 dosing followed 
by 7 days without CFI-400945 dosing was implemented. No cardiac toxicity was observed in the 
phase I dose escalation or expansion. Please refer to the most recent version of the Investigator 
Brochure for full details. 
 
 

 
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3.1.4 
Justification of Dose Selection 
 
In the first in human phase I study of CFI-400945, 64 mg/day was the determined to be the RP2D, 
and was the dose selected for the solid tumour expansion cohort. Because of the occurrence of 
Grade 4 febrile neutropenia in 1 patient in the expansion cohort (1/7 patients treated at 64 mg/day; 
occurring in a patient with other disease-related factors that may have increased susceptibility to 
this event), a 14 day run in consisting of 7 days of daily dosing at 64 mg/day followed by a 7-day 
rest period with no dosing, was implemented to mitigate the small risk of early onset neutropenia. 
Antitumour activity was observed in the phase I study at doses as low as 48 mg/day. 
 
On this study, a starting dose of 64mg/ day was used. Of the first 5 patients enrolled, 4 had 
neutropenia. Of these patients, 2 had grade 4 neutropenia within the first cycle, 1 had grade 4 
neutropenia within the second cycle and 1 had grade 3 neutropenia within the second cycle. One 
patient required hospitalization for febrile neutropenia (and growth factors), while a second patient 
required prophylactic growth factors. Three patients required dose modifications. The study was 
placed on temporary hold and a safety review was conducted. Other than the usage of a different 
lot of CFI-400945, the only apparent correlation with clinical factors was a single patient with 
disease related hepatic dysfunction at baseline. Based upon those data the trial was reopened at 
48 mg/day, with a revised dose modification schema, and provision for escalation in selected 
patients. Six patients were enrolled at this dose level with 5 requiring a dose modification. As a 
result, the trial was reopened at 40mg/day. Eight patients were enrolled at this dose level. Of these 
patients, two had grade 4 neutropenia and one had febrile neutropenia. Five patients required a dose 
hold related to neutropenia and three required a dose reduction related to the neutropenia. As a 
result, 32 mg/day has been declared as the recommended phase II dose and a safety cohort of six 
patients will be enrolled prior to opening accrual to additional centres.  
 
3.1.5 
Pharmaceutical Data 
 
Supplied: 
Refer to the Pharmacy Manual for most current information. 
 
Stability and Storage: 
CFI-400945 tablets will be packaged into high-density polyethylene or polypropylene bottles and 
sealed with a child-resistant closure. CFI-400945 tablets should be stored at ambient temperature 
(15-30°C). 
 
Route of Administration: 
CFI-400945 is taken orally at least 1 hour before, and 2 hours after, any food. 
 
3.2 
Durvalumab 
 
See the current durvalumab product monograph for additional details and the most up to date 
information. 
 
3.2.1 
Name and Chemical Information 
 
Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1κ) subclass 
that inhibits binding of programmed cell death ligand (PD-L1) (B7 homolog 1[B7-H1], cluster of 
differentiation [CD]274) to program cell death 1 (PD-1; CD279) and CD80 (B7-1). 
 
 

 
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3.2.2 
Mechanism of Action 
 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect 
of PD-L1 on primary human. T cells, resulting in their restored proliferation and release of 
interferon gamma (IFN-γ). 
 
3.2.3 
Clinical Trials 
 
As of the most recent Investigator’s Brochure, over 6000 subjects have been enrolled and treated 
in ongoing durvalumab clinical studies. No studies have been completed or terminated prematurely 
due to toxicity. 
 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
appears consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumour types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include pneumonitis, hepatitis, diarrhea/colitis and intestinal perforation, 
endocrinopathies 
(thyroiditis, 
hypo 
and 
hyperthyroidism, 
adrenal 
insufficiency, 
hypophysitis/hypopituitarism diabetes insipidus and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent irAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. Other 
inflammatory responses that are rare with a potential immune-mediated etiology include, but are 
not limited to, pericarditis, sarcoidosis, uveitis and other events involving the eye (e.g. keratitis and 
optic neuritis), skin (e.g. scleroderma, vitiligo and pemphigoid), hematological (e.g. hemolytic 
anemia and immune thrombocytopenic purpura) and rheumatological (e.g. polymyalgia rheumatic 
and autoimmune arthritis) events, vasculitis, non infectious encephalitis or non infectious 
meningitis. It is possible that events with an inflammatory or immune mediated mechanism could 
occur in nearly all organs. Please refer to the most recent version of the Investigator Brochure for 
incidence. 
 
3.2.4 
Justification of Dose Selection 
 
Based on average body weight of 75 kg, a fixed dose of 1500 mg Q4W is planned. Fixed dosing of 
durvalumab is recommended only for subjects with > 30kg body weight due to endotoxin exposure. 
Patients with a body weight less than or equal to 30 kg should be dosed using a weight-based 
(20mg/kg) dosing schedule. This is not expected to be applicable to this trial in an adult patient 
population. 
 
3.2.5 
Pharmaceutical Data 
 
Supplied: 
Please see the Pharmacy Manual. Durvalumab will be supplied by AstraZeneca/MedImmune as a 
500 mg vial solution for infusion after dilution. The solution contains 50 mg/mL durvalumab. The 
nominal fill volume is 10.0 mL. 
 
Storage: 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug 
product should be kept in original packaging until use to prevent prolonged light exposure. 
 
Route of Administration: 
Intravenous. 
 
 

 
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4.0 
STUDY POPULATION 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
4.1 
Eligibility Criteria 
 
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 and to ensure that the results of this study can be useful for making treatment decisions 
regarding other patients with similar disease(s). 
 
These eligibility criteria are expected to be followed. Any proposed variance must be discussed 
with CCTG prior to patient enrollment. 
 
4.1.1 
Patients must have histologically and/or cytologically confirmed diagnosis of breast cancer, that is 
advanced/metastatic or unresectable, for which no curative therapy exists, and be negative for ER, 
PR and HER2 by ASCO/CAP criteria on the most recent sample. Patients with tumour with either 
low (< 10%) ER expression who are PR and HER2 negative, or ER and HER2 negative but with 
low PR (< 10%) may be enrolled after discussion and confirmation with CCTG. 
 
4.1.2 
Only female patients will be enrolled. 
 
4.1.3 
All patients must have a formalin fixed paraffin embedded tissue block (from primary or metastatic 
tumour) available and must have provided informed consent for the release of the block (see 
Section 12.1). 
 
Biopsies are optional but strongly encouraged for patients with accessible disease suitable for 
biopsy. The timing of tumour biopsies for patients who provide informed consent and are willing 
is prior to treatment (after enrollment; patients with biopsies within 90 days of enrollment with 
available blocks do not need re-biopsy), and again in Cycle 3, Day 1-8. An additional biopsy at the 
time of progression in patients with clinical benefit (see Section 5) is also encouraged. Lesions 
planned for biopsy must not be the only target lesion.  
 
4.1.4 
Presence of clinically and/or radiologically documented disease. All radiology studies must be 
performed within 21 days prior to enrollment (within 28 days if negative). 
 
All patients must have measurable disease as defined by RECIST 1.1. The criteria for defining 
measurable disease are as follows: 
Chest x-ray 
≥ 20 mm 
CT scan (with slice thickness of 5 mm) 
≥ 10 mm  longest diameter 
Physical exam (using calipers) 
≥ 10 mm 
Lymph nodes by CT scan 
≥ 15 mm  measured in short axis 
 
4.1.5 
Patients must be ≥ 18 years of age. 
 
4.1.6 
Patients must have an ECOG performance status of 0 or 1. 
 
 

 
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4.1.7 
Patients must have a life expectancy of 3 months or longer. 
 
4.1.8 
Laboratory Requirements 
(must be done within 7 days prior to enrollment) 
 
Hematology 
Absolute neutrophils  
> 1.5 x 109/L 
Platelets 
> 100 x 109/L 
Chemistry 
Bilirubin 
< 1.5 x ULN (upper limit of normal)* 
AST and ALT 
< 2.5 x ULN 
≤ 4.0 x ULN if patient has liver metastases 
Serum creatinine 
or: 
Creatinine clearance** 
< 1.5 x ULN 
 
> 50 mL/min 
* 
If confirmed Gilbert’s, eligible provided ≤ 3 x ULN. 
** Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft and Gault 
equation below: 
Females: GFR = 1.04 x (140-age) x weight in kg / serum creatinine in μmol/L 
 
4.1.9 
Patients must be able to swallow oral medications and have no known gastrointestinal disorders 
that may interfere with absorption (such as malabsorption). 
 
4.1.10 Previous Therapy 
 
Chemotherapy: 
Patients must have had at least 1 prior line of cytotoxic chemotherapy for breast cancer, in any 
setting, which must have included an anthracycline and a taxane (unless contraindicated). Select 
patients that have not received both anthracycline and taxane therapy may be considered eligible 
after discussion with CCTG. There is no limit to the number of prior chemotherapy regimens. 
 
Other Systemic Therapy: 
Patients may have received other therapies including endocrine therapy and/or targeted therapies 
(including CDK4/6 inhibitors and PARP inhibitors). 
 
