Double-Blind Placebo-Controlled Randomized Phase III Trial of Fulvestrant and Ipatasertib as Treatment for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Canadian Cancer Trials Group

 
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CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION: 2020-SEP-15 
 
AMENDMENT #1: 2021-MAR-31 
 
ADMINISTRATIVE UPDATE #1: 2022-JUN-01 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A DOUBLE-BLIND PLACEBO CONTROLLED RANDOMIZED PHASE III TRIAL OF 
FULVESTRANT AND IPATASERTIB AS TREATMENT FOR ADVANCED HER-2 NEGATIVE 
AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER FOLLOWING PROGRESSION 
ON FIRST LINE CDK 4/6 INHIBITORAND AROMATASE INHIBITOR (FINER) 
 
CCTG Protocol Number: MA.40 
BCT Protocol Number: 2101 
Roche Protocol Number: MO41883 
 
 
 
STUDY CHAIR: 
Stephen Chia 
 
 
TRIAL COMMITTEE: 
Jean-Pierre Ayoub 
 
 
Haji Ibrahim Chalchal 
 
 
Daniel Rayson 
 
 
Andrew Redfern 
 
 
SENIOR INVESTIGATOR: 
Wendy Parulekar 
 
 
SENIOR FELLOW: 
Moira Rushton-Marovac 
 
 
BIOSTATISTICIAN: 
Bingshu Chen 
 
 
QUALITY OF LIFE LEAD: 
Christine Simmons 
 
 
HEALTH ECONOMICS LEAD: 
Danielle Rodin 
 
 
CORRELATIVE SCIENCES CHAIR: 
David Cescon 
 
 
STUDY COORDINATOR: 
Lisa Gallinaro 
 
 
REGULATORY SPONSOR (Canada): 
CCTG 
 
 
REGULATORY SPONSOR (Australasia): 
BCT 
 
 
SUPPORTED BY: 
Hoffmann-La Roche Ltd. 
 
(For contact information of study personnel see Final Page.) 
 

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

 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .......................................................................... 1 
 
TREATMENT SCHEMA ............................................................................................................................. 2 
 
1.0 
OBJECTIVES .................................................................................................................................. 3 
1.1 
Primary Objective ............................................................................................................................ 3 
1.2 
Secondary Objectives....................................................................................................................... 3 
1.3 
Tertiary Objectives........................................................................................................................... 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ............................................................... 4 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION .................................................................. 11 
3.1 
Ipatasertib ....................................................................................................................................... 11 
3.2 
Fulvestrant ..................................................................................................................................... 15 
 
4.0 
STUDY POPULATION ................................................................................................................ 16 
4.1 
Eligibility Criteria .......................................................................................................................... 16 
4.2 
Ineligibility Criteria ....................................................................................................................... 19 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT ............................................................................................................................... 22 
5.1 
Follow-up for Ineligible Patients ................................................................................................... 24 
 
6.0 
ENTRY/ENROLLMENT PROCEDURES ................................................................................... 25 
6.1 
Entry Procedures ............................................................................................................................ 25 
6.2 
Stratification ................................................................................................................................... 25 
6.3 
Study Enrollment ........................................................................................................................... 25 
 
7.0 
TREATMENT PLAN .................................................................................................................... 27 
7.1 
Treatment Plan ............................................................................................................................... 27 
7.2 
Dose Adjustments .......................................................................................................................... 27 
7.3 
Adverse Event Management Guidelines ........................................................................................ 29 
7.4 
Duration of Therapy ....................................................................................................................... 36 
7.5 
Concomitant Therapy..................................................................................................................... 37 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ................................................. 38 
8.1 
Definitions ..................................................................................................................................... 38 
8.2 
Response and Evaluation Endpoints .............................................................................................. 38 
8.3 
Response Duration ......................................................................................................................... 41 
8.4 
Stable Disease Duration ................................................................................................................. 41 
8.5 
Methods of Measurement .............................................................................................................. 41 
 
9.0 
SERIOUS ADVERSE EVENT REPORTING .............................................................................. 43 
9.1 
Definition of a Reportable Serious Adverse Event ........................................................................ 44 
9.2 
Serious Adverse Event Reporting Instructions .............................................................................. 44 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting .................... 45 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .......................... 46 
9.5 
CCTG Responsibility for Reporting Serious Adverse Events to Breast Cancer Trials Australia .. 46 
9.6 
CCTG Reporting Responsibility to Hoffman-La Roche Ltd. ........................................................ 46 
9.7 
Hoffman-La Roche Reporting Responsibilities ............................................................................. 47 
9.8 
Reporting Safety Reports to Investigators ..................................................................................... 47 
 
 

 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ..... 48 
10.1 
Criteria for Discontinuing Protocol Treatment .............................................................................. 48 
10.2 
Therapy After Protocol Treatment is Stopped ............................................................................... 48 
10.3 
Follow-up Off Protocol Treatment ................................................................................................ 48 
 
11.0 
CENTRAL REVIEW PROCEDURES .......................................................................................... 49 
11.1 
Central Data Review ...................................................................................................................... 49 
11.2 
Central Radiology Review ............................................................................................................. 49 
11.3 
Central Pathology Review ............................................................................................................. 49 
 
12.0 
CORRELATIVE STUDIES .......................................................................................................... 50 
12.1 
Protocol-Mandated Correlative Studies ......................................................................................... 50 
12.2 
Optional Banking ........................................................................................................................... 53 
 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 55 
13.1 
Objectives and Design ................................................................................................................... 55 
13.2 
Primary Endpoints and Analyses ................................................................................................... 55 
13.3 
Secondary Endpoints and Analyses ............................................................................................... 56 
13.4 
Sample Size and Duration of Study ............................................................................................... 57 
13.5 
Safety Monitoring .......................................................................................................................... 57 
13.6 
Interim Analysis ............................................................................................................................. 57 
13.7 
Quality of Life Analysis................................................................................................................. 57 
13.8 
Health Economics Analysis ........................................................................................................... 58 
 
14.0 
PUBLICATION POLICY ............................................................................................................. 60 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. .............................................................................. 60 
14.2 
Responsibility for Publication ........................................................................................................ 60 
14.3 
Submission of Material for Presentation or Publication ................................................................ 60 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES .............................................. 61 
15.1 
Regulatory Considerations ............................................................................................................. 61 
15.2 
Inclusivity in Research ................................................................................................................... 61 
15.3 
Obtaining Informed Consent .......................................................................................................... 62 
15.4 
Discontinuation of the Trial ........................................................................................................... 63 
15.5 
Retention of Patient Records and Study Files ................................................................................ 63 
15.6 
Centre Performance Monitoring .................................................................................................... 64 
15.7 
On-Site Monitoring/Auditing ......................................................................................................... 64 
 
16.0 
REFERENCES .............................................................................................................................. 65 
 
APPENDIX I - PERFORMANCE STATUS SCALES/SCORES .............................................................. 69 
APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL ................................................... 70 
APPENDIX III - DOCUMENTATION FOR STUDY .............................................................................. 72 
APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ................ 75 
APPENDIX V - QUALITY OF LIFE (AND HEALTH UTILITY) ASSESSMENT(S) ........................... 76 
APPENDIX VI - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS .................................. 90 
APPENDIX VII - EXAMPLES OF STRONG AND MODERATE CYP3A INHIBITORS AND 
STRONG CYP3A INDUCERS ..................................................................................................... 91 
APPENDIX VIII - BLINDING / UNBLINDING ...................................................................................... 92 
APPENDIX IX - EMERGENCY SITUATIONS AND COMPLIANCE .................................................. 93 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 

 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol and any supplementary information that may be added to this document, 
contains information that is confidential and proprietary and must be kept in confidence. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, in accordance with any modifications that may 
occur over the duration of the study, and according to Good Clinical Practice and any applicable local 
regulations. I will make a reasonable effort to complete the study within the time designated. I confirm that 
I and study personnel participating under my supervision have adequate resource to fulfill their 
responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG to study personnel 
under my supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study. 
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of CCTG and Hoffmann-La Roche Ltd. The foregoing shall not 
apply to disclosure required by governmental regulations or laws; however, I will give prompt notice to 
CCTG and Hoffmann-La Roche Ltd. 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 Hoffmann-La Roche Ltd with or without cause. 
 
