A Phase Ib and Open Label Phase II Study of CFI-402257 in Combination With Weekly Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: Canadian Cancer Trials Group

PROTOCOL ADMINISTRATIVE UPDATE #3: 2021-AUG-03 
 
CCTG TRIAL: IND.236 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION: 2018-JUN-05 
 
AMENDMENT #1: 2019-JUN-18 
ADMINISTRATIVE UPDATE #1: 2019-DEC-18 
 
AMENDMENT #2: 2020-DEC-23 
ADMINISTRATIVE UPDATE #2: 2021-MAY-06 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE Ib AND OPEN LABEL PHASE II STUDY OF CFI-402257 IN COMBINATION  
WITH WEEKLY PACLITAXEL IN PATIENTS WITH ADVANCED/METASTATIC  
HER2-NEGATIVE BREAST CANCER 
 
CCTG Protocol Number: IND.236 
 
 
 
STUDY CHAIRS 
Philippe Bedard  
 
 
Mihaela Mates 
 
 
TRIAL COMMITTEE: 
Karen Gelmon 
 
 
David Cescon 
 
 
Kathleen Pritchard 
 
 
SENIOR INVESTIGATORS: 
Pierre-Olivier Gaudreau 
 
 
Lesley Seymour 
 
 
BIOSTATISTICIAN: 
Dongsheng Tu 
 
 
STUDY COORDINATOR: 
Linda Hagerman 
 
 
REGULATORY SPONSOR: 
CCTG 
 
 
SUPPORTED BY: 
Stand Up To Cancer (SU2C) Canada 
 
 
Canadian Breast Cancer Foundation Grant 
 
 
Ontario Institute for Cancer Research (OICR) 
 
 
(For contact information of study personnel see Final Page.) 
 

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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) ...................................................................................... 1 
 
TREATMENT SCHEMA ....................................................................................................................................... 2 
 
1.0 
OBJECTIVES .......................................................................................................................................... 4 
1.1 
Primary Objective ..................................................................................................................................... 4 
1.2 
Secondary Objectives................................................................................................................................ 4 
1.3 
Exploratory Objectives ............................................................................................................................. 4 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ........................................................................... 5 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION ................................................................................ 7 
3.1 
CFI-402257 Chemical Information ............................................................................................................ 7 
3.2 
Chemical Structure ................................................................................................................................... 7 
3.3 
Mechanism of Action ................................................................................................................................ 8 
3.4 
Experimental Antitumour Activity ............................................................................................................ 8 
3.5 
Animal Toxicology ................................................................................................................................... 8 
3.6 
Clinical Trials ........................................................................................................................................... 9 
3.7 
Pharmacokinetic Studies ......................................................................................................................... 10 
3.8 
Pharmaceutical Data ............................................................................................................................... 10 
3.9 
Paclitaxel .............................................................................................................................................. 11 
 
4.0 
STUDY POPULATION ......................................................................................................................... 12 
4.1 
Eligibility Criteria ................................................................................................................................... 12 
4.2 
Ineligibility Criteria ................................................................................................................................ 15 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT ........................................................................................................................................ 16 
5.1 
Follow-up for Ineligible Patients ............................................................................................................. 17 
 
6.0 
ENTRY/ENROLLMENT PROCEDURES .............................................................................................. 18 
6.1 
Entry Procedures .................................................................................................................................... 18 
6.2 
BSA Calculation ..................................................................................................................................... 18 
6.3 
Phase I 
18 
6.4 
Phase II 
21 
6.5 
Study Enrollment .................................................................................................................................... 21 
6.6 
Inclusion of Women and Minorities ........................................................................................................ 21 
 
7.0 
TREATMENT PLAN ............................................................................................................................. 22 
7.1 
Treatment Plan ....................................................................................................................................... 22 
7.2 
Concomitant Therapy.............................................................................................................................. 25 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS .............................................................. 27 
8.1 
Definitions 27 
8.2 
Response and Evaluation Endpoints ........................................................................................................ 27 
8.3 
Response Duration .................................................................................................................................. 30 
8.4 
Stable Disease Duration .......................................................................................................................... 30 
8.5 
Methods of Measurement ........................................................................................................................ 30 
 
 

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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 ........................................ 34 
9.5 
CCTG Reporting Responsibility to UHN................................................................................................. 34 
9.6 
UHN Reporting Responsibilities ............................................................................................................. 34 
9.7 
Reporting Safety Reports to Investigators ................................................................................................ 35 
 
10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ................... 36 
10.1 
Criteria for Discontinuing Protocol Treatment ......................................................................................... 36 
10.2 
Duration of Protocol Treatment ............................................................................................................... 36 
10.3 
Therapy After Protocol Treatment is Stopped .......................................................................................... 36 
10.4 
Follow-up Off Protocol Treatment .......................................................................................................... 36 
 
11.0 
CENTRAL REVIEW PROCEDURES .................................................................................................... 37 
11.1 
Central Pathology Review ....................................................................................................................... 37 
 
12.0 
CORRELATIVE STUDIES .................................................................................................................... 38 
12.1 
Protocol-Mandated Correlative Studies ................................................................................................... 38 
12.2 
Pharmacokinetic Studies ......................................................................................................................... 39 
 
13.0 
STATISTICAL CONSIDERATIONS ..................................................................................................... 41 
13.1 
Objectives and Design ............................................................................................................................ 41 
13.2 
Primary Endpoints and Analysis.............................................................................................................. 41 
13.3 
Sample Size and Duration of Study ......................................................................................................... 41 
13.4 
Safety Monitoring ................................................................................................................................... 42 
13.5 
Pharmacokinetics .................................................................................................................................... 42 
13.6 
Correlative Studies.................................................................................................................................. 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 
15.4 
Discontinuation of the Trial .................................................................................................................... 46 
15.5 
Retention of Patient Records and Study Files .......................................................................................... 46 
15.6 
Centre Performance Monitoring .............................................................................................................. 46 
15.7 
On-Site Monitoring/Auditing .................................................................................................................. 46 
 
16.0 
REFERENCES ....................................................................................................................................... 47 
 
APPENDIX I - PERFORMANCE STATUS SCALES/SCORES........................................................................... 48 
APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL ................................................................. 49 
APPENDIX III - DOCUMENTATION FOR STUDY........................................................................................... 51 
APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ............................... 53 
APPENDIX V - PROHIBITED MEDICATIONS ................................................................................................. 54 
APPENDIX VI - EMERGENCY SITUATIONS AND COMPLIANCE ................................................................ 55 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 

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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to University Health 
Network (UHN). 
 
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 and CCTG. The foregoing shall not apply to disclosure 
required by governmental regulations or laws; however, I will give prompt notice to UHN and CCTG of 
any such disclosure. 
 
I understand that I may terminate or suspend enrollment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG or UHN with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
UHN and CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG IND.236 
 
CENTRE: ___________________________________________ 
 
 

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TREATMENT SCHEMA 
 
This is an open-label, multicentre, phase Ib/II study of CFI-402257 in patients with advanced/metastatic 
breast cancer. Approximately 12-18 patients will be enrolled in the phase Ib portion, and 15-37 patients 
will be enrolled in the phase II portion. This study is being conducted by the Canadian Cancer Trials Group 
(CCTG) and supported by a Stand Up To Cancer (SU2C) Canada – Canadian Breast Cancer Foundation 
Grant and Ontario Institute for Cancer Research (OICR). 
 
Phase Ib: 
Patients with advanced/metastatic breast cancer 
(12-18 patients) 
 
Starting dose and schedule assigned at enrollment: 
Oral CFI-402257 on intermittent schedule:*  
days 1, 2, 8, 9, 15 & 16 q4w 
+ 
Paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days 
 
Dose escalation of CFI-402257 to MTD, 3+3 dose 
escalation design 
 
Confirm RP2D of CFI-402257 to be used in phase II 
 
* may be revised (see Section 6.3.2) 
 
 

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Phase II: 
 
Patients with advanced/metastatic breast cancer 
(15-37 patients) 
 
Starting dose and schedule assigned at enrollment: 
Oral CFI-402257 at RP2D and schedule determined in Phase I 
+ 
Paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days 
 
Continue treatment until criteria for discontinuation are met 
(Section 10.0) 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
Phase I: 
• 
To establish the safety and tolerability of CFI-402257 given orally in combination with weekly 
paclitaxel in a q4w schedule and to identify the recommended phase II dose (RP2D) in patients 
with advanced/metastatic breast cancer. 
 
Phase II: 
• 
To evaluate the anti-tumour activity of the CFI-402257 + paclitaxel combination when 
administered at the RP2D by determining the objective Overall Response Rate by RECIST 1.1 
(RR, including Complete (CR) and Partial Responses (PR)). 
 
1.2 
Secondary Objectives 
 
• 
To estimate the Clinical Benefit Rate (CBR, defined as CR or PR or stable disease (SD) > 16 
weeks in duration). 
• 
To evaluate the safety and tolerability of CFI-402257. 
• 
To explore, if indicated, the pharmacokinetic profile of CFI-402257 and paclitaxel. 
 
1.3 
Exploratory Objectives 
 
• 
In serial tumour biopsies, to explore evidence of a pharmacodynamic (PD) target effect 
(compared to published literature), and to estimate CFI-402257 levels. 
• 
To evaluate the genomic alterations and other molecular features (e.g. gene or protein 
expression levels) which may be associated with response and/or clinical benefit. 