Patients may not have received prior immunotherapies of any kind, nor any agent targeting PLK4. 
 
Patients must have recovered (to at least grade 0 or 1) from all reversible toxicity related to prior 
chemotherapy or systemic therapy and have adequate washout as follows: 
 
Longest of one of the following: 
• 
Two weeks, 
• 
5 half-lives for investigational agents, 
• 
Standard cycle length of standard therapies. 
 
Radiation: 
Prior external beam radiation is permitted provided a minimum of 28 days (4 weeks) have elapsed 
between the last dose of radiation and date of enrollment. Exceptions may be made for low-dose, 
non-myelosuppressive radiotherapy after consultation with CCTG. Concurrent radiotherapy is not 
permitted. 
 
 

 
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Surgery: 
Previous surgery is permitted provided that a minimum of 21 days (3 weeks) have elapsed between 
any major surgery and date of enrollment, and that wound healing has occurred. 
 
4.1.11 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial to document 
their willingness to participate. 
 
4.1.12 Patients must be accessible for treatment and follow-up. Patients enrolled on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 
The patient’s city of residence may be required to verify their geographical proximity. Call the 
CCTG office (613-533-6430) if questions arise regarding the interpretation of this criterion. 
Investigators must assure themselves the patients enrolled on this trial will be available for 
complete documentation of the treatment, adverse events, and follow-up. 
 
Patients must agree to return to their primary care facility for any adverse events and response 
assessment which may occur through the course of the trial. 
 
4.1.13 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
enrollment. 
 
4.1.14 Women 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 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, she is responsible for beginning contraceptive measures. 
 
Female patients of childbearing potential who are sexually active with a non-sterilized male partner 
must use at least one highly effective method of contraception (failure rate of < 1% per year) while 
on study and for 3 months after the last dose of CFI-400945 and durvalumab. Cessation of birth 
control after this point should be discussed with a responsible physician. See Section 9.3 for 
additional details. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Section 5.0); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
4.1.15 Subjects should not donate blood while participating in this study, or for at least 90 days following 
the last infusion of durvalumab. 
 
4.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
 

 
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4.2.1 
Patients with a history of other malignancies, except: adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with 
no evidence of disease for > 2 years and which do not require ongoing treatment. 
 
4.2.2 
Patients with serious illnesses or medical conditions which would not permit the patient to be 
managed according to the protocol (including corticosteroid administration), or would put the 
patient at risk. This includes but is not limited to: 
• 
History of significant neurologic or psychiatric disorder which would impair the ability to 
obtain consent or limit compliance with study requirements. 
• 
Active infection requiring systemic therapy; (including any patient known to have active 
hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or tuberculosis or any 
infection requiring systemic therapy). 
• 
Active peptic ulcer disease or gastritis. 
• 
Known pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary 
function. 
• 
Patients with diabetes mellitus are eligible but must be clinically stable on therapy (if 
applicable) and investigator and patient should be aware of the potential risk of immune 
mediated pancreatic toxicity and B cell destruction. 
 
4.2.3 
Patients are not eligible if they have a known hypersensitivity to the study drug(s) or their 
components. 
 
4.2.4 
Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have 
symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction 
within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 
3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if 
controlled, should have a LVEF ≥ 50%. 
 
4.2.5 
Patients may not receive concurrent treatment with other anti-cancer therapy (other than bone- 
targeted therapy, if already taking and stable) or investigational agents while on protocol therapy. 
 
4.2.6 
Patients who have received growth factors within 28 days prior to initiation of dosing of CFI- 
400945 or who will require treatment with growth factors throughout the duration of the trial. 
 
4.2.7 
Pregnant or breastfeeding women. 
 
4.2.8 
Patients being treated with drugs listed in Appendix VI Table 1 are excluded. Patients being treated 
with drugs listed in Appendix VI Table 2 may be enrolled, but should be monitored carefully for 
toxicities resulting from potential interactions between CFI-400945 and these drugs. In addition, 
patients must avoid consumption of the fruit or juice of Seville oranges (e.g. marmalade), 
grapefruit, pomelos and star fruit from 7 days before the first dose of study drug and during the 
entire study due to potential CYP3A4 interaction with the study drug. Regular orange juice is 
allowed. 
 
 

 
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4.2.9 
Patients with history of central nervous system metastases or spinal cord compression unless they 
have received definitive treatment, are clinically stable and do not require corticosteroids. 
 
4.2.10 Patients with any medical condition that would impair the administration of oral agents including 
significant bowel resection, inflammatory bowel disease or uncontrolled nausea or vomiting. 
 
4.2.11 Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel 
disease (e.g. colitis or Crohn’s disease), diverticulitis with the exception of diverticulosis, celiac 
disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic 
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with 
polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the 
start of treatment. The following are exceptions to this criterion: 
• 
Patients with alopecia. 
• 
Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within the 
last 2 years). 
• 
Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone 
replacement. 
 
4.2.12 History of primary immunodeficiency, history of allogenic organ transplant that requires 
therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of 
enrollment *. 
* 
NOTE: Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day of 
prednisone or equivalent dose of an alternative corticosteroid are permissible. 
 
4.2.13 Live attenuated vaccination administered within 30 days prior to enrollment or within 30 days of 
receiving durvalumab. 
 
4.2.14 Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4. 
 
4.2.15 Patients being treated with full dose warfarin. Patients with history of deep vein thrombosis or 
pulmonary embolus who are being treated with therapeutic doses of low molecular weight heparin, 
direct factor Xa inhibitors or prophylactic dose anticoagulants may be enrolled. 
 
 

 
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5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT  
 
All patients entered on study must be evaluated according to the schedule outlined below with 
documentation submitted according to the schedule in Appendix IV. 
 
Required Investigations 
Pre-study 
(≤ 7 days 
prior to 
enrollment) 
Biweekly 
cycles 1 and 
2 and then 
Weekly 
Day 1 each 
cycle, and as 
clinically 
indicated 
Every 8 weeks 
4 weeks 
after end of 
last cycle 
date 
3 monthly follow-up 
(only required for pts 
without PD and 
ongoing toxicities1) 
then every 6 months 
until death 
History and Physical Exam* 
 
 
 
 
 
 
Including: height2 and weight, ECOG 
performance status, documentation of all 
measurable and non-measurable disease, 
clinical tumour measurements (if applicable); 
Vital signs: blood pressure, heart rate, 
temperature 
X 
 
X 
 
X 
 
Laboratory Procedures/Assessments* 
 
 
 
 
 
 
CBC (neutrophils, platelets) 
X 
X3 
 
 
X4 
X4 
PTT, PT/INR 
X 
 
 
 
 
 
Serum creatinine5, calcium, magnesium, 
phosphate, bilirubin, ALP, AST, ALT, 
LDH, albumin, glucose, amylase/lipase6 
X 
 
X 
 
X4 
X4 
TSH7 
X 
 
X 
 
X4 
X4 
Pregnancy Test8 
X 
 
X9 
 
 
 
Urinalysis 
X10 
 
 
 
 
 
Radiology 
 
 
 
 
 
 
Tumour Imaging (Chest/upper abdomen CT 
scan; bone scan11; other scans as necessary 
to document disease)12 
X13 
(within 21 days 
prior to 
enrollment or 
28 days if 
negative) 
 
 
X 
X14 
X14 
Other Investigations 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
LVEF 
X10 
 
 
 
 
 
Archival Tumour Tissue  
X15 
 
 
 
 
 
Correlative Studies Blood Sampling 
X16 
See Section 12.0 for details 
Tumour biopsies 
X17 
X17 
 
Patient Drug Administration Diary  
(CFI-400945) 
 
Each cycle 
 
Adverse events 
X 
Continuously 
X1 
 
Footnotes on next page … 
 
 