 
_____________________________ 
______________________ 
___________________ 
Qualified Investigator Signature 
Printed Name 
Date 
 
 
Protocol Number: CCTG MA.40 
 
CENTRE: ___________________________________________ 

 
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TREATMENT SCHEMA 
 
This is an international multi-centre, double-blind, randomized phase III trial comparing ipatasertib and 
fulvestrant with placebo and fulvestrant in patients with advanced (metastatic or loco-regionally recurrent 
not amenable to curative therapy) estrogen receptor positive (ER+) and human epidermal growth factor 
receptor 2 (HER-2) negative breast cancer after progression on first line CDK 4/6 inhibitor and aromatase 
inhibitor (AI). 
 
Stratification: 
• 
PIK3CA/PTEN/AKT-1 status: altered versus wildtype/unknown; 
• 
Prior treatment duration with CDK 4/6 inhibitor: < 6 months versus ≥ 6 months. 
 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N 
 
1:1 
 
ARM 1: 
 
Ipatasertib 400 mg PO QD 
 
days 1-21 every 28 days 
 
+ Fulvestrant*  
 
Continue treatment until 
disease progression, 
intolerable toxicity, 
withdrawal of consent 
End of Treatment 
Assessment 
(4 weeks after 
final treatment) 
Follow-up of 
disease status 
and survival  
(every 12 weeks) 
 
 
 
ARM 2: 
 
Placebo PO QD 
 
days 1-21 every 28 days 
 
+ Fulvestrant* 
N = 250 patients 
* Fulvestrant 500 mg IM cycle 1 days 1 and 15 followed by 500 mg IM day 1 q 28 days subsequent cycles 
 
 
 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To compare investigator assessed progression free survival (PFS) using RECIST 1.1 in patients 
with ER+/HER2- advanced (metastatic or loco-regionally recurrent not amenable to curative 
therapy) breast cancer treated with ipatasertib and fulvestrant versus placebo and fulvestrant after 
progression on first line CDK 4/6 inhibitor plus AI treatment. 
 
1.2 
Secondary Objectives 
 
Key Secondary Objective: 
• 
To compare the two treatment arms with respect to investigator assessed PFS (per RECIST 
1.1) in the PIK3CA/AKT1/PTEN altered cohort; 
 
Additional Secondary Objectives: 
 
To compare the two treatment arms with respect to: 
• 
Investigator assessed PFS (per RECIST 1.1) in the PIK3CA/AKT1/PTEN non-altered cohort; 
• 
PFS as assessed by blinded central radiology review in all enrolled patients, 
PIK3CA/AKT1/PTEN altered and non-altered cohorts; 
• 
Response rate (RR) (per RECIST 1.1); 
• 
Duration of Response (DoR); 
• 
Clinical Benefit Rate (CBR); 
• 
Overall survival (OS); 
• 
Time to commencement of subsequent line of systemic therapy or death (TSST); 
• 
Safety and tolerability (CTCAE version 5.0); 
• 
Quality of Life (QOL) as measured using EORTC QLQ-C30 and NCI PRO-CTCAE 
questionnaires; 
• 
Economic Evaluation, including both healthcare utilization and health utilities, the latter 
measured using EQ-5D-5L. 
 
1.3 
Tertiary Objectives 
 
• 
To compare the PFS (per RECIST 1.1) between the two treatment arms based on 
PIK3CA/AKT1/PTEN altered status as determined using archival tissue. 
• 
To identify prognostic and predictive biomarkers/signatures for response and resistance. 
• 
To create a biobank of FFPE and cfDNA for future studies (to be specified). 
• 
To create a biobank of digital anatomical images to identify possible predictive and prognostic 
biomarkers as part of a radiomics analysis. 
• 
To characterize the pharmacokinetics of ipatasertib (Cmin and C2-4h) when administered in 
combination with fulvestrant. PK data may be used for population PK modeling and exposure-
response modeling as data allow and will be reported separately. 
 
 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Breast cancer is the most frequent cancer diagnosed in women, with an estimated global incidence 
of 2.09 million new cases reported in 2018 [Bray 2018] accounting for approximately 7% (~626,679) 
of all cancer deaths each year. 
 
The most common subtype of breast cancer is hormone receptor-positive (ER+) with no 
amplification of HER2 (HER2-), accounting for approximately 60%–70% of incident cases. This 
subtype of breast cancer also accounts for the greatest proportion of deaths related to breast cancer. 
The backbone of treatment for ER+/HER2- breast cancer (both in early and advanced stage) is 
endocrine therapy. The multitude of trials comparing one endocrine agent to another in the 
treatment of ER+/HER2- metastatic breast cancer (MBC) have generally failed to improve either 
progression free (PFS) or overall survival (OS) [Matutino 2018]. In the era of targeted therapies, CDK 
4/6 inhibitors (CDK4/6i) added to an endocrine agent have nearly doubled PFS (and extended OS 
in those with OS results); a result seen consistently across the marketed CDK4/6i (palbociclib, 
ribociclib and abemaciclib) [Finn 2016; Hortobagyi 2016; Goetz 2017]. The median PFS with 1st line 
CDK4/6i and AI is approximately 24 months and this treatment regimen is recommended in the 
first line setting for patients with ER/HER2- advanced breast cancer [NCCN Guidelines 2020]. Despite 
the significant improvements in PFS in the 1st line setting with this combination, ER+/HER2- 
breast cancer will ultimately progress, fuelling an ongoing need/rationale for identification of novel 
and effective treatments in the second line setting. 
 
The most frequently altered pathway in breast cancer is the PI3K-AKT-mTOR pathway [Cancer 
Genome Atlas Network 2012]. Approximately 45%-50% of ER+ breast cancers display 
PIK3CA/AKT1/PTEN alterations [Cancer Genome Atlas Network 2012; Curtis 2012; Pereira 2016]. PTEN is 
a tumour suppressor gene involved in multiple important cell functions relating to cell proliferation, 
survival and genome stability via multiple pathways. Specifically, it acts as a negative regulator of 
the PI3K/AKT pathway. [Bazzichetto 2019]. Upregulation of AKT signalling (whether intrinsic or 
induced following chemotherapy) represents a potentially important survival pathway in response 
to genotoxic/mitotic stress. Somatic non-silent mutations in PTEN, PIK3CA and AKT1 are also 
described. In pre-clinical models, activation of this pathway can lead to ligand independent 
activation of the estrogen receptor [Miller 2011]. Alterations in this pathway have been implicated as 
a mechanism of resistance to hormonal therapy and potentially also to CDK4/6i–particularly loss 
of PTEN function [Herrera-Abreu, 2016]. In a correlative sub-study of PALOMA-3, cell free DNA 
(cfDNA) analyses on the end of study treatment samples demonstrated an increased detection rate 
of PIK3CA mutations (28%) and also demonstrated AKT1 mutations (3.2%) [O’Leary 2018]. 
 