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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Over the past decades, relapse rates for early stage breast cancer have declined significantly due to 
improvements in adjuvant systemic therapy, such as taxanes, aromatase inhibitors, and 
trastuzumab. However, metastatic breast cancer (MBC) remains the second most common cause of 
cancer-related mortality in women. Commonly used treatment options for patients who have 
relapsed after adjuvant therapy include hormonal therapy for patients who have hormone receptor 
positive tumours. Patients with receptor negative tumours, those who have organ metastases and 
those patients who are refractory to hormonal manipulation may be treated with systemic 
chemotherapy, usually with agents that they have not received as adjuvant therapy. Chemotherapy 
may include capecitabine, taxanes or eribulin, among others, while anthracyclines are rarely used 
because of prior exposure. Weekly paclitaxel is commonly used, especially in patients with prior 
taxane exposure, and is well tolerated [Seidman 2001, Seidman 2008]. Although many patients respond 
to cytotoxic chemotherapy, their disease is incurable and invariably progresses, usually within 6-8 
months of starting treatment. New treatment approaches are needed. 
 
TTK protein kinase (Mps1) is a recognized potential anti-cancer drug target. TTK is a dual-
specificity serine-threonine kinase that is critical for the spindle assembly checkpoint (SAC), 
chromosome alignment and error correction in mitosis. Inhibition of TTK kinase activity causes 
cells to prematurely exit mitosis with unattached chromosomes, resulting in severe chromosome 
missegregation, aneuploidy and eventually cell death. TTK is overexpressed in 38% of all breast 
tumours and in 85% of triple negative/basal-like breast cancer (TNBC), which is the most 
genomically unstable breast cancer subtype, indicating that inhibition of TTK is a potential 
therapeutic strategy in this disease. 
 
CFI-402257 is a selective and potent inhibitor of TTK (Mps1), a key kinase in maintaining genomic 
integrity during mitotic cell division through establishment and maintenance of the mitotic 
checkpoint. In vitro, CFI-402257 inhibits the growth of seven breast cancer (luminal/HER2) cell 
lines tested with a range 1-1250 nM (median IC50 of 9 nM, mean of 188 nM). The growth inhibition 
of five basal breast cancer cell lines tested was also observed with a range 2-30 nM) (median IC50 
of 26 nM, mean IC50 of 18.4 nM). Furthermore, oral QD treatment of CFI-402257 demonstrated 
dose dependent monotherapy efficacy in mice with established tumours from xenografted human 
TNBC cells and similar results were also obtained with another TNBC xenograft. These preclinical 
results indicate that CFI-402257, as monotherapy, may have clinical activity in patients with breast 
cancer. 
 
Paclitaxel, a chemotherapeutic agent, is a microtubule stabilizer that inhibits mitosis through the 
activation of the spindle assembly checkpoint (SAC) and has proven clinical efficacy in patients 
with advanced/metastatic breast cancer. In vivo preclinical data using TNBC-derived cell lines 
showed that combination of CFI-402257 and paclitaxel was tolerated with no additional toxicities 
and resulted in a higher rate of complete regression in 2 different cell line models. In the MDA-
MB231 cell line xenograft model, while single agent treatment with either paclitaxel at 18 
mg/kg/week or CFI-402257 at 25 mg/kg on a 2 days on/5 days off schedule resulted in no long 
term complete regressions in any animals, the combination of these two regimes induced long term 
complete regressions in 3 of 8 animals. Emerging preclinical data from other groups also indicate 
that abrogation of SAC using TTK inhibitors is synergistic with paclitaxel in tumour growth 
inhibition. This was, in fact, observed in a broad range of xenograft models, including those 
showing acquired or intrinsic paclitaxel resistance. These novel findings provide the rationale for 
this study, combining CFI-402257 and paclitaxel chemotherapy in patients with MBC. 
 
 

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This study includes a dose escalation phase to identify the recommended phase II dose (RP2D) of 
oral CFI-402257 when used in combination with paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 
days, followed by a single arm phase II to evaluate the anti-tumour activity of the combination. The 
overall response rate will be benchmarked against a historical cohort from the recently reported 
IND.213 CCTG trial [Bernstein 2018]. In the control arm, patients (n=38) received paclitaxel 80 
mg/m2 IV days 1, 8 & 15 every 28 days and the ORR was 23.7% (all partial responses). With a 
median follow-up of 29.5 months, the median PFS for the control arm was 3.38 months and the 
median overall survival (OS) was 10.4 months. The phase II portion of this study will aim to enroll 
a similar patient population to IND.213. 
 
 

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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
Consult the most recent version of the investigators brochure for current information. 
 
3.1 
CFI-402257 Chemical Information 
 
CFI-402257, 
which 
has 
the 
chemical 
name 
N-cyclopropyl-4-(7-(((cis-3-hydroxy-3-
methylcyclobutyl)methyl)amino)-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-
methylbenzamide bisphosphate hemihydrate, is being developed by the University Health Network 
(UHN) as a new chemical entity for the treatment of cancer. This molecule was identified in the 
course of a focused synthetic medicinal chemistry effort directed towards the discovery of 
inhibitors of TTK protein kinase, also known as monopolar spindle 1 (Mps1). 
 
The clinical drug substance of CFI-402257 is bisphosphate hemihydrate. CFI-402257 capsules are 
intended for oral (po) administration. 
 
3.2 
Chemical Structure 
 
The chemical structure of CFI-402257 is shown below: 
 
Table 1: Chemical structure and formula of CFI-402257. 
 
Molecular Formula: 
C28H30N6O3·2H3PO4·0.5H2O 
Formula Weight: 
703.57 (bisphosphate hemihydrate) 
Molecular Weight: 
498.57 (free base) 
Solubility: 
Water, pH 2: 26 μg/mL 
Water, pH 7: <1 ug/mL 
Appearance: 
Off-white to light yellow crystalline solid 
 
Table 2: Nomenclature. 
 
Chemical Name: 
N-cyclopropyl-4-(7-(((cis-3-hydroxy-3- 
methylcyclobutyl)methyl)amino)-5-(pyridin-3- 
yloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzamide 
bisphosphate hemihydrate 
Chemical Class:  
Pyrazolopyrimidine 
CAS Registry Number: 
TBD 
 
 

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3.3 
Mechanism of Action 
 
CFI-402257 is a selective and potent inhibitor of TTK (Mps1), a key kinase in maintaining genomic 
integrity during mitotic cell division through establishment and maintenance of the mitotic 
checkpoint. TTK is a dual-specificity serine-threonine kinase that is critical for the recruitment of 
spindle assembly checkpoint (SAC) proteins to unattached kinetochores, mitotic checkpoint 
complex (MCC) formation, and thus anaphase promoting complex/cyclosome (APC/C) inhibition. 
TTK is also required for chromosome alignment and error correction. Inhibition of TTK kinase 
activity causes cells to prematurely exit mitosis with unattached chromosomes, resulting in severe 
chromosome missegregation, aneuploidy and eventually cell death. TTK is overexpressed in 
several tumours, and higher levels correlate with worse prognosis and may contribute to the 
survival and proliferation of aneuploid cells. Depletion of TTK expression in cancer cells by RNA 
interference leads to gross chromosome segregation errors and cell death. Thus, pharmacologic 
inhibition of this target would be expected to produce antiproliferative and cytotoxic effects against 
cancer cells. 
 
3.4 
Experimental Antitumour Activity 
 
Non-clinical pharmacology studies with CFI-402257 have been performed in vitro in enzyme 
assays, human tumour cell lines, and tumour initiating cell lines, and in vivo in human cancer cell 
line xenografts and primary tumour xenografts. 
 
CFI-402257 is a potent and specific inhibitor of TTK (Ki = 0.09 nM, IC50 = 1.2 nM), with minimal 
activity (≤50% inhibition at 1 μM) against 265 other protein kinases. CFI-402257 has 
antiproliferative activity against a number of cancer cell types, and causes effects consistent with 
inhibition of TTK kinase activity. The molecule is a potent intracellular inhibitor of exogenous 
TTK autophosphorylation with an EC50 = 6.5 nM. No effect on Aurora kinase A (AURKA), 
Aurora kinase B (AURKB) or Histone H3 phosphorylation is observed (EC50s > 400 nM). CFI-
402257 causes failure of the SAC, leading to gross aneuploidy (with minimal polyploidy) and cell 
death. Oral administration of CFI-402257 effectively inhibits growth in multiple murine models of 
human tumours, including cancer cell line xenografts and primary tumour xenografts. In these non-
clinical studies, CFI-402257 demonstrates dose-dependent antitumour activity, is active when 
administered under a range of dosing schedules, and is well-tolerated by mice when administered 
at efficacious doses. Immunohistochemical analysis of sections taken from MDA-MB-231 breast 
cancer xenograft tumours study revealed a decrease in the percentage of phospho-histone H3 
(pHH3)-positive cells with CFI-402257 treatment, consistent with inhibition of TTK in vivo. 
 