 
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*  
Pre-treatment blood draws and physical exams may be done up to two working days prior to treatment if necessary (e.g. Friday for 
treatment on Monday, or to accommodate holidays). In order to ensure that nadir counts are not missed, every effort should be made to do 
interim blood draws within 24 hours of the day specified in the protocol. If a patient shows an AST or ALT ≥ 3 x ULN together with total 
bilirubin ≥ 2 x ULN, refer to Appendix II for further instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law. 
These cases should be reported as SAEs if, after evaluation, they meet the criteria for a Hy’s law case or if any of the individual liver test 
parameters fulfill any of the SAE criteria 
1 
Adverse events felt to be related to protocol therapy will be followed until resolved to ≤ Grade 2. Reversible durvalumab- related adverse 
events ≥ grade 3 should be followed until resolved to baseline grade including related toxicity that occurs in the follow up period.  
Irreversible events may not need to be followed.  Contact CCTG to discuss.  Adverse Events to be evaluated using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE v5.0) (see Appendix V). 
2 
Height is only required at baseline. 
3 
Hematology is to be done twice weekly cycles 1 and 2. Provided patient has not experienced grade 3 or 4 neutropenia, hematology can be 
done weekly cycle 3 onward. For patients on for 6+ cycles, contact CCTG for a waiver if appropriate. See section 7 for additional 
monitoring of patients with toxicity. 
4 
Required at 4 weeks. To be done additionally every 3 months thereafter to follow abnormal lab results felt related until resolved to ≤ 
Grade 2. 
5 
If creatinine > 1.5 x ULN, calculated CrCl is required and must meet eligibility criteria for re-treatment. For patients who have discontinued 
CFI-400945 and are continuing on durvalumab alone, criteria for creatinine clearance may be lower. Please contact CCTG to discuss. 
6 
Required at baseline then as clinically indicated. It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 
of these parameters is routinely measured then either lipase or amylase is acceptable. 
7 
Free T3 and free T4 will be measured if TSH is abnormal. 
8 
For women of childbearing potential only (urine or serum test). Within 72 hours prior to enrollment. Pregnancy test (in women of 
childbearing potential), as part of Pre-Study Evaluation, may include an ultrasound to rule-out pregnancy. 
9 
As clinically indicated in WOCBP. 
10 
Required at baseline then as clinically indicated. 
11 
Bone scan is required at baseline for all patients. Thereafter, bone scan is only required to be repeated if positive at baseline to confirm 
CR/iCR, PR/iPR or SD/iSD, and/or when PD is suspected and as clinically indicated. 
12 
To ensure comparability, baseline scans and subsequent scans to assess response must be performed using identical technique (i.e. scans 
performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast agent, and 
preferably the same scanner). Maintain schedule every 8 weeks, even if cycles are delayed. 
13 
In order to evaluate tumour growth rate, if additional imaging was done prior to baseline radiology (done 3-12 weeks prior to Baseline 
scan), scans should also be evaluated according to RECIST 1.1 criteria and submitted with baseline reports. Note selection of target and/or 
non-target lesions is based on baseline imaging only. The same lesions (target and/or non-target) selected on baseline imaging should then 
be assessed on the pre-baseline scans if present. 
14 
To be done every three months until relapse or progression (iCPD), for patients with CR/iCR, PR/iPR, SD/iSD response as defined in 
Section 8.0. Patients with CR/iCR or PR/iPR or equivocal PD (pseudoprogression)/iUPD should have scans repeated after 4 weeks, but no 
more than 8 weeks, to confirm response. 
15 
Must be confirmed available prior to enrollment on ALL patients. See Section 12.0 for details. 
16 
After enrollment but before the first dose of study treatment. Please refer to Section 12 and the Correlative Studies Manual for details 
regarding collection. 
17 
Optional paired biopsies should be obtained after enrollment (unless biopsy with available block within 90 days of enrollment) but prior to 
first dose and Cycle 3 (D1-8). Biopsies are also strongly recommended in all consenting patients when radiological disease progression on 
therapy is confirmed among patients who had initial response of CR/iCR, PR/iPR or SD/iSD greater than 4 months. See Section 12.1 for 
details. 
 
5.1 
Follow-up for Ineligible Patients 
 
The follow-up requirements for ineligible patients who have received no protocol therapy include 
submission of the Baseline Report and End of Treatment Report. Data submission for ineligible 
participants who have received at least one dose of protocol therapy should be followed according 
to the protocol to allow for treatment and adverse event assessment. 

 
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6.0 
ENTRY/ENROLLMENT PROCEDURES 
 
6.1 
Entry Procedures 
 
All enrollments 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 
enrolling patients will be provided at the time of study activation and will also be included in the 
“EDC Generic Data Management Guidebook”, posted on the IND.239 trial specific web-site. If 
sites experience difficulties accessing the system and/or enrolling patients please contact the help 
desk (link in EDC) or the IND.239 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.239) 
• 
patient's initials (may be coded) 
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
tissue banking/optional consent version date 
• 
confirmation of the requirements listed in Section 4.0, including dates of essential tests and 
actual laboratory values 
• 
height and weight 
 
6.2 
Study Enrollment 
 
Enrollment will be provided electronically. 
 
At the time of enrollment, all data reported within the Patient Enrollment folder must be accurate, 
complete and verifiable against source documentation. If a system query is issued indicating that 
the patient is not eligible, enrollment within the EDC system will not proceed. CCTG should be 
contacted for assistance if needed. Under no circumstances should inaccurate data be entered in 
order to permit enrollment. 
 
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 enrollment. 
 
All patients are to be followed until death or until sites are informed by CCTG that further follow-up 
is no longer required. The follow-up requirements for ineligible patients are outlined in Section 5.1. 
 
 

 
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6.3 
Inclusion of Women and Minorities 
 
This trial will only enroll women. Men are excluded because the historical comparison cohort used 
to benchmark the response rate from this study included only one male patient. There are no 
exclusions based on race or ethnicity in this trial. This study, however, will be presented to patients 
through the major cancer-treatment institutions of the Canadian provinces, to which all racial/ethnic 
groups have equal access. The intention, therefore, is to recruit subjects from racial/ethnic groups 
in close approximation to the incidence of the disease in these groups. 

 
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7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
enrollment. 
 
7.1 
Treatment Plan 
 
No pharmacokinetic or pharmacodynamic interaction is expected to occur and given the non- 
overlapping toxicity profiles, no formal dose escalation phase will occur. A safety  review after the 
enrollment of 6 patients, who received at least 1 cycle and up to 3 cycles, will be conducted prior 
to reopening to further accrual. If needed, the starting dose of CFI-400945 will be reduced by one 
dose level. 
 
7.1.1 
Drug Administration 
 
Cycle 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Cycle duration (days) 
1 
CFI-400945 
32 mg 
Oral 
- 
Days 1-7 then 
Days 15-21 
28 
2 onwards 
- 
Daily* 
28 
2 onwards 
Durvalumab 
1500 mg 
IV 
60 min 
Day 1 
28 
*  An intermittent schedule may be used (see 7.1.3). 
 
Cycle 1 will consist of CFI-400945 administered at the starting dose on a one week on and one 
week off schedule.  
 
Depending on the toxicity observed in Cycle 1, Cycle 2 Day 1 will begin with durvalumab 
administration and CFI-400945 at either 32 mg continuously or on an intermittent schedule 
(Section 7.1.3 Table 1) continuously in subsequent 28-day repeating treatment cycles. Patients who 
experience no myelosuppression in 2 consecutive cycles may have CFI-400945 dose escalated to 
40 mg (see 7.1.3). Patients may have the CFI-400945 dose reduced at any time due to toxicity. If 
either agent is held for toxicity, the other agent should also be held unless the toxicity is neutropenia 
alone.  
 
Patients will take CFI-400945 by mouth at least 1 hour before, and 2 hours after, any food and 
should be encouraged to take the CFI-400945 at the same time each day at the time they find most 
convenient and are least likely to forget. On days when both CFI-400945 and durvalumab are 
administered, the timing of durvalumab administration in relation to CFI-400945 is not important, 
as long as they are started on the same day. 
 
 

 
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7.1.2 
Premedication 
 
No routine premedication (e.g. for nausea) or prophylaxis for hypersensitivity is required. For 
durvalumab, management of symptoms should take place as necessary (see Appendix II). 
Premedication is not expected to be required. See Appendix II with respect to premedication of 
patients that have had a prior < Grade 2 infusion-related reaction. Details of any premedication or 
concomitant medication given to manage or prevent adverse events should be recorded on the 
electronic case report form (eCRF). 
 
7.1.3 
Dose Levels 
 
The following are dose levels for CFI-400945, which will be titrated according to the degree of 
toxicity: 
 
DL+1 (escalation) 
DL1 
DL-1 
DL-2 
40 mg daily 
32 mg daily 
32 mg  / 5 days per week (5 days 
on/2 days off) 
32 mg / 3 days per week 
Note: intermediate dose levels/schedules may be selected after review of data by CCTG and investigators. 
 
Durvalumab will be administered as a flat dose of 1500 mg for patients > 30 kg in weight. If patient 
weight falls to ≤ 30 kg, weight-based dosing at 20 mg/kg will be administered. No dose reductions 
are planned. 
 
7.1.4 
Patient Monitoring 
 
Patients will be monitored before, during infusion and after the infusion of durvalumab. A 1-hour 
observation period is recommended after the first durvalumab infusion period. If no clinically 
significant infusion reactions are observed during or after the first cycle, subsequent observation 
periods can be at the discretion of the investigator (30 minutes is suggested). 
 
Guidelines for management of infusion-related reaction are summarized in Appendix II. 
 
All patients should be closely monitored according to guidelines in Section 5.0 and be advised to 
contact the treating centre in the case of significant toxicities. 
 
7.1.5 
Dose Modifications – CFI-400945 
 
Doses will be reduced for hematologic and other adverse events. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity. Adverse events will be graded 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (see Appendix V). 
 
Reported and/or expected toxicities include, but are not limited to: amylase/lipase increases, 
neutropenia and leucopenia, febrile neutropenia fever and chills, infection, typhlitis/diarrhea, 
fatigue, increased liver function tests, nausea, vomiting, mucositis. The guidelines which follow 
outline dose adjustments for several of these toxic effects. If a patient experiences several adverse 
events and there are conflicting recommendations, please use the recommended dose adjustment 
that reduces the dose to the lowest level.Doses should only be modified for toxicity related to CFI-
400945. 
 