Targeting the PI3K-AKT-mTOR pathway 
 
Evidence exists in the clinical setting for targeting the PI3K-AKT-mTOR pathway in ER+/HER2- 
breast cancer. BOLERO-2, a phase III study with an mTOR inhibitor, led to regulatory approval of 
everolimus [Baselga 2012]. BOLERO-2 compared everolimus plus exemestane vs. placebo plus 
exemestane in postmenopausal patients with ER+/HER2- MBC who had recurrence or progression 
after treatment with a nonsteroidal AI in either adjuvant setting or in advanced disease. Median 
PFS in the everolimus group was 6.9 months, compared with 2.8 months in the placebo group. The 
hazard ratio (HR) for PFS by investigator assessment was 0.43; p=0.001. Furthermore, in the 
randomized, double-blind, placebo-controlled, Phase II study PrE0102 [Kornblum 2018] in 
postmenopausal women with ER+/HER2-, AI-resistant MBC, the addition of everolimus to 
fulvestrant improved the median PFS (mPFS) from 5.1 to 10.3 months (HR=0.61, stratified log-
rank p=0.02). 
 
 

 
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Several PI3K inhibitors have been combined with fulvestrant showing promising activity in Phase 
III studies in patients with ER+/HER2- MBC who had progressed on or after an AI. In the Phase 
III BELLE-2 study, buparlisib (a pan-PI3K inhibitor) when combined with fulvestrant resulted in 
mPFS of 6.9 months versus 5.0 months in the placebo group (HR 0.78; one-sided p=0.00021) in 
unselected patients [Baselga 2017]. In an exploratory analysis of patients with PIK3CA-mutant 
tumour by circulating tumour DNA (ctDNA), mPFS was 7.0 months in the buparlisib group versus 
3.2 months in the placebo group (HR 0.58; one-sided p=0.001). 
 
In the phase III SANDPIPER study, the addition of taselisib (a beta-sparing PI3K inhibitor) to 
fulvestrant showed a statistically significant improvement in investigator-assessed PFS in patients 
with PIK3CA-mutant tumours who comprised the primary endpoint population. Median PFS 
increased from 5.4 months in the placebo arm to 7.4 months in the taselisib arm (HR 0.70, 
p=0.0037) [Baselga 2018]. The study also enrolled a smaller cohort of patients without detectable 
PIK3CA-mutant tumours for exploratory analyses of PFS. Although the study was not powered to 
compare the two cohorts, the HR for PFS was similar in patients without detectable PIK3CA-
mutant tumours and those with PIK3CA-mutant tumours based on an exploratory analysis. Thus, 
a treatment effect of taselisib and fulvestrant in patients without detectable PIK3CA mutations 
could not be completely ruled out. 
 
In the phase III SOLAR-1 study, the addition of alpelisib (an alpha selective PI3K inhibitor) to 
fulvestrant showed a statistically significant improvement in investigator-assessed PFS in patients 
with PIK3CA-mutant tumours [André 2019]. Median PFS increased from 5.7 months in the placebo 
arm to 11 months in the alpelisib arm (HR 0.65, p-value = 0.00065) [André 2019]. Based on the 
exploratory analysis, patients without detectable PIK3CA-mutant tumours did not seem to benefit 
from the addition of alpelisib to fulvestrant. 
 
More pertinent to this protocol was a recently presented randomized placebo-controlled phase II 
FAKTION trial of an AKT inhibitor, capivasertib (AZD5363) given with fulvestrant upon 
progression on an AI in ER+ MBC [Jones 2019]. This study of 140 patients all received an AI either 
in the adjuvant setting (11%) or in the metastatic setting (89%); 28% of patients had two or more 
lines of endocrine therapy for MBC. 26% received one line of chemotherapy for MBC. In the ITT 
analysis, the PFS was improved from 4.8 to 10.3 months (HR 0.58; p=0.005). Interestingly, the HR 
for the PI3K/AKT/PTEN-altered tumours (0.59) was similar compared to the HR for the 
PI3K/AKT/PTEN non-activated tumours (0.56). Thus the benefit appears to be regardless of 
pathway status as determined by study definition. Grade 3 toxicities were frequent with 14% of 
patients experiencing grade 3 diarrhea, 20% experiencing grade 3 rash, and 4% experiencing grade 
3 hyperglycemia. There were no grade 4/5 events in these categories. Grade 3 infections occurred 
in 5% of patients and 1% of patients experienced grade 4 infection. 
 
Ipatasertib 
 
Ipatasertib is a potent, highly selective, small-molecule inhibitor of all three isoforms of the 
serine/threonine kinase AKT. Ipatasertib is being developed by Genentech/Roche as both a single 
agent and in combination with other therapies for the treatment of cancers in which activation of 
the PI3K-AKT-mTOR pathway may be relevant for tumour growth or therapeutic resistance. 
 
 

 
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In pre-clinical models with high levels of phosphorylated AKT or PI3K-AKT-mTOR pathway 
activity (i.e. PIK3CA mutation, PTEN alterations), sensitivity to ipatasertib has been observed 
across different tumour models, including breast cancers [Lin 2013]. In vivo efficacy studies support 
the use of ipatasertib as a single agent or in combination with chemotherapeutic, hormonal, or 
targeted agents for the treatment of patients with advanced or metastatic solid tumours [Lin 2013]. 
Clinical studies in a variety of tumour types have been conducted with ipatasertib both as 
monotherapy and in combination [Saura 2017]. Combination partners have included hormonal 
therapies (i.e. abiraterone and enzalutamide), chemotherapy, and immunotherapy. Randomized 
studies with ipatasertib have been conducted in breast, prostate, and gastric cancer. 
 
Combination with Fulvestrant 
 
At present the standard of care for the majority of patients newly diagnosed with ER+/HER2- MBC 
is first line treatment with a CDK 4/6 inhibitor in combination with an AI. The optimal second line 
of therapy remains unclear. Current guidelines recommend fulvestrant as a treatment option for 
receptor positive breast cancer in the advanced/metastatic setting, including in combination with 
targeted PI3K inhibitor therapy [NCCN Guidelines 2020]. 
 
Quality of Life (QOL) 
 
Given the incurable nature of advanced breast cancer and the incidence of treatment related adverse 
events associated with therapy, patient reported outcomes (PRO) data provide an important 
perspective on the impact of an intervention, above and beyond treatment induced changes in 
lifespan. Increasingly, values of new drugs are evaluated with framework combining benefit (e.g. 
survival, progression-free survival), toxicities and cost. ASCO and ESMO have created scales to 
capture these elements including QOL [Cherny 2017; Schnipper 2015]. These scales allow comparisons 
of benefits of different treatment and their cost. 
 
In the current protocol, we will evaluate the addition of an oral targeted therapy to an endocrine 
treatment, the last one having relatively few side effects. Available toxicity data about ipatasertib 
showed toxicities that can impact QOL such as diarrhea and rash. Therefore, once the trial is 
completed, if positive, we will need to weigh the added benefit, against the added toxicity and 
impact on overall quality of life. In other trials examining the addition of a targeted therapy to a 
backbone of endocrine therapy, QOL data have been helpful to inform clinicians and patients that 
even if the combination treatment has more side effects, overall there was no detrimental effect on 
QOL [Rugo 2018; Harbeck 2016; Verma 2018; Kaufman 2019; Campone 2013]. 
 