CFI-402257 demonstrated a desirable combination of potent inhibition of cancer cell growth in 
vitro and significant exposure upon oral dosing in mice, rats and dogs. Robust, dose-dependent 
suppression of tumour growth was achieved upon oral dosing in a number of xenograft models with 
minimal effects on mouse body weight and other parameters of toxicity. 
 
3.5 
Animal Toxicology 
 
The potential toxicity of CFI-402257 was investigated in a genetic toxicity study (bacterial Ames 
reverse mutation assay), two multiple dose tolerability studies, and two multiple dose toxicity and 
toxicokinetics (TK) studies. An oral route of exposure for the in vivo preclinical studies was used 
which is the clinical route of administration, and the studies were conducted using rodent (rat) and 
non-rodent (dog) species. 
 
 

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In both rats and dogs, the primary targets were the hematopoietic system and the gastrointestinal 
tract. The effects in the hematopoietic system included depression of WBC lineages and 
reticulocytes which correlated with hypocellularity of the bone marrow. Although increases in RBC 
mass cell parameters were compatible with hemoconcentration secondary to dehydration, the CFI-
402257-related decreases of reticulocytes in rats and dogs could potentially translate into anemia 
with longer treatment duration. Decreases in circulating and resident lymphocytes in lymphoid 
tissues may have been a direct effect of compound administration, secondary to stress, or a 
combination of both factors. Changes supporting an increase in endogenous corticosteroids (stress) 
included adrenal cortical hyperplasia and increased glucose levels in some animals. 
 
The gastrointestinal tract effects were consistent between species, involving all segments, and 
minimal to marked in severity with cecum most severely affected. Clinical effects in animals 
included loose or liquid, hemorrhagic, or otherwise abnormal stool. The gastroenteropathy was 
characterized by necrosis of epithelium, crypts, or glands with erosions or ulcerations, and 
regenerative/reparative changes including increased mitoses, cellular atypia piling up of cells, and 
villous fusion. In the 28-day GLP rat toxicity study, the highest non-severely toxic dose was 
5 mg/kg/day. In the 28-day GLP dog toxicity study, the highest non-severely toxic dose and the no 
observable adverse effect level were 1.0 mg/kg/day. Both the gastrointestinal tract effects and the 
hematological changes were reversed upon cessation of dosing or a reduction in dose level. 
 
A safety pharmacology study conducted in freely moving telemetrized female beagle dogs showed 
that treatment with CFI-402257 at doses up to 2.25 mg/kg had no adverse effects on cardiovascular 
or respiratory systems. 
 
3.6 
Clinical Trials 
 
The first in human dose escalation phase I trial with CFI-402257 (CL-001) is currently ongoing 
(NCT02792465). As of 13 November 2020, a total of 55 subjects with various solid malignancies 
have been evaluated with unformulated CFI-402257 bisphosphate hemihydrate powder-in-capsule 
in 28-day continuous cycles ranging from 5 to 294 mg/day. 54 (98%) subjects experienced at least 
one treatment-emergent adverse event (TEAE). The most common  adverse events (AEs) by 
preferred term (PT) were fatigue (50.9%), nausea (38.2%), and diarrhea (34.5%). The majority of 
AEs were either mild (21.8%) or moderate (36.4%). A total of 34 (61.8%) subjects reported at least 
one AE considered by the investigator to be related to study drug. There were 26 treatment-
emergent serious adverse events (SAEs) in 16 (29%) subjects, 9 of which were considered by the 
investigator to be related to study drug. There were 17 deaths in total. Most were due to disease 
progression. 
 
 

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3.7 
Pharmacokinetic Studies 
 
Absorption: 
In pre-clinical studies, the bioavailability of CFI-402257 was determined to be 53% in rats and 
114% in dogs. The pharmacokinetics of CFI-402257 after a single oral dose was characterized by 
a moderate to rapid rate of absorption with a Tmax generally of 30 minutes to 1 hour. The elimination 
half-life of the compound following oral administration averaged between 2.25 and 3.2 hours in 
mice, 2.0 and 4.6 hours in rats, and 1.5 and 5.5 hours in dogs. Repeated dose toxicokinetics studies 
indicated dose dependent increases in systemic exposure over the tested dose range in rats and dogs. 
 
PK data from the current ongoing first in human Phase I study of CFI-402257 showed that there 
was linear dose dependent increase in Cmax in the 6 dose escalating cohorts that had been cleared. 
At 56 mg oral daily dosing (N=4), which is the proposed starting dose of CFI-402257 in Phase Ib 
part of this study, average Cmax was 261 ng/ml (range 45-496), AUC0-24 was 2621 ng.h/ml (range 
575-4783), and t1/2 was 11.3 hours (range 8.3-16.2). Tmax was reached within 2 hours of 
administration. 
 
Distribution: 
CFI-402257 was 92% bound to plasma proteins in human plasma, 95% in mouse, 95% in rat, and 
94% in dog plasma. 
 
Metabolism: 
At high concentrations, CFI-402257 inhibits the activity of cytochrome P450 isoenzymes CYP2C8 
and CYP3A4, which metabolize paclitaxel. CFI-402257 also inhibits the activity of paclitaxel 
transporters OATP1B3, BCRP and PGP. Therefore, there is some potential for drug-drug 
interactions between CFI-402257 and paclitaxel. This potential drug-drug interaction will be 
investigated in the Phase II part of this study using a sparse PK sampling strategy. 
 
Elimination: 
Preliminary results from experiments in rats indicate that the primary route of excretion is in feces. 
 
3.8 
Pharmaceutical Data 
 
Supplied: 
CFI-402257 is currently supplied as a 2.5 mg, 14 mg, and a 42 mg capsule. The actual capsule 
strength used in this study will depend on the single agent RP2D. Doses are based on the active 
moiety alone.  
 
Bottles are induction sealed and capped with 38 mm child-resistant closures. Bottles are 
appropriately labeled to reflect drug product strength, contents, and recommended storage 
condition. Capsules should be swallowed whole. CFI-402257 is to be taken on an empty stomach. 
Patient should avoid food for 2 hours before taking CFI-402257 and 1 hour after taking CFI-
402257. 
 
Stability: 
Stability studies indicate the drug product is stable for at least three months when not refrigerated. 
Shipments to site pharmacies will be temperature controlled and monitored. Refrigeration or 
temperature monitoring is not required for Patient transport of study drug to and from the clinic. 
 
 

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Storage: 
Storage facilities and clinical site pharmacies should store CFI-402257 capsules at refrigerated 
temperature (2-8 °C). Patients should store capsules at ambient temperature. 
 
Route of Administration: 
Oral. 
 
3.9 
Paclitaxel 
 
Paclitaxel is not supplied for this study as it is commercially available and will be sourced from the 
Canadian market. Centres should consult the manufacturer’s guidelines for further details. 
 
In brief, paclitaxel has extensive extravascular distribution and/or tissue binding. Paclitaxel is 
metabolized by cytochrome P450 isoenzymes CYP2C8 (primarily) and CYP3A4, and caution 
should be exercised when administering paclitaxel with known substrates, inducers or inhibitors of 
these isoenzymes. 
 
 

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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 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of enrollment. Questions 
about eligibility criteria should be addressed prior to enrollment. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
4.1.1 
Patients must have histologically and/or cytologically confirmed diagnosis of breast cancer that is 
advanced/metastatic/recurrent or unresectable, for which no curative therapy exists, and for which 
systemic therapy is indicated. Only female patients will be enrolled. 
 
4.1.2 
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. 
 
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) and again no later than the end of the day following the day 
8 paclitaxel infusion. Lesions planned for biopsy may not be the only target lesion.  
 
4.1.3 
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). 
 
For phase Ib, patients are not required to have measurable disease as defined by RECIST 1.1 but 
must not have bone-only or marker only disease. 
 
For phase II, 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 
 
4.1.4 
Patients must be > 18 years of age. 
 
 

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4.1.5 
Patients must have an ECOG performance status of 0 or 1. 
 
4.1.6 
Patients must be able to swallow oral medications. 
 
4.1.7 
Previous Therapy 
 
Chemotherapy: 
Patients must have received at least one non-taxane containing chemotherapy regimen for advanced 
or metastatic disease unless:  
a) they have relapsed within 6 months of completion of adjuvant/neoadjuvant chemotherapy  
AND the regimen did not contain taxane, or; 
b) they have received taxane and/or anthracycline containing adjuvant/neoadjuvant chemotherapy 
6 or more months prior to relapse, or; 
c) they have a documented contraindication to palliative chemotherapy other than weekly 
paclitaxel. 
 
Patients must not be considered appropriate for endocrine therapy and must not have received 
taxanes in the metastatic setting. 
 
Other Systemic Therapy: 
Patients may have received other therapies including endocrine therapy, immunotherapy, and/or 
targeted therapies (including CDK4/6 inhibitors).  
 
Patient may NOT have had previous exposure to any therapy within the pharmacological class 
(TTK/MPS1 inhibitor). 
 
Patients must have recovered (to at least grade 0 or 1) from all reversible toxicity other than alopecia 
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 (e.g. at least 3 weeks for capecitabine). 
 
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. 
 
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 wound healing has occurred. 
 
 

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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 
≤ 1.0 x ULN (upper limit of normal)* 
AST and ALT 
≤ 3.0 x ULN  
≤ 5.0 x ULN if patient has liver metastases 
Serum creatinine 
or: 
Creatinine clearance** 
≤ 1.5 x ULN  
 
≥ 60 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 
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 vasectomy/vasectomized partner. However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
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 6 months after the last dose of CFI-402257. 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. 
 