Diarrhea > Grade 1 is not a common toxicity of CFI-400945. Patients who experience diarrhea 
should be carefully evaluated for possible immune mediated colitis and managed accordingly. 
 
 

 
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Following any interruption of dosing for toxicity as described below, CFI-400945 should not be re- 
started until ANC ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L and resolution of all drug related toxicity 
to ≤ grade 2. 
 
Table 1. Guidelines for CFI-400945 Dose Modifications for Neutropenia: 
 
ANC (for dosing during cycle  
AND worst in prior cycle) 
Cycles 
Dose and management1, 3, 4 
≥ 1.5 x109/L 
All 
No change. 
Note: If ≥ 1.5 x109/L for cycles  2 and 3 (or any 2 cycles 
after cycle 1) despite continuous oral dosing and having 
received at least 90% of planned doses2: may escalate 1 DL  
1.0 x109/L- <1.5 x109/L 
All 
Hold4  until ≥ 1.5 x109/L.  
No change in dose for next cycle. 
Inability to receive at least 75% of 
planned dose within prior cycle  
All 
Hold4 until ≥ 1.5 x109/L.  
 
Reduce 1 DL 
<1.0 x109/L (with no fever) <5 days 5 
<1.0 x109/L ≥ 5 days or febrile 
neutropenia  
Cycle 1 Discontinue6 
Other 
cycles 
Hold4 until ≥ 1.5 x109/L.  
 
Reduce 2 DL 
1. Hold if ANC < 1.5 x109/L; do not restart or start next cycle until ANC ≥ 1.5x109/L. 
2. May also re-escalate after a prior dose reduction providing no febrile neutropenia and growth factors were not required 
and same conditions are met. 
3. If Grade 3 or 4 ANC, CBC monitoring is required twice weekly for at least one full cycle after last event.  
4. From Cycle 3 onward, CCTG may be contacted for an exemption to continue dosing if ANC ≥ 1.2 x109/L. If cannot 
restart dosing within 21 days, discontinue. 
5. If grade 3 neutropenia occurs in Cycle 3 onwards, contact CCTG to discuss option of no DL reduction. 
6. Consult CCTG for clarification for borderline values in asymptomatic patients. 
 
Table 2. Guidelines for CFI-400945 Dose Modifications for Other Toxicity 
 
Worst Toxicity 
Management/Action 
Dose of CFI-4000945  
when re-started* 
Hematologic 
 
 
Grade 1 or 2 thrombocytopenia 
No action. If grade 2, increase 
surveillance with twice weekly CBC 
for 2 cycles provided no further dose 
modification needed 
No change 
Grade 3 thrombocytopenia 
Hold until ≥ 100 x 109/L 
Reduce by 1 DL AND increase 
surveillance with twice weekly CBC 
for at least 2 cycles 
Thrombocytopenic bleeding 
Hold and treat, increase surveillance 
with twice weekly CBC 
Reduce by 2 DL or discontinue, AND 
increase surveillance with twice 
weekly CBC for at least 2 cycles 
Non-Hematologic** 
 
 
Grade 2 AST and/or ALT AND 
Grade 2 bilirubin 
Discontinue 
Discontinue 
Hy’s Law  
(AST or ALT ≥ 3 x ULN AND 
total bilirubin ≥ 2 x ULN) 
Discontinue 
Discontinue 
Diarrhea Grade 2 
Hold until immune mediated diarrhea 
excluded (or treated) and until 
recovered to ≤ grade 1 
Restart without dose reduction 
Other Grade 3 
Hold until ≤ grade 2 
Reduce by 1 DL 
Other Grade 4 
Discontinue 
Discontinue 
* 
If CFI-400945 cannot be restarted within 21 days, discontinue permanently. 
** 
Despite adequate supportive care. 
 
 

 
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7.1.6 
Dose Adjustments – Durvalumab 
 
The major toxic effects of durvalumab which are anticipated to limit dosing are hypersensitivity/ 
infusion related reactions and possible class related immune related AEs, based on the mechanism 
of action of durvalumab leading to T-cell activation and proliferation. Potential immune related 
AEs across the class include pneumonitis, hepatitis, diarrhea/colitis and intestinal perforation, 
endocrinopathies 
(thyroiditis, 
hypo 
and 
hyperthyroidism, 
adrenal 
insufficiency, 
hypophysitis/hypopituitarism diabetes insipidus and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent irAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. Other 
inflammatory responses that are rare with a potential immune-mediated etiology include, but are 
not limited to, pericarditis, sarcoidosis, uveitis and other events involving the eye (e.g. keratitis and 
optic neuritis), skin (e.g. scleroderma, vitiligo and pemphigoid), hematological (e.g. hemolytic 
anemia and immune thrombocytopenic purpura) and rheumatological (e.g. polymyalgia rheumatic 
and autoimmune arthritis) events, vasculitis, non infectious encephalitis or non infectious 
meningitis. It is possible that events with an inflammatory or immune mediated mechanism could 
occur in nearly all organs. 
 
If a patient experiences several adverse events and there are conflicting recommendations, please 
use the recommended dose adjustment that requires the greatest dose hold or discontinuation. 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (see Appendix V). 
 
Dose adjustments (slowing/interruption of infusion rate, omission of a dose, or permanent 
discontinuation) will be made for durvalumab- related adverse events. 
 
If the infusion cannot be administered, it should be omitted until the next planned infusion. 
 
The next cycle should not be given until the laboratory criteria in Section 4.1.8 are met and 
resolution of drug related toxicity, as detailed in Appendix II. For patients who have discontinued 
CFI-400945 and are continuing on durvalumab alone, criteria for creatinine clearance may be 
lower*. Please contact CCTG to discuss. 
 
* For patients with low platelet counts that are not believed to be related for durvalumab please 
contact CCTG to discuss. 
 
7.1.7 
Management of Toxicity 
 
See Appendix II for full details of toxicity management. 
 
The following general guidance should be followed for management of toxicities: 
1. Treat each of the toxicities with maximum supportive care (including slowing / interrupting / 
omitting the agent suspected of causing the toxicity where required). 
2. If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab along with appropriate continuing supportive care. 
3. All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
 

 
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In addition to the detailed toxicity management guidelines described in Appendix II, 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 2 to 3 days) low-grade (Grade 2) or severe (Grade ≥ 3) events 
promptly start prednisone PO 1-2 mg/kg/day or IV equivalent. 
• 
If symptoms recur or worsen during corticosteroid tapering (≥ 4 weeks of taper), increase the 
corticosteroid dose (prednisone dose [e.g. up to 2-4 mg/kg/day or IV equivalent]) until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate. 
• 
More potent immunosuppressives (refer to individual sections of the immune related adverse 
event for specific type of immunosuppressive) should be considered for events not responding 
to systemic steroids. 
• 
Discontinuation of study drug is not mandated for Grade 3 / Grade 4 inflammatory reactions 
attributed to local tumour response (e.g. inflammatory reaction at sites of metastatic disease, 
lymph nodes etc.). Continuation of study drug in this situation should be based upon a 
benefit/risk analysis for that patient and be discussed with CCTG. 
 
7.1.8 
Management of Infusion Reactions 
 
Guidelines for management of infusion-related reaction are summarized in Appendix II. The 
standard infusion time for durvalumab is 1 hour. However, if there are interruptions during infusion, 
the total allowed time should not exceed 8 hours at room temperature. 
 
Study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to appropriate drugs and medical equipment to treat acute anaphylactic reactions, 
emergency resuscitation teams and equipment in addition to the ability to admit patients to an 
intensive care unit if necessary. 
 
7.1.9 
Dose Adjustments for Immune Related Adverse Events and Other (Non-Immune Related) Adverse 
Events Related to Study Therapy 
 
Guidelines for dose modification and toxicity management of immune related and non-immune 
related adverse events are summarized in Appendix II. 
 
Centres must contact CCTG in the event of severe event(s), especially when the use of drugs such 
as infliximab are considered. 
 
7.1.10 Duration of Therapy 
 
Treatment will continue until the criteria for removal from protocol treatment have been met (see 
Section 10). 
 
7.1.11 Patient Compliance 
 
Treatment compliance will be monitored by drug accountability, as well as recording drug 
administration in the patient’s medical record and case report form (CRF). 
 
 

 
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7.2 
Concomitant Therapy 
 
7.2.1 
Permitted 
• 
Other supportive and palliative care (e.g. pain control) as required throughout the study. 
• 
Bone-targeted therapy for patients with bone metastases (bisphosphonates or denosumab). 
• 
Anti-emetics or anti-diarrheal agents as required. 
• 
Growth factors may be used according to centre policy to treat life threatening toxicity but 
cannot be used in place of protocol defined dose adjustments or prophylactically. Please consult 
CCTG in the case of patients experiencing multiple delays/omissions as exceptions may be 
made for patients who are benefitting from protocol therapy. 
 