We know from the FAKTION study (fulvestrant plus capivasertib or placebo) and from the LOTUS 
study (paclitaxel plus ipatasertib or placebo) that diarrhea is the most commonly reported adverse 
event experienced with AKT inhibitors, with any grade of diarrhea being reported in 81% and 92% 
of patients respectively. It is also known that this symptom is usually underreported by patients, 
and the impact of diarrhea on overall quality of life can be missed [Atkinson 2012; Lui 2017]. In the 
recent published PAKT trial [Schmid 2020] using capivasertib or placebo with paclitaxel, there was 
a statistically significant increase in the capivasertib arm of diarrhea, skin dryness, rash and fatigue. 
 
The objectives of the quality of life components of this study are to compare patients’ overall 
quality of life between the two treatment arms with specific analyses related to the symptoms of 
diarrhea, rash, fatigue and pain as described below. 
 
 

 
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Two instruments will be used to capture the QOL experience of patients: the EORTC QLQ-C30 
and the PRO-CTCAE. The EORTC QLQ-C30 will be used to capture the multidimensionality of 
QOL in metastatic breast cancer. The EORTC QLQ-C30 is a widely used, cancer specific health-
related QOL questionnaire which is well accepted by patients [Aaronson 1993; Conroy 2004]. It contains 
five functional subscales (physical, role, cognitive, emotional, social), three multi-item symptom 
subscales (fatigue, pain and nausea), six single items (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea, financial impact) and a global health measure (physical condition and global 
QOL). The questionnaire uses 4 and 7-point scales. For each subscale, the range of possible scores 
is between 0 and 100. Convergent and criterion validity has been demonstrated for this 
questionnaire in metastatic breast cancer [Bottomlay 2004; Mclachlan 1998] and reliability is adequate 
[Aaronson 1993; Hjermstad 1995]. The EORTC QLQ-C30 has been shown to be responsive to change 
associated with chemotherapy and with disease progression [Osoba 1998; Lemieux 2007]. The 
questionnaire is available in multiple languages. 
 
Given important toxicities/symptoms in this population (eg. diarrhea, rash, fatigue and pain), we 
will complement the EORTC QLQ-C30 with the PRO-CTCAE. Although these symptoms (except 
skin problems) are measured in the EORTC QLQ-C30, they are measured using a 5-point Likert 
scale with PRO-CTCAE (compared to a 4-point in the EORTC QLQ-C30) and also look at the 
frequency, severity and interference of symptoms. PRO-CTCAE is a validated tool designed by the 
National Cancer Institute by multidisciplinary investigators and patients, which provides a patient-
centred approach to adverse event assessment in clinical research [Basch 2014]. Its content has been 
evaluated for validity through a cognitive interviewing study, and its construct validity, reliability 
and responsiveness were examined in a US multicenter study [Hay 2014]. This tool was designed to 
complement the CTCAE and can be utilized in phase III clinical trials to assess adverse reactions 
and provide data comparing tolerability between regimens. It is available in multiple languages. 
Selected items of the PRO-CTCAE for diarrhea, skin toxicities, pain and fatigue will be used. To 
date, there are no standardization as what is a minimally clinically important difference. 
 
The two questionnaires will be administered at baseline, at day 1 of cycles 2-4 and then every 2 
cycles (corresponding with the timing of imaging for disease assessments), 4 weeks after 
discontinuation of study medication and at 3 months follow up  (only required for patients without 
confirmed progressive disease and/or with ongoing toxicities). Given this trial has a small sample 
size, we will collect data on all patients enrolled in this study. 
 
Economic Evaluation 
 
Determining health care value is critical to the adoption of new technologies and procedures in the 
health system and society. The health economic evaluation of this study will evaluate the cost-
effectiveness and cost-utility of ipatasertib and fulvestrant combination therapy in comparison with 
fulvestrant alone. If the addition of ipatasertib is found to produce a clinical benefit as a second-
line treatment for metastatic ER+ breast cancer, the economic evaluation will assist decision-
makers in defining the cost-benefit trade-offs of adding this drug to their formulary. Collecting 
cost, productivity, and utilization data will also facilitate a robust estimate of the value of 
fulvestrant. The primary model outcomes of this model will be the cost per additional year of 
progression-free survival (PFS) and overall survival (OS), the cost per additional quality-adjusted 
life year (QALY) gained, and a budget impact analysis. 
 
 

 
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We will conduct the analysis from the perspective of the public healthcare payer. Direct health care 
costs will be based on the cost of treatment at a tertiary cancer centre in current Canadian dollars. 
It is assumed that the Ontario provincial perspective could be considered representative of the 
Canadian public healthcare system; therefore, costs will be derived using local estimates and 
Ontario Health Insurance Plan (OHIP) billing codes. Costs of outpatient medications will be 
determined with the Ontario Drug Benefit Formulary plus an 8% markup fee as permitted by the 
Ontario government. Non-formulary medications will include a 15% markup, reflecting current 
outpatient pharmacy practice. Costs of outpatient visits will be determined using the hotel 
approximation method, which includes all overhead and staffing costs. 
 
Utilization data will be collected prospectively from all patients on the trial. A mean treatment cost 
per patient in each arm of the study (Arm 1: ipatasertib + fulvestrant; Arm 2: placebo + fulvestrant) 
will be generated based on the following utilization data: 
 
1. Drug Costs: 
a. Cost of ipatasertib, fulvestrant, and any supportive medication used during the study. 
b. Costs related to administration and outpatient assessment. 
 
2. Costs of managing adverse events: 
a. Investigations. 
b. Emergency department visits. 
c. Additional physician visits (primary care, specialist care). 
d. Inpatient admissions (duration, most responsible diagnosis). 
 
3. Cost of subsequent cancer therapy at time of relapse: 
a. Outpatient assessment. 
b. Chemotherapy and radiotherapy administration, surgical intervention as appropriate. 
c. Hospitalization and supportive care. 
 
The EQ-5D-5L will be administered to all participants to generate a utility (with values from 0 to 
1) to quality-adjust the clinical outcomes. The EQ-5D-5L consists of 5 dimensions, including 
mobility, self-care, usual activity, pain/discomfort, and anxiety/depression and respondents use 3-
level response categories to indicate the level most descriptive of their current level of function on 
each dimension. Five dimensions, each with three levels, yield 243 possible distinct health states 
comprising the classification system, which can then be used to generate a utility (with values from 
0 to 1). Mean utility values for the two study arms will be estimated. 
 
The EQ-5D-5L will be administered at the following intervals: baseline (pre-risk notification at 
time 0), after every second cycle, and 3 months after protocol completion. The EQ-5D-5L will be 
additionally administered at 24 months after enrollment and annually thereafter until the time of 
second treatment, death, removal from study, or completion of 5 years of follow-up. 
 
 

 
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Correlative Studies 
 
Tissue and Fluid Based Correlative Studies 
 
Correlative studies are a key component of this clinical trial. Randomization to treatment arms will 
be stratified by PIK3CA/PTEN/AKT-1 alteration status derived from cfDNA analysis and 
secondary endpoints will be calculated for each strata to determine if this pathway alteration 
impacts ipatasertib activity. 
 
The planned cfDNA and tissue based assays are intended to capture quantifiable genomic, 
epigenomic and proteomic longitudinal alterations. When integrated with response data, this will 
facilitate the development of prognostic and predictive biomarkers related to ipatasertib sensitivity. 
 