4.1.10 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. 
 
4.1.11 Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 
The patient’s city of residence may be required to verify their geographical proximity. (Call the 
CCTG office (613-533-6430) if questions arise regarding the interpretation of this criterion.) 
Investigators must assure themselves the patients registered on this trial will be available for 
complete documentation of the treatment, adverse events, and follow-up. 
 
 

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Patients must agree to return to their primary care facility for any adverse events which may occur 
through the course of the trial. 
 
4.1.12 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
enrollment. 
 
4.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
4.2.1 
Patients with a history of other untreated malignancies or malignancies which required therapy 
within the past 2 years. Patients with other malignancies of a nature that do not require treatment 
may be eligible after consultation with the CCTG. 
 
4.2.2 
Patients with HER2 positive breast cancer. 
 
4.2.3 
Patients with active or uncontrolled infections or with serious illnesses or medical conditions which 
would not permit the patient to be managed according to the protocol. 
 
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 are not eligible if they have a known hypersensitivity to the study drug(s) or their 
components. 
 
4.2.6 
Patients with history of central nervous system metastases or spinal cord compression unless have 
received definitive treatment, are clinically stable and do not require corticosteroids. 
 
4.2.7 
Patients who have contraindications to treatment with paclitaxel and/or neuropathy > grade 1. 
(Please contact CCTG if any questions about the interpretation of this criterion.) 
 
4.2.8 
Concurrent treatment with other investigational drugs or anti-cancer therapy. 
 
4.2.9 
Pregnant or breast feeding women. 
 
4.2.10 Prohibited medications as listed in Appendix V Table 1. Patients being treated with drugs listed in 
Appendix V Table 2 may be enrolled, but should be monitored carefully for toxicities resulting 
from potential interactions between CFI-402257 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. 
 
4.2.11 Patients with any medical condition that could impair the administration of oral agents including 
significant bowel resection, inflammatory bowel disease or uncontrolled nausea or vomiting. 
 
4.2.12 Patients 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 III. 
 
Required Investigations 
Pre-study 
(< 7 days prior 
to enrollment) 
Within 21 
days prior to  
enrollment 
Weekly, 
and as 
clinically 
indicated 
Day 1 each 
cycle, and 
as 
clinically 
indicated 
Every 8 
weeks for 3 
assessments 
then every 
12 weeks 
4 weeks after 
end of last 
cycle date 
3 monthly follow-up 
(only required for pts 
without confirmed PD 
and ongoing toxicities1) 
then every 6 months 
until death 
History and Physical Exam* 
 
 
 
 
 
 
 
Including: height and weight, ECOG 
performance status, documentation of all 
measurable and non-measurable disease, 
clinical tumour measurements (if 
applicable); 
Vital signs: blood pressure, heart rate, 
temperature 
X 
 
 
X 
 
X 
 
Laboratory Procedures/Assessments* 
 
 
 
 
 
 
 
CBC (neutrophils, lymphocytes, 
hemoglobin, platelets) 
X 
 
X2 
 
 
X4 
X4 
PTT, PT/INR 
X 
 
 
X 
 
 
 
Serum creatinine3, electrolytes (calcium, 
potassium, magnesium) bilirubin, ALP, 
AST, ALT, LDH, albumin, glucose 
X 
 
X2 
X 
 
X4 
X4 
Pregnancy Test5 
X 
 
 
X6 
 
 
 
Urinalysis 
X7 
 
 
 
 
 
 
Radiology 
 
 
 
 
 
 
 
Tumour Imaging (Chest/upper abdomen 
CT scan; bone scan8; other scans as 
necessary to document disease) 
 
X9,10 
 
 
X11 
X11 
X11 
Other Investigations 
 
 
 
 
 
 
 
EKG  
X 
 
 
X 
 
 
 
LVEF 
X12 
 
 
As clinically 
indicated 
 
 
 
Archival Tumour Tissue  
X13 
 
 
 
 
 
 
Correlative Studies and PK Blood 
Collection (plasma and serum) 
X14 
 
See Section 12.0 for details 
Tumour biopsies 
X15 
 
X15 
 
Patient Drug Administration Diary 
(CFI-402257) 
 
Each Cycle 
 
Adverse events 
X 
 
Continuously 
X1 
 
footnotes on following page ... 
 
 

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* Pre-treatment blood draws and physical exams may be done one working day prior to treatment if necessary (e.g. Friday for treatment on 
Monday, or to accommodate holidays). In order to ensure that nadir counts are not missed, every effort should be made to do interim blood 
draws within 24 hours of the day specified in the protocol. 
1 Adverse events felt to be related to protocol therapy will be followed until resolved to ≤ Grade 2. 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 IV). 
2 CBC prior to each planned paclitaxel dose (all cycles); biochemistry weekly for cycles 1 and 2 (which also includes week 4 in cycle 1 and 2), 
more frequently if clinically indicated. Patients with grade 3 or 4 thrombocytopenia, febrile neutropenia, grade 3 or 4 neutropenia or grade 3 
or 4 biochemical drug related toxicity must have CBC/biochemistry at least alternate days until recovery to ≤ Grade 2 (consult CCTG if 
biochemistry is not felt to be drug related toxicity). 
3 If creatinine > 1.5 x ULN, calculated CrCl is required and must meet eligibility criteria for re-treatment. 
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 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. 
6 Only required as clinically indicated in WOCBP. 
7 Required at baseline then as clinically indicated. 
8 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, 
PR or SD, and/or PD is suspected and as clinically indicated. 
9 To ensure comparability, baseline scans and subsequent scans to assess response must be performed using identical technique (i.e. scans 
performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast agent, and 
preferably the same scanner). Maintain schedule every 8 or 12 weeks even if cycles are delayed. 
10 28 days if negative. 
11 To be done additionally every three months thereafter until relapse or progression for patients with CR, PR, SD response. 
12 Only if significant cardiac history (see Section 4.2.4) and then as clinically indicated. 
13 Must be confirmed available prior to enrollment on ALL patients. See Section 12.0 for details. 
14 After enrollment but before the first dose of study treatment. 
15 Optional paired biopsies  should be obtained after enrollment but prior to first dose and again no later than the end of the day following the 
day 8 paclitaxel infusion (must be done the day of the day 8 paclitaxel infusion or no later than the following day). Contact CCTG if unable to 
schedule within this time period.) See Section 12.1 for details. 
 
5.1 
Follow-up for Ineligible Patients 
 
The follow-up requirements for patients who have received no protocol therapy include submission 
of the Baseline Report and the Off Treatment Report. Data submission for all other participants 
who have received at least one dose of protocol therapy should follow the protocol to allow for 
treatment and adverse event assessment, irrespective of eligibility status. 
 
 

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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 
registering patients will be provided at the time of study activation and will also be included in the 
“EDC Data Management Guidebook”, posted on the IND.236 trial specific web-site. If sites 
experience difficulties accessing the system and/or registering patients, please contact the help desk 
(link in EDC) or the IND.236 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.236) 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
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 
BSA Calculation 
 
In calculating surface areas, actual heights and weights should be used, that is, there will be no 
downward adjustment to "ideal" weight. This principle applies to individuals whose calculated 
surface area is 2.2 m2 or less. In those rare cases where a patient's surface area is greater than 2.2, 
the actual surface area or 2.2 may be used. CCTG BSA calculations are based on the Mosteller 
formula. 
 
6.3 
Phase I 
 
In the dose escalation part of the study, patients will be treated with oral doses of CFI-402257 on 
an intermittent schedule (planned as 2 days on, 5 days off) in combination with weekly intravenous 
paclitaxel as below. One cycle is defined as 28 days. 
 
Each Cycle 
Week 1 
Week 2 
Week 3 
Week 4 
Day 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
CFI-402257 
X X  
 
 
 
 X X  
 
 
 
 X X  
 
 
 
 
 
 
 
 
 
 
 
Paclitaxel 
X 
 
 
 
 
 
 X  
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
 
 
On cycle days 1, 8, 15 where both drugs are administered, CFI-402257 is to be taken prior to and 
within 60 minutes of the start of paclitaxel infusion. For patients undergoing PK sampling, CFI-
402257 is to be taken immediately prior to (within 5 minutes) the start of the paclitaxel infusion. 
 
 

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6.3.1 
Justification for Starting Dose and Schedule 
 
In a parallel phase I study being conducted by the University Health Network, oral doses of up to 
168 mg single agent CFI-402257 have been tolerated when given on a continuous daily schedule 
(1/6 DLT (Grade 3 ANC)). Please refer to Section 3.0 and the investigator brochure for most up to 
date information.  
 
In this study, we plan to test the highest tolerable continuous dose of CFI-402257 as determined by 
the most recent data of the single agent phase I study, on an intermittent schedule (2 days weekly 
x 3 q28 days) in combination with weekly paclitaxel at a planned dosage of 80 mg/m2. 
 