7.2.2 
Not Permitted 
• 
Administration of any other anti-cancer therapy is not permitted while the patient is receiving 
protocol therapy. Thereafter, patients may be treated at the investigator’s discretion. 
• 
Concurrent radiation treatment. (Note: if patients require palliative radiation or prophylactic 
radiation (e.g. of brain) consult CCTG for exception to this rule; protocol therapy will need to 
be held prior to and during the radiation.) 
• 
Cytokines. 
• 
Corticosteroids IV or PO (except for the treatment of  ≥ grade 3 infusion reaction, or treatment-
related toxicity (See Appendix II). Note: Topical applications (e.g. rash), inhaled sprays (e.g. 
obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed, as 
are oral dose of steroids equivalent to 10 mg or less of prednisone. 
• 
Live attenuated vaccines within 30 days of durvalumab dosing (i.e. 30 days prior to the first 
dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab). 
Inactivated vaccines, such as the injectable influenza vaccine, are permitted 
• 
Drugs listed in Appendix VI Table 1 are not permitted during the study. Drugs listed in 
Appendix VI Table 2 should be used with caution only when it is absolutely necessary. 
 
 

 
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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for Adverse Events 
 
All patients will be evaluable for adverse event evaluation from the time of their first treatment. 
 
8.1.2 
Evaluable for Response 
 
All patients who have received at least one cycle of therapy and have their disease re-evaluated will 
be considered evaluable for response. Patients who exhibit objective disease progression prior to 
the end of cycle 1 are considered to be evaluable. Patients on therapy for at least this period and 
who meet the other listed criteria will have their response classified according to the definitions set 
out below [Eisenhauer 2009]. 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee as well 
as the modified iRECIST guidelines [Seymour 2017]. Investigators should note the different 
requirements for confirmatory scans as well as follow up for the two criteria. 
 
8.2 
Response and Evaluation Endpoints 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee as well 
as the Immune-Related modified RECIST. Investigators should continue treatment, as appropriate, 
in the absence of unacceptable toxicity, until unequivocal disease progression. This is particularly 
important for patients in whom pseudoprogression may have occurred. Follow up response 
assessments must be continued until unequivocal disease progression has occurred. 
 
8.2.1 
Measurable Disease 
 
Measurable tumour lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray and as ≥ 10 mm with CT 
scan or clinical examination. Bone lesions are considered measurable only if assessed by CT scan 
and have an identifiable soft tissue component that meets these requirements (soft tissue component 
≥ 10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumour measurements must be 
recorded in millimetres (or decimal fractions of centimetres). Previously irradiated lesions are not 
considered measurable unless progression has been documented in the lesion. 
 
8.2.2 
Non-measurable Disease 
 
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitic involvement of lung or skin and abdominal masses followed by clinical examination 
are all non-measurable. Lesions in previously irradiated areas are non-measurable, unless 
progression has been demonstrated. 
 
 

 
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8.2.3 
Target Lesions 
 
When more than one measurable tumour lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis of ≥ 15 mm by 
CT scan and only the short axis of these nodes will contribute to the baseline sum. All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target 
lesions. Nodes that have a short axis < 10 mm are considered non- pathological and should not be 
recorded or followed (see 8.2.4). At baseline, the sum of the target lesions (longest diameter of 
tumour lesions plus short axis of lymph nodes: overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately measured 
but are deemed to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be used. 
 
8.2.4 
Non-target Lesions 
 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”. 
 
8.2.5 
Response 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and normalization of 
tumour markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: continue 
to record the measurement even if < 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 required. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumour 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD. Confirmation of response is required. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest sum of diameters on study. 
 
 

 
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Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND an 
absolute increase of ≥ 5mm. Appearance of new lesions will also constitute progressive disease 
(including lesions in previously unassessed areas). In exceptional circumstances, unequivocal 
progression of non-target disease may be accepted as evidence of disease progression, where the 
overall tumour burden appears to have increased by at least 73% in volume or, in select instances 
where tumour burden has increased sufficiently to require urgent medical intervention (e.g. 
radiation for spinal cord compression or drainage of a fluid collection). Modest increases in the size 
of one or more non-target lesions are NOT considered unequivocal progression. If the evidence of 
PD is equivocal (target or non-target), treatment may continue until the next assessment, but if 
confirmed, the earlier date must be used. 
 
Table 1: Integration of Target, non-Target and New Lesions into Response Assessment: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
Documented at least once ≥ 4 wks. 
from baseline* 
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes** 
PD 
 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes < 10 mm 
No Target 
Non-CR/non-PD 
No 
Non-
CR/non-
PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
* 
For this study, baseline is defined as the date of enrollment. 
** 
Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may be continued 
pending further assessments – see Table 2. 
 
 

 
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For non randomized trials, where confirmation of response is required, best overall response can 
be interpreted as follows: 
 
Response:  
First Time Point 
Subsequent  
Time Point 
BEST Overall Response 
Also Requires 
CR 
CR 
CR 
Normalization of tumour 
markers, tumour nodes 
< 10 mm 
CR 
PR 
SD, PD or PR (see comment*) 
 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
 
PR 
CR 
PR 
 
PR 
PR 
PR 
 
PR 
SD 
SD 
 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
 
NE 
NE 
NE 
 
*  
may consider PR providing initial “CR” likely PR on subsequent review – then original CR should be corrected. 
Recurrence of lesion after true CR is PD. 
 
8.3 
Immune-Related Response Assessment 
 
Overall response will also be assessed using iRECIST [Seymour 2017]. Immunotherapeutics may 
result in infiltration of immune cells leading to transient increase in the size in malignant lesions, 
or undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumour burden, 
or the appearance of new lesions, does not reflect true tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are designated 
with a prefix. iRECIST time-point and best overall responses will be recorded separately. 
 
Confirming Progression 
 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen as 
evidenced by one or more of the following: 
• 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions - Progression 
in target disease worsens with an increase of at least 5 mm in the absolute value of the sum: 
 
 

 
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− Continued unequivocal progression in non-target disease with an increase in tumour burden; 
− Increase in size of previously identified new lesion (s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions. 
• 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in table 2, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. 
 
New Lesions 
 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to 
allow clear differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of NLT should NOT be included in the sum of measures of original target lesions 
identified at baseline. Rather, these measurements will be collected on a separate table in the case 
record form. 
 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with either 
an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but not 
necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of additional new 
lesions. 
 
 
 

 
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Table 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: 
- further increase in SOM of at least 5 mm, otherwise 
remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
- previously identified T lesion iUPD SOM ≥5 mm and / 
or 
- NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
- previously identified T lesion iUPD ≥5 mm and / or 
- previously identified NT lesion iUPD (need not be 
unequivocal) and /or 
- size or number of new lesions previously identified 
Non- 
iUPD/PD 
Non-iUPD/PD Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
- increase in size or number of new lesions previously 
identified 
* 
Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD would 
be the same. 
** In any lesion category. 
*** Previously identified in assessment immediately prior to this TP. 
 
 
 

 
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Table 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. 
 
8.4 
Response Duration (RECIST 1.1 and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including baseline). 
 
8.5 
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). 
 
8.6 
Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy, which may be treatment 
arm dependent. While on study, all lesions recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned. For lesions which fragment/split add together the 
longest diameters of the fragmented portions; for lesions which coalesce, measure the maximal 
longest diameter for the “merged lesion”. 
 
 

 
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8.6.1 
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. 
 
8.6.2 
Chest X-ray 
 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions ≥ 
20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
 
8.6.3 
CT, MRI 
 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). Other specialized imaging or other techniques 
may also be appropriate for individual case [Eisenhauer 2009]. For example, while PET scans are not 
considered adequate to measure lesions, PET-CT scans may be used providing that the measures 
are obtained from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT 
(with IV and oral contrast). 
 
8.6.4 
Ultrasound 
 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT is advised. 
 
8.6.5 
Endoscopy, Laparoscopy 
 
The utilization of these techniques for objective tumour evaluation is not advised. However, they can 
be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response or surgical resection is an endpoint. 
 
8.6.6 
Tumour Markers 
 
Tumour markers alone cannot be used to assess objective tumour response. If markers are initially 
above the upper normal limit, however, they must normalize for a patient to be considered in 
complete response. 
 
8.6.7 
Cytology, Histology 
 
These techniques can be used to differentiate between PR and CR in rare cases if required by protocol 
(for example, residual lesions in tumour types such as germ cell tumours, where known residual 
benign tumours can remain). When effusions are known to be a potential adverse effect of treatment 
(e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of 
the neoplastic origin of any effusion that appears or worsens during treatment when the measurable 
tumour has met criteria for response or stable disease is advised to differentiate between response 
or stable disease and progressive disease. 
 
 

 
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9.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG. 
 
9.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events, regardless of whether they are unexpected or related to protocol 
treatment, occurring during the treatment period and within 30 days after the last protocol 
treatment administration, must be reported in an expedited manner. Any late serious adverse 
event occurring after this 30-day period which is unexpected and related to protocol treatment 
must also be reported in an expedited manner (see Section 9.2 for reporting instructions). 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
• 
Any immune related adverse event (irAE) requiring high dose steroids is by definition 
medically significant and must be reported as such. 
• 
If a patient shows an AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, refer to 
Appendix II for further instructions on cases of increases in liver biochemistry and evaluation 
of Hy’s Law. These cases should be reported as SAEs if, after evaluation, they meet the criteria 
for a Hy’s law case or if any of the individual liver test parameters fulfil any of the SAE criteria. 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life- 
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
9.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the IND.239 section of the CCTG website (www.ctg.queensu.ca). 
 