Assays will be repeated at regular intervals while patients are on study to explore genomic changes 
associated with response, progression and resistance to fulvestrant and ipatasertib. The correlative 
samples collected will allow for comparison of differential genomic and proteomic changes 
between the two study arms. 
 
Additionally, an evaluation of blood-derived exosomes is planned. Exosomes are small vesicular 
particles produced by viable cells that have recently been implicated in key cellular processes 
including paracrine and autocrine cell signalling. A variety of cellular molecules are packaged 
within exosomes including proteins, lipids, messenger RNAs, microRNAs, and DNA. It is believed 
that cancer cells release an increased number of exosomes as compared to normal cells; thus the 
exosomal contents represent potential biomarkers that may be related to patient prognosis or 
response to therapy. 
 
A tertiary endpoint of this study is to build a bank of blood and tissue samples for future exploratory 
investigations. Details of correlative study requirements can be found in section 12.0 of the 
protocol. 
 
Image Based Correlative Studies (Radiomics) 
 
Radiomics refers to processes of automated computational extraction and analysis of quantitative 
information derived from anatomic/functional imaging of tumours and surrounding tissue with a 
goal of deriving information related to response to treatment and disease outcomes [Nie, 2019]. 
Advantages of radiomics compared to tumour tissue analysis relate to the avoidance of invasive 
procedures and potentially a better assessment of tumour heterogeneity, a recognized phenomenon 
in metastatic breast cancer [Lindstrom 2012; Roulot 2016]. 
 
Currently, radiomics research is mainly exploratory with respect to biological and analytical 
validity [Hayes 2014, Tagliafico 2020]. Integration of radiomic research into clinical trials thus offers 
an important opportunity to collect and analyze imaging data using a recognized framework that is 
based on biomarker collection, storage and analysis of biological tissue [McShane 2013]. 
 
Ultimately, research from this trial and others will further the goal of adding radiomics information 
to the personalized medicine paradigm that currently includes host, epidemiological and biological 
tissue derived information to individualize anticancer treatment plans. 
 
A tertiary endpoint of this study is to build an anatomical image bank for future exploratory 
investigations. Details of correlative study requirements can be found in section 12.0 of the 
protocol. 
 
 

 
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Summary 
 
This international, randomized, placebo-controlled phase III trial of fulvestrant with 
ipatasertib/placebo will examine the existing gap in breast cancer knowledge and treatment in the 
second line setting for ER+/HER2- patients after progression on CDK4/6i and AI therapy. 
Correlative work will examine the impact of pathway alterations on prognosis and response to 
therapy. 
 
The current proposal entails a comprehensive examination of the impact of treatment with 
fulvestrant and ipatasertib/placebo via the collection of efficacy, quality of life, economic, safety 
and adverse event data. 
 
 

 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Ipatasertib 
 
Please see the current ipatasertib Investigator Brochure for the most up to date information. 
 
3.1.1 
Name and Chemical Information (Ipatasertib) 
 
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-
cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 
 
3.1.2 
Chemical Structure 
 
 
 
3.1.3 
Mechanism of Action 
 
Ipatasertib is a potent and selective small-molecule inhibitor of all three isoforms of the 
serine/threonine kinase AKT and is being developed by Genentech/Roche as a single agent and in 
combination with other therapies for the treatment of cancers in which activation of the PI3K-AKT-
mTOR pathway may be relevant for tumour growth or therapeutic resistance. Ipatasertib selectively 
binds to the active conformation of AKT and inhibits its kinase activity [Lin 2012]. Ipatasertib has 
proven to be especially effective on cells with activated AKT, including PTEN-null and PI3K-
mutated tumour models, leading to suppression of the phosphorylation of its direct substrates. 
Consistent with the role of AKT in insulin signalling, ipatasertib also exhibited dose-dependent and 
reversible elevation of serum glucose in pre-clinical studies. In vivo studies support the use of 
ipatasertib as a single agent or in combination with chemotherapeutic, hormonal, or targeted agents 
for the treatment of patients with advanced or metastatic solid tumours [Lin 2013]. 
 
 

 
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3.1.4 
Experimental Anti-tumour Activity 
 
In vivo efficacy of ipatasertib was established using various in vivo mouse xenograft models, in 
which the PI3K-AKT-mTOR pathway is aberrantly activated as a result of PI3Kα mutation or 
decreased PTEN expression. Anti-tumour activity was evaluated, shown as percentage of tumour 
growth inhibition (TGI) relative to vehicle controls for ipatasertib as a single agent or in 
combination with either chemotherapeutics or targeted agents (e.g. docetaxel, paclitaxel, 
mFOLFOX6, abiraterone, and MDV3100). These in vivo studies demonstrated that ipatasertib has 
robust anti-tumour activity as a single agent and improved efficacy when administered in 
combination with other marketed or experimental cancer agents. 
 
In the phase Ib study PAM4983g, 2 of 5 patients with ER+/HER2- breast cancer who were treated 
with the combination of ipatasertib and paclitaxel, had confirmed partial responses. The 
randomized phase Ib/II study GO27983 was conducted in patients with metastatic castration 
resistant prostate cancer (mCRPC) post-docetaxel. When added to hormonal therapy abiraterone 
plus prednisone/prednisolone, ipatasertib (400 mg) showed improved PFS compared with 
abiraterone and prednisone/prednisolone in the all-comer population and in patients with PTEN-
loss tumours (HR 0.75 in all-comers; HR 0.39 in PTEN-loss by immunohistochemistry [IHC] 
assay) [de Bono, 2019]. There is an ongoing randomized Phase III study CO39303 evaluating 
ipatasertib 400 mg when added to abiraterone and prednisone/prednisolone compared to 
abiraterone and prednisone/prednisolone in front-line mCRPC. 
 
The randomized phase II study, GO29227, evaluated the addition of ipatasertib to paclitaxel in 
front-line metastatic triple-negative breast cancer (TNBC) patients and those with a PTEN loss (by 
IHC) and separately, patients with PIK3CA/AKT1/PTEN-altered tumours [Dent 2018]. Results from 
this study showed improvement in mPFS in the intent-to-treat (ITT) population of 6.2 months in 
the ipatasertib arm compared with 4.9 months in the control arm (stratified HR 0.60; p=0.037) with 
even greater improvement in PIK3CA/AKT1/PTEN-altered tumours of 9 months vs. 4.9 months 
(non-stratified HR 0.44; log-rank p=0.041). There is an ongoing randomized phase III study 
CO40016 evaluating 400mg ipatasertib when added to paclitaxel compared to paclitaxel for 
patients with PIK3CA/AKT1/PTEN altered tumours in both first-line TNBC and HR+/HER2-
breast cancer with no prior chemotherapy. 
 
3.1.5 
Animal Toxicology 
 
Ipatasertib was not mutagenic or clastogenic when evaluated in a standard ICH genotoxicity 
battery, was not phototoxic in-vitro, and did not demonstrate adverse effects on cardiovascular and 
respiratory function in monkeys or on neurological system function in rats. Daily oral dosing of 
ipatasertib for up to 26 weeks was well tolerated at doses up to 2 mg/kg in rats and 15 mg/kg in 
monkeys. The toxicity profile of ipatasertib was generally consistent in the 4, 13, and 26 week 
studies; no new adverse findings or evidence of progression of previously identified toxicities were 
identified in the 26-week studies. 
 