6.3.2 
Dose Escalation  
 
Dose escalation of CFI-402257 will occur in a standard 3+3 design. Dosing is ‘flat’ and not by 
weight or BSA. Dose cohorts will initially include a minimum of 3-4 patients. If no DLTs are 
observed in the first 3 evaluable patients, CFI-402257 dose escalation will proceed according to 
the dose escalation schema below. If 1 patient out of 3 experiences a dose limiting toxicity (DLT), 
up to 3 additional patients will be recruited at that dose level (for a maximum of 6). If only 1 out 
of 6 patients in that dose level experiences a DLT, escalation to the next level will occur. If 2 out 
of 3, or 2 out of 6 patients experience DLT at dose level 1, the dose will be de-escalated as shown 
in the table below. If 2 out of 3, or 2 out of 6, patients experience DLT at other dose levels, no 
further dose escalation will occur. For the first dose level, the first patient will be followed for at 
least 7 days before the next patient is enrolled. 
 
Toxicity will be evaluated according to the CTEP Active Version of the CTCAE (See 
Appendix IV). Dose escalation decisions will be made after review of the data from the current 
dose level by the CCTG and investigators. 
 
If the first dose level of CFI-402257 is not tolerable, dose level -1 may be used. The planned starting 
dose may be adjusted if data from ongoing studies suggest that a higher or lower dose would be 
appropriate. Intermediate dose levels, other than those defined below, may be determined by the 
CCTG and investigators following a review of the data from this trial and other emergent data. If 
appropriate, based on review of clinical or pharmacokinetic data, an intermediate schedule (for 
example, 3 days on and 4 days off) will be tested. No intra-patient dose escalation will occur. 
 
A. Planned Starting Dose Levels 
 
Dose level 
CFI-402257 (mg) 
Dose on Days 1, 2, 8, 9, 15 & 16 (every 28 days) 
DL-1 
42 
Starting Dose (DL1)* 
56 
DL2 
84 
DL3 
126 
DL4 
168 
table continues on next page ... 
 
 

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B. Subsequent Dose Levels 
 
Subsequent Dose Levels 
Worst grade* toxicity in previous dose level 
% increase in dose of CFI-402577  
from previous dose level 
Hematologic 
Non-hematologic 
DLT? 
 
2 
1 
no DLT 
50% 
3 
2 
no DLT 
30-49% 
Follow DLT definition below 
≤ 1 DLT of 
6 pts 
0-29% 
2 DLT of 
3/6 pts 
0% 
* 
Considered related to CFI-402257. Actual doses will be dependent on this table and capsule size.  If required, 
schedule may also be modified (i.e. number of days dosed per week). 
 
Paclitaxel will not be dose escalated. No intra-patient dose escalation will occur. The planned 
starting dose of paclitaxel may be de-escalated if drug-drug interaction occur and safety data 
suggest that a lower dose would be appropriate. 
 
6.3.3 
Dose Limiting Toxicity, Maximum Tolerated Dose and Recommended Phase II Dose 
 
Dose Limiting Toxicity: 
Dose limiting toxicity (DLT) will be defined as any of the following related (to either drug) adverse 
events occurring during cycle 1: 
Hematologic Toxicity: 
• 
Grade 3 or 4 neutropenia complicated by fever ≥ 38.3°C or infection, 
• 
Grade 4 neutropenia of ≥ 7 days duration, 
• 
Grade 3 thrombocytopenia complicated by bleeding, 
• 
Grade 4 thrombocytopenia of any duration. 
Non-Hematologic Toxicity: 
• 
Grade 3 or 4 non-hematologic toxicity (excluding inadequately managed nausea and vomiting, 
alopecia or grade 3 fatigue lasting < 7 days). 
• 
Other toxicities of concern to the investigators and CCTG including the omission of 2 doses of 
paclitaxel or toxicities requiring > 21 days delay in next cycle and or late toxicities. 
 
Maximum Tolerated Dose: 
The maximum tolerated dose (MTD) will be determined, and will be defined as the dose level at 
which < 1/6 patients experience a dose limiting toxicity (DLT; defined below) during cycle 1. 
 
Recommended Phase II Dose (RP2D): 
The recommended phase II dose will be determined prior to proceeding to the phase II study, based 
on the observed MTD in cycle 1, with additional consideration of tolerability in subsequent cycles 
beyond the DLT period. 
 
 

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6.3.4 
Replacement of Patients 
 
If a patient is not evaluable for toxicity for Cycle 1, that patient may be replaced to ensure the 
minimum number of patients are evaluable. Patients must receive ≥ 75% planned dose of 
CFI-402257 and paclitaxel to be considered evaluable for toxicity, unless the study drug/s was 
held or discontinued for CFI-402257 or paclitaxel-related toxicity and/or DLT has occurred. 
 
6.4 
Phase II 
 
In the single arm phase II part, the RP2D of the CFI-402257+paclitaxel combination will be 
evaluated. 
 
6.5 
Study Enrollment 
 
Enrollment will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, should 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 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 patients who don’t receive treatment are 
outlined in Section 5.1. 
 
6.6 
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 
 
7.1.1 
Drug Administration 
 
Agent 
Dose 
Route 
Duration 
Schedule 
CFI-402257 
See Section 6 
Oral 
- 
Days 1, 2, 8, 9, 15, 16 q4w* 
Paclitaxel 
80 mg/m2 
IV 
1 hour 
Days 1, 8, 15 q4w 
* May be modified based on data from Phase 1 component. 
 
One cycle will be defined as 4 weeks. On days when both CFI-402257 and paclitaxel are 
administered, oral CFI-402257 should be taken prior to paclitaxel infusion (see Section 6.3 for 
timing). 
 
7.1.2 
Premedication 
 
All patients will receive prophylactic dexamethasone, diphenhydramine and ranitidine as per 
standard centre practice prior to each paclitaxel infusion. 
 
The suggested premedication regimen is: dexamethasone 10 mg IV, diphenhydramine 50 mg IV, 
and ranitidine 50 mg IV all given 30 minutes before paclitaxel infusion. 
 
7.1.3 
Dose Modifications 
 
Doses will be held or reduced for hematologic and other adverse events. Dose adjustments are to 
be made according to the system showing the greatest degree of toxicity. Adverse events will be 
graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (see Appendix 
IV). The use of an institution’s written standard procedures for dose modifications of paclitaxel is 
permitted. Dose reductions or treatment interruption for reasons other than those described below 
may be made by the clinical investigator if it is deemed in the best interest of patient safety. 
Whenever possible, these decisions should first be discussed with the senior investigator. Note: 
response evaluation must be performed every 8 weeks even if cycles are delayed. Centres should 
follow local policy regarding dose modifications based on changes in weight. 
 
The major toxic effects which may limit paclitaxel dose are cytopenias, arthralgia and/or myalgia, 
and peripheral neuropathy. 
 
 

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The most common CFI-402257 adverse event was nausea in thirteen subjects (23.6%). Other events 
include myelosuppression (including neutropenia and anemia) and febrile neutropenia, diarrhea, 
infection (including typhlitis and colitis), mucosal inflammation and stomatitis, vomiting, 
decreased appetite, dry mouth, dysgeusia, dyspepsia, alopecia, flushing/hot flush, headaches, 
fatigue, arthralgia, myalgia, pruritus and rash. 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. 
 
The next cycle should not be given until ANC ≥ 1.0 x 109/L and platelets ≥ 100 x 109/L and 
resolution of all drug related toxicity to ≤ grade 2. Contact CCTG if clinically appropriate 
exceptions are indicated. Note: growth factors may not be used to maintain dosing (see 7.2.1). 
 
If paclitaxel is held or delayed, CFI-402257 should be held or delayed to maintain the concurrent 
dosing schedule. Doses reduced for toxicity will not be re-escalated. Omitted doses will not be 
replaced (if day 8 is not given, it will be considered omitted for that cycle, and day 15 will be given 
on time (if appropriate). 
 
Patients who discontinue paclitaxel for toxicity may continue receiving CFI-402257, at the 
discretion of the investigator, providing that the patient has no evidence of disease progression. 
 
Specific details of dose adjustments are listed below. 
 
Table 1. Guidelines for CFI-402257 and Paclitaxel Dose Modifications for Treatment Related 
Adverse Events at D1, D8 and D15 of each treatment cycle. 
 
Dose on Day 1 of cycle 
 
On D1, paclitaxel and CFI-402257 should not be given until ANC ≥ 1.0 x 109/L and platelets 
≥ 100 x 109/L, and all other toxicity ≤ grade 2. 
 
Worst toxicity in previous cycle 
Management/Action for paclitaxel and CFI-402557 
HEMATOLOGIC 
 
2 consecutive omissions for hematologic toxicity 
(including delay of Day 1 ≥ 7 days) 
1st occurrence: Reduce paclitaxel by 1 DL 
2nd occurrence: Reduce CFI-402257 by 1 DL 
Febrile neutropenia or thrombocytopenic bleeding 
Reduce paclitaxel and CFI-402257 by 1 DL 
Grade 4 thrombocytopenia  
Grade 4 neutropenia ≥ 7 days  
NON-HEMATOLOGIC 
 
Grade ≥ 2 myalgia and/or arthralgia 
Consider NSAIDS, acetaminophen and, if not relieved, 
prednisone or gabapentin, according to local standard of 
care. If persistent and intolerable, reduce paclitaxel by 1 DL. 
Grade 2 and 3 motor or sensory neuropathy 
Reduce paclitaxel by 1 DL (if not already reduced at D8 or 
D15 in previous cycle) 
Other grade 3  
Reduce the causal drug by 1 DL (if not already reduced at 
D8 or D15 in previous cycle) 
Other grade 4 
Discontinue 
• For grade 3-4 hematologic/biochemistry toxicity, repeat CBC and biochemistry alternate days until recovered to ≤ grade 2. 
• If the treatment-related toxicity is not resolved within 21 days, the patient will be removed from the study, except in the case of 
patients benefiting from treatment, in whom treatment may be resumed following interruptions of > 21 days upon resolution of 
toxicity to baseline or Grade 1, after discussion with CCTG. 
• Two DL reductions are permitted for paclitaxel and CFI 402257 before discontinuation. 
 