 

 
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Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
IND.239 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.239 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application. 
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430). 
 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting 
 
9.3.1 
Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) who are enrolled in the trial must have agreed to use 
contraceptive method(s) as described in Eligibility Criterion 4.1.14. 
 
Females of childbearing potential are defined as those who are not surgically sterile (i.e. bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (defined as 
12 months with no menses without an alternative medical cause). 
 
A highly effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Highly effective methods of 
contraception are described in the table below. Note that some contraception methods are not 
considered highly effective (e.g. male or female condom with or without spermicide; female cap, 
diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; 
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary 
mode of action (excluding Cerazette/desogestrel which is considered highly effective); and 
triphasic combined oral contraceptive pills). 
 
 

 
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Highly Effective* Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• Copper T intrauterine device 
• Levonorgesterel-releasing 
intrauterine system (e.g. 
Mirena®)** 
• “Implants”: Etonogestrel-releasing implants: e.g. Implanon® 
or Norplan® 
• “Intravaginal Devices”: Ethinylestradiol/etonogestrel-
releasing intravaginal devices: e.g. NuvaRing® 
• “Injection”: Medroxyprogesterone injection: e.g. Depo-
Provera® 
• “Combined Pill”: Normal and low dose combined oral 
contraceptive pill 
• “Patch”: Norelgestromin/ethinylestradiol-releasing 
transdermal system: e.g. Ortho Evra® 
• “Minipill***”: Progesterone based oral contraceptive pill 
using desogestrel e.g. Cerazette® 
* 
Highly effective (i.e. failure rate of <1% per year). 
** 
This is also considered a hormonal method. 
*** Cerazette® is currently the only highly effective progesterone based pill. 
 
9.3.2 
Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants. 
Pregnancies occurring up to 3 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, under the 
"Toolbox" link. 
 
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 participants, if required by local policy, a copy of the 
signed signature page of the pregnancy follow-up consent must be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533- 
2812/ safety-desk@ctg.queensu.ca). 
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
9.3.3 
Exposure Reporting (Non-study Participants) 
 
The investigator is required to report to CCTG any incidence of exposure to study agent(s). 
Exposure is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- study 
participant (an individual who is not otherwise participating in this clinical trial). An example of 
an exposure includes a non-study participant swallowing study medication. The investigator is 
responsible for determining significance, based on the agent to which the individual is exposed. 
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of the 
exposure using the CCTG Exposure Reporting Form available from the trial webpage, under the 
“Toolbox” link. 
 
 

 
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Once informed consent has been obtained, the form should be updated to provide further exposure 
information and to reflect the outcome of the exposure as the information becomes available upon 
appropriate follow-up of the exposed individual for a duration of 30 days. All follow-up reports 
must be submitted to CCTG in a timely manner. A copy of the signed exposure follow-up consent 
signature page must also 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 exposure results in death; 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. 
 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada for those events which meet 
regulatory requirements for expedited reporting, i.e. events which are BOTH serious AND 
unexpected, AND which are thought to be related to protocol treatment (or for which a causal 
relationship with protocol treatment cannot be ruled out). 
 
9.5 
CCTG Reporting Responsibility to AstraZeneca 
 
AstraZeneca will be notified of all serious adverse events within 1 working day of receipt by CCTG. 
CCTG, as sponsor, will determine regulatory reportability in Canada. AstraZeneca will be notified 
of all pregnancies and outcomes of pregnancies within 30 days of receipt of the report at CCTG. 
 
9.6 
CCTG Reporting Responsibility to UHN 
 
UHN will be notified of all serious adverse events related to CFI-400945 within 1 working day of 
receipt by CCTG. 
 
9.7 
UHN and AstraZeneca Reporting Responsibilities 
 
UHN and AstraZeneca shall notify CCTG of individual safety reports from other studies using CFI- 
400945 and durvalumab respectively, which may affect the overall safety profile of the study and 
which they have reported to Health Canada. In addition, UHN and AstraZeneca will provide 3 
monthly line listings to CCTG for all other reports. 
 
9.8 
Reporting Serious Adverse Events 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.239 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.239 web based safety monitoring utility and documentation of REB submission must be 
retained in the study binder on site. The REB submission template provided by CCTG can be used 
to assist with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 
 
 

 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
10.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients who are clinically stable but meet the criteria for iUPD should be continued on treatment 
until the next disease assessment at least 4 weeks later. It is recommended that the next imaging 
assessment be no longer than 8 weeks later in order to ensure patients remain fit for salvage 
therapies. Clinical stability is defined as: 
• 
Stability or improvement in performance status; 
• 
No clinically relevant increase in disease related symptoms such as pain or dyspnea (generally 
understood to mean a requirement for increased palliative intervention as below); 
• 
No requirement for increased management of disease related symptoms including increased 
analgesia, radiation or other palliative care. 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 7.0. 
• 
Tumour progression or disease recurrence as defined in Section 8.0. 
• 
Request by the patient. 
 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if 
patients discontinue protocol treatment prematurely and/or no longer attend the participating 
institution. 
 
10.2 
Duration of Protocol Treatment 
(see Section 8.0 for response definition) 
• 
Treatment with will continue until progression in the absence of unacceptable toxicity 
(Section 7). 
• 
Patients who progress (treatment failure) will go off study at the time progression is 
documented clinically and/or radiographically by RECIST 1.1 and iRECIST as appropriate. 
• 
Patients who discontinue one protocol therapy for toxicity may continue the other protocol 
therapy until progression in the absence of unacceptable toxicity. 
 
10.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
10.4 
Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy. 
 
For patients who go off protocol treatment with CR/iCR, PR/iPR, or SD/iSD ongoing, follow-up 
will be required every 3 months until relapse (see Section 5.0 for investigations to be performed).  
 
Continued follow up after progression (on treatment or during follow up), using an abbreviated 
form (including subsequent therapies) every 6 months is required until CCTG advises centres that 
the final analysis has been performed and follow up can be discontinued. 
 
 

 
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If patient is unable to return to participating centre for follow up, please contact CCTG to discuss 
possible options prior to considering ‘withdrawal of consent’ processes. Remote oversight allowing 
data submission may be feasible. 
 
Death report will be required on all patient unless advised by CCTG. Due within 2 weeks of 
knowledge of death (see Appendix IV - Documentation for Study). 

 
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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Central Data Review 
 
CCTG receives core support from the Canadian Cancer Society. To ensure efficient use of limited 
funding, the CCTG has, over the past 40 years, optimized their risk based trial oversight and 
monitoring program. A critical component is central data review of submitted deidentified source 
documents, allowing source data verification and confirmation of key aspects including eligibility, 
endpoints and safety outcomes. Depending on the trial’s design, these source documents may 
include such source documents as surgical and histopathology reports to confirm disease stage and 
type, imaging reports to confirm extent of disease and assess efficacy, or include submission of 
tumour samples (to confirm diagnosis and eligibility or DICOM images (to verify response or 
radiation therapy planning). These source documents are reviewed by experienced data managers 
and physicians and are critical to ensuring the accuracy of the data and consistency of conclusions 
drawn. 
 
The collection of this critical data involves uploading documents through the password protected 
and secure CCTG electronic Supporting Document Upload Tool (SDUT) data capture linked 
system. See Appendix III (Documentation for Study) for details of supporting document 
requirements for this trial and for requirements for the redaction of personal identifiers. Although 
it remains the centres responsibility to ensure adequate redaction of any information provided to 
CCTG, submitted source documents are reviewed prior to acceptance at CCTG; in the case of 
incomplete redaction, documents are removed and the site assigned a violation and required to 
resubmit. 
 
All patients will provide written informed consent for submission of source documents, and the 
rationale and documents to be collected will be detailed in the informed consent document. 
 
11.2 
Central Radiology Review 
 
As part of the trial, copies of x-rays and/or scans may be collected to evaluate cancer response to 
treatment. There will be no central radiology review for this study. 
 
11.3 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
 

 
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12.0 
CORRELATIVE STUDIES 
 
Collection and immediate shipment of time sensitive samples (e.g. cfDNA) MUST occur after 
enrollment. This is to ensure that the samples shipped to the Tumour Bank have a CCTG patient 
ID, which is required, in order to track and catalogue specimens. 
 
A detailed Correlative Studies Manual will be provided on the IND.239 trial specific website, 
which will include details regarding sample preparation, handling and shipping. 
 
Samples will be used for research purposes only and will not be sold. Patients will not be identified 
by name. The only identification of tissue will be by a patient study number assigned at the time of 
enrollment to the trial the surgical/ histology number and/or patient initials. Material issued to 
researchers will be anonymized and only identified by a coded number. 
 
All patients on whom a diagnostic tumour block is collected will be aware of this retrieval and will 
have given their consent. 
 