 

 
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The most prominent findings in rats and monkeys administered ipatasertib were 
pharmacologically-mediated, acute hyperglycemia and increased serum insulin concentration, and 
compensatory hypertrophy and hyperplasia of pancreatic islet cells and hepatocellular glycogen 
accumulation in the liver. These effects were observed at subclinical exposures (AUC0−24) of 
approximately 0.02-fold that in patients receiving 400 mg/day, and are indicative of PD activity 
based on the key role of AKT in signal transduction downstream of the insulin/insulin growth factor 
receptor [Whiteman 2002]. The dose-dependent increases in glucose and insulin resolved rapidly after 
discontinuation of dosing, while hepatic and pancreatic changes demonstrated evidence of 
reversibility during the recovery period. Of note, for the 26-week studies, the pancreatic islet and 
hepatic findings in the rat were similar to the 13-week study, but in the monkey, the hyperglycemic 
response was not maintained for the full dosing period, nor were there histologic correlates. There 
was no evidence of adverse effects on male or female reproductive organs in monkeys or rats given 
ipatasertib for up to 26-weeks or male reproductive assessment parameters (i.e. sperm count, 
morphology, and motility) in the 13-week repeat-dose studies, but the potential for ipatasertib-
mediated embryo-fetal toxicity was identified in rat and rabbit embryo-fetal development studies. 
Other clinical pathology changes that were observed in both species included decreased circulating 
reticulocyte and lymphocyte counts and increased total serum cholesterol concentration. The mild, 
reversible elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
serum levels and hepatocellular vacuolation observed at the high dose in the 4-week study in rats 
(not observed in the 13- or 26-week studies) occurred at exposures approximately 3-fold the 
AUC24h,ssexposure (4450ng•hr/mL) in patients administered 600mg QD. 
 
3.1.6 
Phase I Trials 
 
Study PAM4743g was an open-label, phase I, dose-escalation study that used a 3 + 3 design to 
assess the safety, tolerability, and PK profile of oral ipatasertib administered daily to patients with 
refractory solid tumours. A total of 52 patients were enrolled in this study; 51 patients received 
treatment with ipatasertib. 
 
Study PAM4743g is complete. The MTD was exceeded at 800 mg daily on a 21/7-dosing schedule, 
with DLTs of grade 3 asthenia (n = 1) and grade 3 nausea (n = 1). The MTD of ipatasertib is 600 
mg daily for 21 days followed by 7 days off-dosing schedule. The recommended phase II dose was 
400mg daily for 21 days on a 4 week schedule. 
 
 
The combination of ipatasertib and fulvestrant +/- palbociclib is currently being investigated in the 
phase Ib setting with the TAKTIC (NCT03959891) and CO41012 (NCT04060862) studies. 
 
3.1.7 
Phase II Trials 
 
Study GO29227 is a multi-center, phase II, global study to estimate the tolerability and clinical 
activity of ipatasertib 400 mg in combination with paclitaxel versus placebo in combination with 
paclitaxel in patients with locally advanced or metastatic TNBC, as measured by PFS, OS, ORR, 
and duration of confirmed response in all patients and in patients with tumours that have low PTEN 
expression. A total of 63 patients received treatment with ipatasertib. 
 
145 patients have received ipatasertib in combination with paclitaxel in the HR+, HER2- cohort of 
the phase III IPATunity130 (NCT0333772) study.  
 
 

 
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3.1.8 
Pharmacokinetic Studies 
 
The PK of ipatasertib and its major metabolite, G-037720, was assessed in patients with cancer in 
the phase I study PAM4743g. Ipatasertib showed rapid absorption, with median tmax ranging from 
0.5 to 3.0 hours across all doses. In general, the exposure of ipatasertib was dose-proportional from 
200 to 800 mg. The mean terminal half-life ranged from 31.9 to 53 hours at doses of 100 mg and 
above. Steady-state exposures were achieved following 8 days daily oral dosing. 
 
In vitro metabolism data indicate that ipatasertib is a time-dependent inhibitor of CYP3A. 
Therefore, sensitive substrates of CYP3A with a narrow therapeutic index should be avoided or 
administered with caution. Given the mean change of 2.22-fold, ipatasertib would be classified as 
a mild-moderate CYP3A inhibitor at doses of 400-600 mg, and is not expected to cause clinically 
significant DDIs for those CYP3A substrates that do not have a narrow therapeutic index. 
 
Ipatasertib is primarily metabolized by CYP3A4 (refer to ipatasertib Investigator’s Brochure), and 
itraconazole, a strong CYP3A4 inhibitor, increased ipatasertib area under the concentration-time 
curve (AUC) and maximum concentration (Cmax) by approximately 5-fold and 2-fold, respectively 
as observed in Study GP30057. 
 
Co-administration of 400 mg or 600 mg ipatasertib with 160 mg enzalutamide, a strong CYP3A4 
inducer, decreased the steady state Cmax and AUC of ipatasertib by approximately 50% as observed 
in the PAM4983g study. 
 
Based on two relative bioavailability studies, exposure to ipatasertib following phase II or phase III 
formulation film-coated tablets is expected to be comparable and food is not expected to impact 
level of exposure to the drug. 
 
Although fulvestrant is a CYP3A4 substrate, strong CYP3A inhibitors and inducers did not have 
clinically relevant effect on fulvestrant disposition (Faslodex® package insert). Based on this, 
although ipatasertib is a mild-to-moderate inhibitor of CYP3A4 (Study PAM4743g; see the 
Ipatasertib Investigator’s Brochure for details), ipatasertib is not expected to alter the exposure of 
fulvestrant in a clinical meaningful way. Fulvestrant is not an inhibitor or inducer of CYP3A 
(Faslodex® package insert), and therefore, it is not expected to alter plasma exposure of ipatasertib. 
 
3.1.9 
Justification of Dose Selection 
 
The dose and schedule of ipatasertib (400 mg QD, days 1-21 of each 28 day cycle) is based on the 
RP2D identified in studies PAM4743g (phase I), PAM4983g Arm C (Phase Ib) and GO27983 
(phase Ib/II). 
 
3.1.10 Pharmaceutical Data 
 
Supplied: 
 
The phase III formulation film-coated tablets 100 mg and 200 mg are differentiated by size, colour, 
and weight of the tablets. The ingredients in the tablets include microcrystalline cellulose, pre-
gelatinized maize starch, croscarmellose sodium, colloidal silicon dioxide, povidone, magnesium 
stearate (non-bovine), and OpadryII Yellow film coat (100 mg tablet) or Opadry II Pink film coat 
(200 mg tablet). 
 
 

 
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The ipatasertib phase III placebo tablets have been manufactured to match the size, shape, and 
colour of the ipatasertib active tablets (100 mg and 200 mg) and are indistinguishable in appearance 
from the ipatasertib active tablets. The ingredients in the phase III placebo tablets include 
microcrystalline cellulose, mannitol, magnesium stearate (non-bovine), and OpadryII Yellow 
film coat (placebo for 100 mg tablet) or Opadry II Pink film coat (placebo for 200 mg tablet). 
 
All excipients used in the phase III active and placebo tablet formulations are compendial grade, 
with the exception of the film coatings. The ingredients in the film coatings are compendial. 
 
Storage: 
 
Ipatasertib active and placebo tablets are packaged in high-density polyethylene bottles with 
desiccant. The storage condition is “Do not store above 25°C, protect from moisture.” Information 
on storage conditions and shelf life of the active and placebo tablets is provided on the label. 
 
Route of Administration: 
 
Oral (PO). 
 
3.2 
Fulvestrant 
 
Fulvestrant is an approved endocrine therapy for advanced ER+ breast cancer. Please see the 
current fulvestrant Product Monograph for the most up to date information. 
 