 

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Dose on Day 8 or 15 of Cycle 
 
On D8 and D15, paclitaxel and CFI-402257 should not be given until ANC ≥ 1.0 x 109/L and 
platelets ≥ 100 x 109/L, and all other toxicity has resolved to ≤ grade 2. 
 
Worst toxicity on Day 8 or 15 
Management/Action for paclitaxel and CFI-402557 
HEMATOLOGIC 
 
Grade 3 and 4 ANC 
Omit both and follow table above  
Grade 2 and 3 platelets 
Omit both and follow table above  
Grade 4 platelets or thrombocytopenic bleeding 
Omit both and follow table above  
NON-HEMATOLOGIC 
 
Grade ≥ 2 myalgia and/or arthralgia 
Consider NSAIDS, acetaminophen and, if not relieved, 
prednisone or gabapentin according to local standard of 
care. If persistent, reduce paclitaxel by 1 DL. 
Grade 2 and 3 motor or sensory neuropathy 
Omit both and then reduce only paclitaxel by 1 DL 
Other grade 3 
Omit both and then reduce the causal drug by 1 DL 
Other grade 4 
Discontinue 
• For grade 3-4  thrombocytopenia, febrile neutropenia, grade 3 or 4 neutropenia or grade 3 or 4 biochemical drug related toxicity, 
repeat CBC and biochemistries on alternate days until recovered to ≤ grade 2. (Consult CCTG if biochemistry is not felt to be drug 
related toxicity).Two DL reductions are permitted for paclitaxel and CFI-402257 before discontinuation. 
• If the treatment-related toxicity is not resolved within 21 days, the patient will be removed from the study (except in the case of 
patients benefiting from treatment, in whom treatment may be resumed following interruptions of > 21 days upon resolution of 
toxicity to baseline or Grade 1, after discussion with CCTG. 
 
Table 2: Dose Reductions for CFI-402257. (See Table A. Section 6.3.2) 
 
Initial Dose* 
1st Reduction 
2nd Reduction 
3rd Reduction 
56 mg 
42 mg 
28 mg 
DISCONTINUE 
84 mg 
56 mg 
42 mg 
DISCONTINUE 
126 mg (range 112-126) 
84 mg 
56 mg 
DISCONTINUE 
168 mg (range 140-168) 
126 mg 
84 mg 
DISCONTINUE 
Higher doses 
Reduce by 1 DL 
Reduce by 1 DL 
DISCONTINUE 
* For intermediate doses (or higher doses) not listed, calculate dose reductions using ranges listed under initial dose column or 
contact CCTG. 
 
Table 3: Dose Reductions for Paclitaxel. 
 
Initial Dose 
1st Reduction 
2nd Reduction 
3rd Reduction 
80 mg/m2 
65 mg/m2 
50 mg/m2 
DISCONTINUE 
 
 

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Paclitaxel Hypersensitivity Reaction 
 
Severity 
Action 
Mild (e.g. mild flushing, rash, pruritus) 
Attempt to complete the infusion under close supervision. 
Moderate (e.g. moderate rash, flushing, 
mild dyspnea, chest discomfort, mild 
hypotension) 
• Stop the paclitaxel infusion and give diphenhydramine 25-50 mg 
IV and methylprednisolone 125 mg IV. 
• Once symptoms have resolved, resume paclitaxel infusion at a 
rate of 10% of original rate for 15 minutes, then at 25% of 
original rate for 15 minutes, and if no further symptoms develop, 
continue at original rate until infusion is complete. 
Severe (e.g. one or more of: respiratory 
distress requiring treatment, generalized 
urticaria, angioedema, hypotension 
requiring therapy) 
• Stop the paclitaxel infusion; give diphenhydramine and 
methylprednisolone as above. Use epinephrine or 
bronchodilators if indicated. 
• Do not rechallenge with paclitaxel 
 
If hypersensitivity reactions occur, pre-medications for re-challenge include dexamethasone 20 mg 
PO given 12 hours and 6 hours prior to treatment, plus IV pre-medications given 30 minutes prior 
to paclitaxel: dexamethasone 10 mg, diphenhydramine 25 mg, and H2-antagonist (e.g. ranitidine 
50 mg). If no hypersensitivity reactions occur, standard pre-medications (see above) will be used 
for subsequent paclitaxel doses. Contact CCTG in advance if responding patients have severe 
hypersensitivity reactions and treating investigator feels a switch to standard nab-paclitaxel is 
indicated. 
 
Paclitaxel Renal and Hepatic Dysfunction 
 
Follow product monograph/local policies for hepatic and renal dysfunction dose modifications. 
 
7.1.4 
Duration of Therapy  
 
Treatment will continue until the criteria for removal from protocol treatment have been met (see 
Section 10.0). Patients who discontinue paclitaxel for toxicity may continue receiving CFI-402257 
at the discretion of the investigator. 
 
7.1.5 
Patient Compliance  
 
Treatment compliance will be monitored by drug accountability, as well as recording drug 
administration in the patient’s medical record and case report form (CRF). 
 
7.2 
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. 
 
 

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7.2.2 
Not Permitted 
 
• 
Administration of any other anti-cancer or investigational 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.) 
• 
Patients should avoid the ingestion of large amounts of grapefruit and Seville oranges (and 
other products containing these fruits (e.g. grapefruit juice or marmalade). 
• 
Prohibited medications as listed in Appendix V Table 1. Drugs listed in Appendix V Table 2 
may be used, but patients should be monitored carefully for toxicities resulting from potential 
interactions between CFI-402257 and these drugs. 

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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for Adverse Events 
All patients will be evaluable for adverse event evaluation from the time of their first treatment. 
 
8.1.2 
Evaluable for Response 
All patients who have received at least one cycle of therapy and have their disease re-evaluated will 
be considered evaluable for response (exceptions will be those who exhibit objective disease 
progression prior to the end of cycle 1 who will also be considered evaluable). Patients on therapy 
for at least this period and who meet the other listed criteria will have their response classified 
according to the definitions set out below [Eisenhauer 2009]. 
 
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. 
 
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. 
 
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. 
 
 

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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. Pathological lymph 
nodes must have short axis measures < 10 mm (Note: continue to record the measurement even if 
< 10 mm and considered CR). Residual lesions (other than nodes < 10 mm) thought to be non-
malignant should be further investigated (by cytology specialized imaging or other techniques as 
appropriate for individual cases [Eisenhauer 2009]) before CR can be accepted. Confirmation of 
response is only required in non-randomized studies. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumour 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD. Confirmation of response is only required in non-
randomized studies. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND an 
absolute increase of ≥ 5mm. Appearance of new lesions will also constitute progressive disease 
(including lesions in previously unassessed areas). In exceptional circumstances, unequivocal 
progression of non-target disease may be accepted as evidence of disease progression, where the 
overall tumour burden has increased sufficiently to merit discontinuation of treatment or where the 
tumour burden appears to have increased by at least 73% in volume. Modest increases in the size 
of one or more non-target lesions are NOT considered unequivocal progression. If the evidence of 
PD is equivocal (target or non-target), treatment may continue until the next assessment, but if 
confirmed, the earlier date must be used. 
 
 

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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 
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 
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 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 
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. 
 
 

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8.3 
Response Duration 
 
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). 
 
8.4 
Stable Disease Duration 
 
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
 
8.5 
Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
8.5.1 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm as 
assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging 
is preferred. 
 
8.5.2 
Chest X-ray 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
≥ 20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung. 
 
8.5.3 
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). 
 
8.5.4 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
 
 

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8.5.5 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumour evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response or surgical resection is an endpoint. 
 
8.5.6 
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 IV). 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 
 
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.236 section of the CCTG website (www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
 

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EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
Linda Hagerman 
IND.236 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.236 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 4.1.9. 
 
9.3.2 
Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants. 
Pregnancies occurring up to 6 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). 
 
 

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If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
9.3.3 
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. 
 
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 (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which causal relationship with protocol treatment cannot be ruled out). 
 
9.5 
CCTG Reporting Responsibility to UHN 
 
UHN will be notified of all reportable serious adverse events within 1 working day of receipt by 
CCTG. 
 
9.6 
UHN Reporting Responsibilities 
 
UHN shall notify CCTG of individual safety reports from other studies using CFI-402257, which 
may affect the overall safety profile of the study and which they have reported to Health Canada. 
In addition, UHN will provide 3 monthly line listings to CCTG for all other reports. 
 