Genetic Testing 
 
Planned testing for hereditary genetic defects predisposing to malignant disease will not be carried 
out. 
 
As all biomarker testing done for this study will be conducted in a research laboratory, the results 
are not validated. There are no plans to return results to patients. 
 
12.1 
Protocol-Mandated Correlative Studies 
 
Tumour Tissue Collection - Archival 
 
The submission of a representative block of the diagnostic tumour tissue is mandatory for 
participation in this trial. One tumour block and one adjacent normal tissue block are requested 
from all of the biopsies or resections of the breast tumour. 
 
If no primary cancer blocks are available, one block of metastatic tissue can be sent alone. Where 
local centre regulations prohibit submission of blocks of tumour tissue, the approval of the CCTG 
must be sought prior to enrollment of the first patient to allow cores (two 2 mm cores of tumour 
from the block) and a predetermined number of slides of representative tumour tissue to be 
substituted in response to the Central Tumour Bank request. 
 
Tumour Tissue Collection (Serial Paired Samples) 
 
Biopsies are optional but strongly encouraged for patients with accessible disease suitable for 
biopsy. Optional biopsies may be performed at baseline (after enrollment, prior to treatment; 
patients with biopsies within 90 days of enrollment with available blocks do not need re-biopsy), 
and between Cycle 3 Day 1 and 8 (contact CCTG if unable to schedule within this time period). An 
additional optional biopsy is strongly recommended for all consenting patients when radiological 
disease progression on therapy is confirmed among patients who had initial response of CR/iCR, 
PR/iPR or SD/iSD greater than 4 months. 
 
 

 
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Blood Collection 
 
The CCTG is interested in exploring the use of surrogate tissues such as blood, serum and plasma 
in evaluating potential prognostic or predictive biomarkers, or as evidence of pharmacodynamics 
effects. Mandatory samples will be collected for circulating free DNA (cfDNA) at baseline, C3D1, 
C5D1, C7D1 and at progression (iUPD; will need to be repeated after initial iUPD if the patient 
has a subsequent response, followed by iUPD again). Samples will be collected to measure dynamic 
changes in levels of tumour-derived DNA in plasma with study treatment. 
 
Planned Assays on Tissue 
 
Molecular analyses including but not limited to next-generation DNA/RNA sequencing and 
immunohistochemistry will be performed on archival and recent tumour (or normal tissue) 
materials to identify potential biomarkers of response, histologically assess centrosomes and 
aberrant mitoses, and evaluate genomic alterations and other molecular features (i.e. gene or protein 
expression levels). 
 
 

 
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13.0 
STATISTICAL CONSIDERATIONS 
 
This is an open label multicentre phase II trial to evaluate the anti-tumour activity of CFI-400945 
when given with durvalumab by determining the objective response rate in patients as defined in 
Section 4.1.1. A 2-stage Simon minimax design will be used. 
 
13.1 
Primary Endpoints and Analysis 
 
The primary endpoint of this study is objective response rate, which will be estimated by the 
proportion of evaluable patients who had complete response (CR) or partial response (PR) as their 
best response as assessed by RECIST 1.1 criteria. The exact 95% confidence interval for the 
response rate will be calculated. The median and range of the duration of response, defined as the 
time from date of CR or PR to the date when progression or death is observed, will be estimated 
based on Kaplan-Meier method. 
 
Secondary objectives include Disease Control Rate (DCR, defined as CR or PR or stable disease 
(SD) > 16 weeks in duration) which will be analyzed similarly as objective response rate, as well 
as response rate determined by iRECIST. 
 
13.2 
Sample Size and Duration of Study 
 
A 2-stage Simon minimax design will be used. 
 
For sample size estimation, a response rate of 0.15 to monotherapy is assumed. The null hypothesis 
that the true response rate is 15% or less will be tested against a one-sided alternative. In the first 
stage, 15 patients will be accrued. If 2 or less responses are observed, the study will be stopped. 
Otherwise, accrual will continue to a total of 28. The null hypothesis will be rejected if 8 or more 
responses are observed in 28 patients. This design yields a type I error rate of 5% and power of 0.8 
when the true response rate is 35%. 
 
13.3 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported semi-annually at investigators’ meetings. A safety review after the enrollment of 6 patients, 
who have received at least 1 cycle and up to 3 cycles, will be conducted prior to reopening to further 
accrual. 
 
 

 
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14.0 
PUBLICATION POLICY 
 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
14.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group may be credited as 
authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
 
14.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
“A study supported and coordinated by the Canadian Cancer Trials Group. 
Participating investigators included: (a list of the individuals who have 
contributed patients and their institutions). Research supported by 
AstraZeneca and University Health Network.” 
 
14.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair/s to write up the results of the study within a 
reasonable time of its completion. If after a period of six months following study closure the 
manuscript has not been submitted, the central office reserves the right to make other arrangements 
to ensure timely publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
14.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by the CCTG 
Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. 
Individual participating centres may not present outcome results from their own centres separately. 
Supporting groups and agencies will be acknowledged. 
 
 

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

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

 
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For reporting an exposure, the parent/guardian is required to sign an “Exposure Follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
15.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why. 
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
15.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP. 
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site. 
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained. 
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access. 
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained. 
 
15.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI). 
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
15.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
 

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

 
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16.0 
REFERENCES 
Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, 
Armstrong A, Liu MC, Iwata H, Ryvo L, Wimberger P, Card D, Ding Y, Karantza V, Schmid P. Phase 2 study 
of pembrolizumab as first-line therapy for PD-L1–positive metastatic triple-negative breast cancer (mTNBC): 
Preliminary data from KEYNOTE-086 cohort B. J Clin Orthod. 2017 May 20;35(15_suppl):1088–1088. 
Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, Cescon DW, Iwata H, Campone M, Nanda R, 
Hui R, Curigliano G, Toppmeyer D, O’Shaughnessy J, Loi S, Paluch-Shimon S, Card D, Zhao J, Karantza V, 
Cortes J. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple- 
negative breast cancer (mTNBC): KEYNOTE-086 cohort A. J Clin Orthod. 2017 May 20;35(15_suppl):1008– 
1008. 
Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and 
with reduced response to immunotherapy. Science [Internet]. 2017 Jan 20;355(6322). Available from: 
http://dx.doi.org/10.1126/science.aaf8399 
Dominguez-Brauer C, Thu KL, Mason JM, Blaser H, Bray MR, Mak TW. Targeting Mitosis in Cancer: 
Emerging Strategies. Mol Cell. 2015 Nov 19;60(4):524–36. 
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. 
Emens LA, Cruz C, Eder JP, et al. Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab 
Therapy for Patients With Metastatic Triple-Negative Breast CancerA Phase 1 Study. JAMA Oncol. Published 
online September 13, 2018. doi:10.1001/jamaoncol.2018.4224 
Hu Z, Fan C, Oh DS, at al. The molecular portraits of breast tumors are conserved across microarray platforms. 
BMC Genomics 7:96, 2006. 
Mason JM, Lin DC-C, Wei X, Che Y, Yao Y, Kiarash R, Cescon DW, Fletcher GC, Awrey DE, Bray MR, Pan 
G, Mak TW. Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer 
agent. Cancer Cell. 2014 Aug 11;26(2):163–76. 
Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, Curiel TJ, Colon-Otero G, Hamid O, Sanborn 
RE, Others. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune 
checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25. 
Miller LD, Smeds J, George J, et al. An expression signature for p53 status in human breast cancer predicts 
mutation status, transcriptional effects, and patient survival. Proc. Natl Acad. Sci. USA.102:13550-13555, 2005. 
Seymour L, Bogaerts J, Perrone A et al. iRECIST: Guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18:143-52. 
Van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast 
cancer. N. Engl. J. Med. 347: 1999-2009, 2002. 
Yu B, Yu Z, Qi P-P, Yu D-Q, Liu H-M. Discovery of orally active anticancer candidate CFI-400945 derived 
from biologically promising spirooxindoles: success and challenges. Eur J Med Chem. 2015 May 5;95:35–40. 
 

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

 
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APPENDIX II - DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED AND NON IMMUNE-MEDIATED 
REACTIONS 
(MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or Tremelimumab Monotherapy) 
 
The Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion Related 
and Non Immune-Mediated Reactions can be downloaded at: 
DoseMod-ToxicityMgmntGuidelines_17Nov2020.pdf 
 
 
 

 
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APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
General 
 
Details of Drug Distribution, Supply and Control/Accountability are provided in the IND.239 Pharmacy 
Information Manual, available on the IND.239 website (http://www.ctg.queensu.ca/trials/.html). 
 
Distribution 
 
CFI-400945 and durvalumab will be supplied to the CCTG distributor, Bay Area Research Logistics 
(BARL) and distributed by BARL to participating sites in Canada. 
 
Investigational product should be stored in a secure area according to local regulations and under the storage 
conditions stipulated on the investigational product label 
 
Resupply 
 
For re-supply of CFI-400945 and durvalumab, sites should print off and submit a Drug Re-Supply Form 
available on the IND.239 website. This form should be submitted directly to BARL. Once received, BARL 
will process the request and initiate shipment of re-supply. Sites should allow for 5-7 working days for 
shipment to arrive. 
 