Ovarian suppression therapy (LHRH agonists, surgical or radiologic ovarian ablation) is required 
for all pre-menopausal women receiving fulvestrant who have not had a bilateral oophorectomy. 
LHRH agonists will not be supplied or reimbursed. 
 
3.2.1 
Mechanism of Action 
 
Fulvestrant is an estrogen receptor (ER) antagonist that has a mode of action leading to 
downregulation of ER protein. Fulvestrant is a nonagonist ER antagonist that blocks the trophic 
actions of estrogens without itself having any partial agonist (estrogen-like) activity. Fulvestrant 
binds to estrogen receptors in a competitive manner with an affinity comparable to that of estradiol. 
 
3.2.2 
Pharmaceutical Data 
 
Supplied: 
Fulvestrant solution for injection is a clear, colourless to yellow, viscous liquid provided in a 
package of two pre-filled 250 mg/5mL (50 mg/mL) syringes. In addition to the active ingredient 
fulvestrant, each syringe also contains the following non-active ingredients: ethanol 96%, benzyl 
alcohol, benzyl benzoate and castor oil. 
 
Storage: 
Store refrigerated at 2 to 8°C. Store in original package and do not break the seal, in order to protect 
it from light. Packages are single use only and any unused portion must be discarded. 
 
Route of Administration: 
Fulvestrant 500 mg is to be administered intramuscularly as two 5 mL (250 mg/5 mL) injections 
(one in each buttock), on day 1 of each cycle as well as on day 15 of cycle 1. 
 
 

 
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4.0 
STUDY POPULATION 
 
This study will include patients with advanced (metastatic or loco-regionally recurrent not 
amenable to curative therapy) ER+ and HER-2 negative breast cancer who have progressed on 
first-line CDK 4/6 inhibitor and aromatase inhibitor. 
 
This study has two steps: 
1. Screening (registration to assess stratification parameters prior to enrollment); 
2. Enrollment to a treatment arm. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy and to ensure that the results of this study can be useful for making treatment decisions 
regarding other patients with similar disease(s). 
 
These eligibility criteria are expected to be followed. Any proposed variance must be discussed 
with CCTG prior to patient enrollment. 
 
Note: Prior to registration, sites must ensure that patients meet all criteria listed below in sections 
4.1 and 4.2.  
 
4.1 
Eligibility Criteria 
 
4.1.1 
Patients must have histologically and/or cytologically confirmed ER positive and HER-2 negative 
breast cancer by local assessment that is advanced (metastatic or loco-regionally recurrent not 
amenable to curative therapy) and for which no curative therapy exists. Note: Pathology reports 
from all prior procedures must indicate ER positive and HER-2 negative if this testing was 
performed. Please contact CCTG prior to patient registration if previous results do not meet this 
criteria or are equivocal. 
 
ER positive is defined as ≥ 1% of tumour nuclei positive for ER via IHC analysis. [CAP Guidelines 
2020]. 
 
HER-2 negative is defined as a negative ISH test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a 
negative ISH result is also required. [CAP Guidelines 2018]. 
 
4.1.2 
Female patients must be post-menopausal as defined by meeting one of the following criteria [NCCN 
Guidelines 2020]: 
a. Prior bilateral oophorectomy. 
b. Age ≥ 60 years. 
c. Age < 60 years and amenorrhoeic for 12 or more months in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and 
estradiol in the postmenopausal range. 
d. If taking tamoxifen or toremifene and age < 60 years, then FSH and plasma estradiol level in 
post-menopausal ranges. 
 
Female patients who are pre-menopausal must have ovarian suppression using LHRH agonist while 
on study and for at least 28 days prior to registration with estradiol level assessed within 7 days 
prior to registration within the local post-menopausal normal range. 
 
 

 
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4.1.3 
Patients must have evidence of clinical and/or radiographic progression during treatment with or 
within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an AI 
for advanced/metastatic disease, as judged by the investigator.  
 
4.1.4 
Presence of clinically and/or radiologically documented disease at the time of registration. Patients 
must have evaluable disease (as per RECIST 1.1), however, measurable disease is not mandatory. 
Baseline radiology studies must be performed within 28 days prior to enrollment in order to 
accurately assess baseline disease burden. 
 
4.1.5 
Patients must be ≥ 18 years of age. 
 
4.1.6 
Patients must have an ECOG performance status of 0 or 1. 
 
4.1.7 
Patients must not be receiving any concurrent anti-cancer therapy and must satisfy the following 
criteria for previous therapy: 
a. Must not have received more than one prior line of treatment with a CDK 4/6 inhibitor and an 
AI in the advanced disease setting. Treatment with CDK 4/6 inhibitor and AI must have been 
the most recent treatment prior to registration for this study and treatment with both agents 
must be discontinued by the date of registration. 
b. Must not have received more than one prior line of chemotherapy in the advanced setting. 
Chemotherapy must have been given prior to first line treatment with CDK 4/6 inhibitor and 
AI. 
c. Patients must have recovered to grade ≤ 1 from all reversible toxicity related to prior anti-
cancer systemic therapy. Patients with fatigue ≤ grade 2 related to prior therapy are permitted 
to enroll. 
d. Prior external beam radiation is permitted provided a minimum of 28 days have elapsed 
between the last dose of radiation and date of enrollment. Exceptions may be made for low-
dose, non-myelosuppressive radiotherapy after consultation with CCTG. Concurrent 
radiotherapy is not permitted. 
e. Prior surgery is permitted provided that a minimum of 28 days have elapsed between any major 
surgery and date of registration for screening and that wound healing has occurred. 
 
 
 

 
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4.1.8 
Adequate hematology and organ function, in the absence of growth factors, as defined below (must 
be done within 7 days prior to registration for screening). 
 
Hematology 
Absolute neutrophils 
> 1.5 x 109/L 
Platelets 
≥ 100 x 109/L 
Hemoglobin 
> 90 g/L 
Chemistry 
Total Bilirubin 
≤ 1.5 x ULN (upper limit of normal) or 
≤ 3 x ULN if confirmed Gilbert’s 
ALT and AST 
≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver or bone metastasis) 
Alkaline phosphatase ≤ 2.0 x ULN (or ≤ 5.0 x ULN if liver metastases, ≤ 7.0 x ULN if 
bone metastasis) 
Fasting glucose 
≤ 8.3 mmol/L 
HbA1c 
≤ 7.5% 
Serum albumin 
≥ 30 g/L 
INR 
≤ 1.2 
Serum Creatinine 
or 
Creatinine clearance 
≤ 1.5 x ULN 
or 
≥ 50 mL/min; measured directly by 24 hour urine sampling or as 
calculated by Crockcroft and Gault equation: 
 
Females: 
GFR = 1.04 x (140-age) x weight in kg 
serum Cr in μmol/L 
Males: 
GFR =1.23 x (140-age) x weight in kg 
serum Cr in μmol/L 
 
4.1.9 
Patients must consent to blood collection at the time of registration for stratification and at 
subsequent time points for correlative and pharmacokinetic studies. The stratification blood sample 
cannot be sent for analysis prior to patient registration for screening. 
 
4.1.10 Patients must consent to the submission of, and investigator must confirm access to and agree to 
submit within 4 weeks of enrollment, a formalin-fixed, paraffin-embedded tumour (FFPE) tissue 
block, cores (two 2 mm cores of tumour from the block), or a minimum of 20 freshly cut unstained, 
serial tumour slides from the most recently collected tumour tissue for molecular analysis and for 
other protocol-mandated secondary and exploratory assessments. 
 