 

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9.7 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to the CCTG. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. The reports will be posted to the CCTG 
trial IND.236 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
IND.236 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 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. 
• 
Completion of therapy as outlined in Section 10.2. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
 
10.2 
Duration of Protocol Treatment  
(see Section 8.0 for response definition) 
• 
Treatment with CFI-402257 will continue until progression 
• 
Treatment with paclitaxel will continue to the maximum number of cycles permitted per local 
practice or until progression in the absence of unacceptable toxicity (see Section 7). 
• 
Patients who progress will go off study at the time progression is documented clinically and/or 
radiographically. 
• 
If CFI-402257 is discontinued for toxicity, paclitaxel should be continued according to standard 
clinical practice off protocol. 
• 
If paclitaxel is discontinued for toxicity, CFI-402257 may be continued in patients with no 
evidence of disease progression. No other anticancer therapy may be co-administered. If 
patients require other anti-cancer therapy, then CFI-402257 must be discontinued. 
 
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, PR, or SD 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. Death report will be required on all patients unless advised by 
CCTG. Due within 2 weeks of knowledge of death (see Appendix III - Documentation for Study). 

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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
 

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12.0 
CORRELATIVE STUDIES 
 
A detailed Correlative Studies Manual will be provided on the IND.236 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) and 
again no later than the end of the day following the day 8 paclitaxel infusion (must be done the day 
of the day 8 paclitaxel infusion or no later than the following day). Please contact CCTG if unable 
to schedule within this time period. 
 
Blood Collection 
The submission of samples at baseline and after 4 cycles (or at off treatment) for cfDNA is also 
mandatory for participation in this trial. Samples will be collected to measure dynamic changes in 
levels of tumour-derived DNA in plasma with study treatment. 
 
 

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Planned Assays on Tissue 
Molecular analyses including but not limited to next-generation DNA sequencing and 
immunohistochemistry will be performed on archival and fresh tumour (or normal tissue) materials 
to identify potential biomarkers of response, including TTK, pKNL1, expression of APC/C 
components, etc. 
 
Drug levels will also be measured to evaluate distribution of CFI-402257 to tumour. 
 
12.2 
Pharmacokinetic Studies 
 
Clinical pharmacokinetic studies are a required component of study participation and will be 
performed in all patients where required by the protocol, in accordance with the sampling schedule 
detailed in the Pharmacokinetic Manual. 
 
Blood samples for paclitaxel must be collected from the arm opposite to the infusion line. If a 
heparin lock is used, a minimum of 1 mL of whole blood should be withdrawn and discarded prior 
to each collection to ensure that the heparin does not contaminate the specimen. 5 ml venous blood 
samples will be collected into EDTA anticoagulant containing tubes. 
 
Exact infusion start and stop times and as well as infusion parameters (concentration of dose 
solution, total volume delivered, and flow rate settings) for each dose corresponding to 
pharmacokinetic sampling, will be recorded on the Pharmacokinetics Form. If for any reason a 
sample is not collected, the sample date and time should be recorded as not done (ND) on the 
Pharmacokinetics Form. All samples are to be taken at the times specified. If samples are taken at 
times different from this schedule, they are still valuable provided the time is accurately recorded. 
Inaccurately recorded times may hinder the investigation. Changes to the PK sampling schedule 
may occur as emergent clinical data become available. Blood samples for PK will be collected as 
follows: 
• 
In phase I dose escalation, at dose/exposure levels of CFI-402257 that exceed those 
characterized as the RP2D in the phase I First in Human monotherapy study, PK sampling will 
be performed on C1D1 (for CFI-402257 only). 
• 
In phase II, PK sampling for both agents will be performed on C2D8 (if unable to sample on 
day 8 then C2D15 is permissible after discussion with CCTG) in the first 10 patients enrolled. 
Assays on these samples will only be performed if clinically indicated (for example, a PK 
interaction is suspected based on clinical data). 
 
In each case, CFI-402257 is to be administered immediately prior to the start of the paclitaxel 1 hr 
infusion, and samples collected at the following times: 
 
Phase I 
On Cycle 1, Day 1: Pre-dose CFI-402257, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours 
 
Cycle and Day 
Time in Relation to CFI-402257 Administration 
C1D1 
Pre-dose of CFI-402257 
1 hour post administration 
2 hours post administration 
4 hours post administration 
6 hours post administration 
8 hours post administration 
C1D2 
24 hours post administration* (collect sample prior to CFI-402257 dosing) 
*strongly recommended 
 
 

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Phase II: 
 
On Cycle 2, Day 8: Pre-dose  CFI-402257 and paclitaxel, 30 minutes, 1 hour, 2 hours, 3 hours, 4 
hours, 6 hours, 8 hours and 24 hours after CFI-402257 and paclitaxel administration, and pre-CFI-
402257 and paclitaxel administration on Day 15.  
 
Cycle and 
Day 
Time 
Time in Relation to Paclitaxel Infusion 
C2D8 
0 
Pre-dose (of BOTH CFI-402257 and paclitaxel) 
30 min 
30 minutes after beginning of paclitaxel infusion 
60 min 
End of paclitaxel infusion 
2 hours 
1 hour post end of paclitaxel infusion 
3 hours 
2 hours post end of paclitaxel infusion 
4 hours 
3 hours post end of paclitaxel infusion 
6 hours 
5 hours post end of paclitaxel infusion 
8 hours 
7 hours post end of paclitaxel infusion 
C2D9 
 
24 hours post end of paclitaxel infusion (and prior to CFI-402257 dosing) 
C2D15 
 
Pre-dose (of BOTH CFI-402257 and paclitaxel) 
 
Note: if PK sampling is done on Day 15 then the last sample is taken on day 22. 

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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
This is an open label multicentre phase Ib trial to establish the safety and tolerability of CFI-402257 
given orally in combination with weekly paclitaxel in a q4w schedule and to identify the 
recommended phase II dose (RP2D) in patients with advanced/metastatic breast cancer. The phase 
Ib part will utilize a 3+3 design. The phase II part will evaluate the anti-tumour activity of the CFI-
402257 and paclitaxel combination when administered at the RP2D by determining the objective 
Overall Response Rate by RECIST 1.1. 
 
13.2 
Primary Endpoints and Analysis 
 
Phase Ib: the primary endpoint is toxicity and establishing the RP2D of the combination of CFI-
402257 with weekly paclitaxel in a q4w schedule. 
 
Phase II: the primary endpoint of this part is objective response rate, defined as the proportion of 
response evaluable patients who had complete response (CR) or partial response (PR) as their best 
response as assessed by RECIST 1.1 criteria (i.e. a 30% decrease in the sum of the longest diameters 
of the target lesions maintained for at least 4 weeks (CR), or complete disappearance of disease and 
cancer related symptoms, also maintained for at least 4 weeks (CR)). 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 Clinical Benefit Rate (CBR, defined as CR or PR or stable disease 
(SD) > 16 weeks in duration). 
 
13.3 
Sample Size and Duration of Study 
 
Final sample size will be dependent upon the number of dose levels required to reach the RP2D. 
We anticipate recruiting between 12 to 18 patients in the phase Ib. 
 
For phase II, a 2-stage Simon design will be used. The overall response rate is benchmarked against 
a historical cohort from the recently reported IND.213 CCTG trial [Bernstein 2018]. In the control 
arm, patients (n=38) received paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days and the ORR 
was 23.7% (all partial responses). 
 
Stage 1 of Accrual:  
17 response evaluable patients will be entered in the first stage. Using response hypotheses of H0 ≤ 
20% and Ha ≥ 40%, we would reject the drug at the end of the first stage of accrual if 3 or less 
responses are seen. Otherwise, an additional 20 patients will be accrued to the cohort. 
 
Stage 2 of Accrual:  
An additional 20 response evaluable patients will be accrued. We would accept the combination as 
active if 11 or more responses are observed. 
 
 

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Significance Level and Power:  
The procedure described above tests the null hypothesis (H0) that the response rate is 20% versus 
alternating hypotheses (H1) that the response rate is 40%. The significance level (i.e. the probability 
of rejecting H0 when it is true) is α=0.10 and the power (i.e. the probability of rejecting H0, i.e. 
deciding the regimen is active, when H1 is true) is 0.90. 
 
13.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported semi-annually at investigators’ meetings. 
 
13.5 
Pharmacokinetics 
 
Pharmacokinetic samples will be taken as indicated in Section 12.2 but assays will only be 
performed if indicated. Comparisons will be made between the different dose levels of CFI-402257 
for pharmacokinetic analysis. Plasma levels of paclitaxel will also be measured at specific time 
points defined as above to characterize paclitaxel pharmacokinetics when administered in 
combination with CFI-402257. ANOVA and linear regression or comparable nonparametric 
statistical methods will be used to make dose group comparisons. Pharmacokinetic analyses using 
noncompartmental analysis will be conducted. Pharmacokinetic analyses may include plasma 
AUC, T½, Tmax, Cmax, Cmin, and Cavg. 
 
13.6 
Correlative Studies  
 
Tumour biopsies will be collected prior to initiation of study treatment and again no later than the 
end of the day following the day 8 paclitaxel infusion in up to 15 patients to determine any evidence 
of target effects. Results will be compared to those published in literature [Zasadil 2014]. Circulating 
tumour DNA analysis will also be performed to measure dynamic change in levels of tumour 
derived circulating DNA in plasma with study treatment. These analyses are exploratory but will 
be analyzed using appropriate statistical tests. 
 