Drug Accountability 
 
The investigational products are to be prescribed only by the Qualified Investigator or Sub-investigators 
having this delegated duty on the participants list. Under no circumstances will the investigator allow the 
drug to be used other than as directed by the protocol. Accurate records must be maintained, accounting for 
the receipt, dispensation, return and/or destruction of the investigational product utilizing the Drug 
Accountability Log, available on the IND.239 trial website. At the end of the study, it must be possible to 
reconcile shipment records with records of usage/returned stock by completion of the study drug 
accountability form. Any discrepancies must be accounted for and documented. 
 
Drug Destruction 
 
Drug Destruction of Patient Returns 
Unused trial medication returned by the patient may be destroyed per local policy, AFTER accountability 
and reconciliation has been completed and documented by the site and confirmed with CCTG. 
Documentation of destruction must be kept on file in the site pharmacy and is subject to on site 
monitoring/audit. 
 
Drug Destruction of Expired Medication 
The CCTG Study Coordinator must be contacted prior to destruction of expired medication to ensure an 
extension of expiry date is not expected. Expired trial medication may be destroyed per local policy, AFTER 
accountability and reconciliation has been completed and documented by the site and confirmed with 
CCTG. Documentation of destruction must be kept on file in the site pharmacy and is subject to on site 
monitoring/audit. 
 
Drug Destruction of Unused Medication (End of Trial) 
Instructions for return or destruction of unused drug will be supplied at the time of expiry and at trial closure. 
 
 

 
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** PLEASE NOTE ** 
DRUG FROM THIS SUPPLY IS TO BE USED 
ONLY FOR PATIENTS ENROLLED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite 
pharmacy, provided separate drug accountability records are maintained in each pharmacy and appropriate 
storage is available. Investigational agent may NOT however, be transferred to pharmacies or physicians 
outside the participating centre. 

 
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APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of enrollment and will apply to all eligible and ineligible 
patients. This trial will use a web-based Electronic Data Capture (EDC) system for all data collection 
including SAE reporting (see Section 9.0 for details regarding SAE reporting). For details about accessing 
the EDC system and completing the electronic Case Report Forms (eCRFs), please refer to the Data 
Management Guidebook available on the IND.239 web-site (www.ctg.queensu.ca). 
 
This trial will use a web-based Supporting Document Upload Tool for collection of supporting 
documentation. Supporting Documents are required to be uploaded immediately after the report they refer 
to has been submitted electronically). 
 
The ELECTRONIC CRFs to be used in this trial are: 
 
Electronic Case Report Form 
To be Completed/Submitted 
Electronically: 
Supporting Documentation* 
Mandatory Submission:  
To be uploaded immediately after 
the report they refer to has been 
submitted electronically 
Submission On Request: 
To be uploaded immediately after 
request 
BASELINE REPORT 
Due within 2 weeks of patient 
enrollment. 
Signature page of main and 
optional consent forms; 
diagnostic pathology, 
protocol-mandated baseline 
radiology and tumour 
measurement sheet (TMS)  
ECG, LVEF, additional 
clinical, laboratory or 
imaging reports that may 
impact on decision regarding 
eligibility 
TREATMENT REPORT 
To be completed every 4 weeks (i.e. 
after each cycle). Due within 
2 weeks of end of course. This report 
documents treatment, adverse events, 
investigations and response assessment 
for each course. 
Radiology reports for 
protocol-mandated imaging 
and non-protocol mandated 
imaging, if relevant to 
disease assessment, TMS  
Patient drug administration 
diary, additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of safety 
CORRELATIVE STUDIES 
See Section 12.0. 
 
 
END OF TREATMENT 
REPORT 
To be completed when patient goes off 
protocol treatment. Due within 2 weeks 
of end of protocol treatment. 
 
 
4 WEEK POST 
TREATMENT REPORT 
To be completed once on all patients, 4 
weeks after going off protocol 
treatment. Due within 
2 weeks after contact with patient. 
Radiology reports for 
protocol-mandated imaging 
and non-protocol mandated 
imaging, if relevant to 
disease assessment, TMS  
Additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of safety 
FOLLOW-UP REPORT 
To be completed every 3 months or 6 
months (see Section 5.0 and 10.4). Due 
within 2 weeks after contact with 
patient. 
Radiology reports for 
protocol-mandated imaging 
and non-protocol mandated 
imaging, if relevant to 
disease assessment, TMS  
Additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of safety 
RELAPSE/ PROGRESSION 
REPORT 
To be completed at the time of disease 
relapse or progression. Due within 2 
weeks after contact with patient. 
 
 
DEATH REPORT** 
Required for all patients unless advised 
by CCTG. Due within 2 weeks of 
knowledge of death. 
Autopsy report, if done. 
Additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of cause of death 
SERIOUS ADVERSE 
EVENT (SAE) REPORT 
All reportable serious adverse events 
must be reported as described in Section 
9.0. Preliminary CCTG Serious 
Adverse Event Report due within 24 
hours. Updated CCTG Serious Adverse 
Event Report due within 7 days. 
 
Additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of safety 
including admission and 
discharge summaries/notes 
footnotes on next page … 
 
 

 
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*  
 Scan and upload in the EDC Supporting Document Upload Tool (SDUT) - please refer to the slide set on the IND.239 website for 
guidance. Source documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, and/or serious 
adverse events.  EDC forms submitted without supporting documentation are not considered submitted and will be reflected in the Centre 
Performance Index (CPI) as not submitted. All patient identifiers, other than the CCTG patient ID assigned at enrollment, and any other 
prohibited personal information must be fully and completely redacted (blacked-out) on all source documentation, per national and local 
privacy protection regulations and requirements. Acceptable methods include: 
• 
fully opaque sticker/tab placed over the identifiers prior to scanning 
• 
fully opaque black marker; prior to upload please ensure that the information is no longer visible on the scanned document 
• 
electronic black box placed over identifiers in PDF document that is subsequently printed and then scanned. (NOTE: do not send the 
unprotected PDF file with black boxes included as those can be moved / removed easily after opening) 
• 
electronic stripping of identifiers prior to upload (typically only possible for DICOM images) 
Note that supporting documents must include the participant’s trial code, CCTG patient serial number, and participant initials (or a 
two/three masking letter code assigned by your centre). 
**  NB It is the investigator's responsibility to investigate & report the date/cause of death of any patient who dies during this period. Any death 
that occurs during this protocol therapy or within 30 days after last dose must also be reported as a Serious Adverse Event as described in 
Section 9.0. 
 
 

 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
 

 
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APPENDIX VI - PROHIBITED MEDICATIONS 
 
Table 1. Drugs to be Excluded 
 
Alfentanil 
Pimozide 
Cyclosporine 
Quinidine 
Digoxin 
Sirolimus 
Dihydroergotamine 
Tacrolimus 
Ergotamine 
Tizanidine 
Fentanyl 
Theophylline 
Mephenytoin 
Warfarin 
Phenytoin 
 
 
 
Table 2. Drugs to be Used With Caution 
 
Alosetron 
Felodipine 
Quetiapine 
Aprepitant 
Fluticasone 
Ramelteon 
Budesonide 
Indinavir 
Saquinavir 
Buspirone 
Lansoprazole 
Sildenafil 
Caffeine 
Lopinavir 
Simvastatin 
Duloxetine 
Lovastatin 
Tacrine 
Conivaptan 
Lurasidone 
Tiprinavir 
Darifenacin 
Maraviroc 
Tolvaptan 
Darunavir 
Melatonin 
Triazolam 
Dronedarone 
Midazolam 
Vardenafil 
Eletriptan 
Nisoldipine 
 
Eplerenone 
Omeprazole 
 
 
 
 

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

 
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Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
PATIENT ENROLLMENT 
All patients must be enrolled with CCTG before any treatment is given. 
 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca  
under: Clinical Trials 
613-533-6430 
613-533-2411 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Caitlin Burns 
Study Coordinator, CCTG 
Email: cburns@ctg.queensu.ca 
 
or: 
 
Dr. Lesley Seymour 
Senior Investigator, CCTG 
Email: lseymour@ctg.queensu.ca 
 
or: 
 
Dr. Pierre Olivier Gaudreau 
Senior Investigator, CCTG 
Email: p-ogaudreau@ctg.queensu.ca 
 
STUDY CO-CHAIRS 
Dr. David Cescon 
Study Co-Chair 
 
or: 
 
Dr. Andrew Robinson 
Study Co-Chair 
Contact CCTG 
Contact CCTG 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for details 
of reportable events. 
Dr. Lesley Seymour 
Senior Investigator, CCTG 
 
or: 
 
Dr. Pierre Olivier Gaudreau 
Senior Investigator, CCTG 
 
or: 
 
Caitlin Burns 
Study Coordinator, CCTG 
613-533-6430 
613-533-2411 
DRUG ORDERING 
See Appendix III for full details. 
See Appendix III and trial website: http://www.ctg.queensu.ca