Molecular analysis including but not limited to next-generation DNA sequencing and 
immunohistochemistry will be performed on archival and fresh tumour materials to identify 
potential biomarkers of response. Evaluation of the association between genomic alterations, and 
other molecular features (i.e. gene or protein expression levels), and evidence of benefit, will be 
considered exploratory, and associations will be analyzed in a descriptive manner. 

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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 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 a Stand Up to 
Cancer Canada - Canadian Breast Cancer Foundation Breast Cancer 
Dream Team Research Funding, with supplemental support of the Ontario 
Institute for Cancer Research through funding provided by the 
Government of Ontario (Funding Award Number: SU2C-AACR-DT-18-
15). Stand Up to Cancer Canada is a program of the Entertainment 
Industry Foundation Canada. Research funding is administered by the 
American Association for Cancer Research International - Canada, the 
scientific partner of SU2C Canada. 
 
14.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following study closure the manuscript has 
not been submitted, the central office reserves the right to make other arrangements to ensure timely 
publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
14.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by 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. 
 
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 pregnancy/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). 
 
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. 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 

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16.0 
REFERENCES 
Bernstein V, Ellard SL, Dent SF, Tu D, Mates M, Dhesy-Thind SK, Panasci L, Gelmon KA, Salim M, Song X, 
Clemons M, Ksienski D, Verma S, Simmons C, Lui H, Chi K, Feilotter H, Hagerman LJ, Seymour L. A 
randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast 
cancer: final analysis of Canadian Cancer Trials Group IND.213 Breast Cancer Research and Treatment: 167 
(2): 485 - 493, 2018 
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. 
Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro 
CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks 
paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment 
to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 
9840. J Clin Oncol. Apr 1;26(10):1642-9, 2008. 
Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, 
Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D'Andrea G, Cristofanilli M, 
Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast 
cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. May 
15;19(10):2587-95, 2001. 
Zasadil LM, Andersen KA, Yeum D, Rocque GB, Wilke LG, Tevaarwerk AJ, Raines RT, Burkard ME, Weaver 
BA. Cytotoxicity of Paclitaxel in Breast Cancer is due to Chromosome Missegregation on Multipolar Spindles. 
Science Translational Medicine, Vol. 6 Issue 229, 229ra43, 2014. 

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

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APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
General 
 
Details of Drug Distribution, Supply and Control/Accountability are provided in the IND.236 Pharmacy 
Information Manual, available on the IND.236 website: 
(http://www.ctg.queensu.ca/trials/.html). 
 
Distribution 
 
Paclitaxel is commercially available and sourced from the Canadian market. 
 
CFI-402257 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. 
 
A start up supply of CFI-402257 will be distributed to the activated site by BARL following receipt of 
confirmation from CCTG that all essential documents required for study activation have been submitted by 
the participating site to the CCTG office. BARL will ship CFI-402257 directly to the site pharmacy. Sites 
should allow for 5-7 working days for drug shipments to arrive. 
 
Resupply 
 
For re-supply of CFI-402257, sites should print off and submit a Drug Re-Supply Form available on the 
IND.236 website. This form should be submitted directly to the Study Coordinator, Linda Hagerman, at 
lhagerman@ctg.queensu.ca. Once received, request will be sent to BARL and BARL will process 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.236 trial website. At the end of the study, it must be possible to 
reconcile shipment records with records of usage/returned stock by completion of the study drug 
accountability form. Any discrepancies must be accounted for and documented. 
 
Drug Destruction 
 
Drug Destruction of Patient Returns 
Unused trial medication returned by the patient may be destroyed per local policy, AFTER accountability 
and reconciliation has been completed and documented by the site. Documentation of destruction must be 
kept on file in the site pharmacy and is subject to on site monitoring/audit. 
 
 

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

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APPENDIX III - 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 on-line Case Report Forms, please refer to the Data Management 
Guidebook posted on the IND.236 area of the CCTG web-site (www.ctg.queensu.ca). 
 
The ELECTRONIC CRFs to be used in this trial are: 
 
Electronic Case Report Form 
To be Completed/Submitted Electronically: 
Supporting Documentation to be sent using 
Supporting Document Upload Tool* 
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.  
Copies of signature 
pages of main and 
optional consent forms; 
relevant pathology & 
radiology reports. 
ECG, LVEF 
TREATMENT REPORT  
To be completed every 4 weeks (i.e. after each cycle). 
Due within 2 weeks of end of course. This report 
documents treatment, adverse events, investigations 
and response assessment for each course. 
Relevant radiology 
reports. 
 
Patient Diary 
(CFI-402257). 
CORRELATIVE 
STUDIES 
See Section 12. 
 
 
END OF TREATMENT 
REPORT 
To be completed when patient goes off protocol 
treatment. Due within 2 weeks of end of protocol 
treatment. 
 
 
4 WEEK POST 
TREATMENT REPORT 
To be completed once on all patients, 4 weeks after 
going off protocol treatment. Due within 2 weeks 
after contact with patient. 
Relevant radiology 
reports. 
 
FOLLOW-UP REPORT 
To be completed every 3 months or 6 months (see 
Sections 5.0 and 10.4). Due within 2 weeks after 
contact with patient. 
Relevant radiology 
reports. 
 
RELAPSE/ 
PROGRESSION 
REPORT  
To be completed at the time of disease relapse or 
progression. Due within 2 weeks after contact with 
patient. 
Relevant radiology 
reports. 
 
 
 table continues on next page … 
 
 

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Electronic Case Report Form 
To be Completed/Submitted Electronically: 
Supporting Documentation to be sent using 
Supporting Document Upload Tool* 
Mandatory Submission 
To be uploaded immediately 
after the report they refer to 
has been submitted 
electronically. 
Submission On 
Request 
To be uploaded 
immediately after 
request.  
DEATH REPORT** 
Required for all patients unless advised by CCTG. 
Due within 2 weeks of knowledge of death. 
Autopsy report, if 
done. 
 
SERIOUS ADVERSE 
EVENT (SAE) REPORT 
All reportable serious adverse events must be 
reported as described in Section 9.0. Preliminary 
CCTG Serious Adverse Event Report due within 24 
hours. Updated CCTG Serious Adverse Event Report 
due within 7 days. 
 
All relevant 
test reports, 
admission, 
discharge 
summaries/note
s and other 
documentation. 
* 
Source documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, and/or serious adverse 
events. All supporting documents must have personal identifiers redacted. 
** 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 IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 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 V - PROHIBITED MEDICATIONS 
 
Table 1. Drugs to be excluded 
 
Alfentanil 
Pimozide 
Cyclosporine 
Quinidine 
Digoxin 
Sirolimus 
Dihydroergotamine 
Tacrolimus 
Ergotamine 
Warfarin 
Fentanyl 
 
 
 
 
 
Table 2. Substrates of BCRP, OATP1B1, OCT1, OCT2 and MATE. To be used with caution. 
 
Acyclovir 
Everolimus 
Quetiapine 
Amantadine 
Felodipine 
Rifampin 
Aprepitant 
Fexofenadine 
Ritonavir 
Atorvastatin 
Fluticasone 
Rosuvastatin 
Budesonide 
Ganciclovir 
Saquinavir 
Buspirone 
Indinavir 
Sildenafil 
Cimetidine 
Lopinavir 
Simvastatin 
Colchicine 
Lovastatin 
Sulfasalazine 
Conivaptan 
Lurasidone 
Telmisartan 
Darifenacin 
Maraviroc 
Thyroxine 
Darunavir 
Memantine 
Tiprinavir 
Dasatinib 
Metformin 
Tolvaptan 
Desipramine 
Midazolam 
Triazolam 
Dofetilide 
Nisoldipine 
Valsartan 
Dronedarone 
Olmesartan 
Vardenafil 
Eletriptan 
Pitavastatin 
 
Eplerenone 
Pravastatin 
 
 
 

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APPENDIX VI - 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) 
Linda Hagerman 
Study Coordinator, CCTG 
Email: lhagerman@ctg.queensu.ca 
or: 
Dr. Pierre-Olivier Gaudreau 
Senior Investigator, CCTG 
Email: p-ogaudreau@ctg.queensu.ca 
or: 
Dr. Lesley Seymour 
Director, CCTG 
Investigational New Drug Program 
Email: lseymour@ctg.queensu.ca 
STUDY CO-CHAIRS 
Dr. Philippe Bedard 
Study Co-Chair 
or: 
Dr. Mihaela Mates 
Study Co-Chair 
Contact CCTG 
Contact CCTG 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for 
details of reportable events. 
Linda Hagerman 
Study Coordinator, CCTG 
Email: lhagerman@ctg.queensu.ca 
or: 
Dr. Pierre-Olivier Gaudreau 
Senior Investigator, CCTG 
Email: p-ogaudreau@ctg.queensu.ca 
or: 
Dr. Lesley Seymour 
Director, CCTG 
Investigational New Drug Program 
Email: lseymour@ctg.queensu.ca 
613-533-6430 
613-533-2411 
DRUG ORDERING 
See Appendix II for full details. 
See Appendix II and trial website: http://www.ctg.queensu.ca