Where no previously resected or biopsied tumour tissue exists or if the tissue is determined to be 
of inadequate amount or quality, an additional biopsy of the metastatic or primary tumour will be 
required for the patient to be considered eligible for the study. Please refer to the MA.40 
Correlatives Manual for details concerning adequacy of amount and quality of tumour tissue. 
 
4.1.11 Patients must consent to the submission of digital radiology images at the required time points for 
radiomic analysis and central radiology review. 
 
4.1.12 Female patients of childbearing potential must agree to use two effective contraceptive methods 
while on study and for 2 years after the last dose of study drug. A woman is considered to be of 
“childbearing potential” if she has had menses at any time in the preceding 12 consecutive months. 
 
 

 
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Male patients of childbearing potential must have agreed to use a highly effective contraceptive 
method while on study and for 2 years after the last dose of study drug. Men should not father a 
child or donate sperm during this period. 
 
Examples of effective methods of contraception are male condom plus spermicide, cap plus 
spermicide, diaphragm plus spermicide, intrauterine device (Copper T). 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 complete 
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 or she 
is responsible for beginning contraceptive measures.  
 
4.1.13 Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health utility 
questionnaires in either English or French. The baseline assessment must be completed within 
7 days prior to enrollment. Inability (lack of comprehension in English or French, or other 
equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires 
will not make the patient ineligible for the study. However, ability but unwillingness to complete 
the questionnaires will make the patient ineligible. 
 
4.1.14 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to registration for screening to the trial 
to document their willingness to participate. 
 
4.1.15 Patients must be accessible for treatment and follow-up. Patients enrolled on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 
The patient’s city of residence may be required to verify their geographical proximity. (Call the 
CCTG office (613-533-6430) if questions arise regarding the interpretation of this criterion.) 
Investigators must assure themselves the patients enrolled on this trial will be available for 
complete documentation of the treatment, adverse events, and follow-up. 
 
Patients must agree to return to the participating centre for response assessment as well as any 
adverse events which may occur through the course of the trial. 
 
4.1.16 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 prior or concurrent malignancy whose natural history or treatment has the potential 
to interfere with the safety or efficacy assessment of the investigational regimen. When a biopsy 
has been performed of a metastatic lesion(s) and the pathology is supportive of an ER+/HER2- 
metastatic breast cancer, patients with a prior history of other malignancies are eligible as long as 
all other eligibility criteria are met. Please consult with CCTG in these cases prior to enrollment. 
 
 

 
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4.2.2 
Patients with untreated or symptomatic CNS metastases or who have had radiation treatment for 
CNS metastases within 28 days of registration for screening are not eligible. Stable, treated brain 
metastases are permitted (defined as patients who are off steroids and anticonvulsants and are stable 
for at least 30 days at the time of registration for screening). Patients with known leptomeningeal 
disease (LMD) are not permitted to enrol. If the possibility of LMD has been reported 
radiographically on baseline CT/MRI but is not suspected clinically by the investigator, the patient 
must be free of neurological symptoms of LMD. 
 
4.2.3 
Patients with any of the following gastrointestinal (GI) conditions: 
• 
history of or active inflammatory bowel disease (e.g. Crohn’s disease and ulcerative colitis); 
• 
active bowel inflammation (e.g. diverticulitis); 
• 
inability to swallow oral medication; 
• 
impairment of GI function or GI disease that may significantly alter the absorption of the oral 
study drug (e.g. uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small 
bowel resection). 
 
4.2.4 
Patients who have received prior treatment with fulvestrant, selective estrogen receptor degraders 
(SERDs) or known inhibitors of the PI3K pathway including PI3K inhibitors, AKT inhibitors, or 
mTOR inhibitors. 
 
4.2.5 
Patients who have received or are currently receiving treatment with strong CYP3A inhibitors or 
strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior 
to registration for screening. 
 
4.2.6 
Patients with a mean QT interval corrected for heart rate (QTc) ≥ 480 msec by ECG measured 
using standard institutional method or history of familial long QT syndrome. 
 
4.2.7 
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. This includes but is not 
limited to: 
• 
active infection requiring systemic therapy; 
• 
active or known human immunodeficiency virus (HIV) with detectable viral load; 
• 
symptomatic cardiac dysfunction, uncontrolled or recent clinically significant cardiac disease 
including: 
− unstable angina, symptomatic pericarditis, coronary artery bypass grafting, coronary 
antioplasty or stenting, or myocardial infarction in the previous 12 months; 
− history of documented congestive heart failure (New York Heart Association functional 
classification III-IV) or cardiomyopathy; 
− history of 2nd or 3rd degree cardiac ventricular arrhythmias or cardiac ventricular 
arrhythmias requiring medication; 
− patients with uncontrolled hypertension; 
• 
patients with clinically significant liver diseases consistent with Child-Pugh Class B or C, 
including viral/other hepatitis, current alcohol abuse or cirrhosis; 
• 
history of lung disease including pneumonitis, interstitial lung disease, idiopathic pulmonary 
fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia). 
 
 

 
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4.2.8 
Patients with Type 1 or Type 2 diabetes mellitus requiring insulin. Diabetic patients requiring only 
oral medication are eligible provided they are on a stable dose of oral medication ≥ 2 weeks prior 
to registration. Patients must meet the laboratory eligibility criteria for fasting blood glucose and 
glycated hemoglobin (see 4.1.8). 
 
4.2.9 
Patients with grade ≥ 2 uncontrolled hypercholesterolemia or hypertriglyceridemia. 
 
4.2.10 Patients with known abnormalities in coagulation, such as bleeding diathesis, or treatment with 
anticoagulants precluding intramuscular injections of fulvestrant. 
 
4.2.11 Patients with symptomatic disease burden which precludes full participation in the study 
interventions and follow up requirements, as judged by the investigator. 
 
4.2.12 Patients with a history of hypersensitivity to the study drugs or components. 
 
4.2.13 Pregnant or lactating women. Women of childbearing potential must have a pregnancy test (urine 
or serum) proven negative within 3 days prior to enrollment. If urine test is positive, pregnancy 
testing may then include a serum test and 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 may be considered eligible if a serum test and ultrasound are negative for pregnancy, with 
approval from CCTG. 
 
 

 
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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 
Screening 
(within 7 
days prior to 
registration) 
Baseline 
During Protocol 
Treatment 
(1 cycle = 28 days) 
At disease 
progression 
24 months 
after 
enrollment 
After Protocol Treatment 
4 weeks after 
discontinuation 
of protocol 
therapy1 
Every 12 weeks2 
History and Physical Exam 
 
 
 
 
 
 
 
Height (baseline only), 
weight, ECOG performance 
status 
X 
 
Day 1 of each cycle3 
 
 
X 
 
Concomitant medications 
To assess 
patient for 
eligibility 
X 
(within 14 
days prior to 
enrollment) 
Continuous running log 
 
Laboratory Assessments3 
 
 
 
 
 
 
 
Hemoglobin, platelets, WBC, 
neutrophils 
X 
 
Day 1 of each cycle3 
 
 
X 
X4 
Serum creatinine or creatinine 
clearance, sodium, potassium, 
bicarbonate, magnesium, 
calcium, phosphate, urea (or 
BUN), total bilirubin, ALT, 
AST, ALP, LDH, albumin 
glucose (fasting)5 
X 
 
Day 1 of each cycle3 
and day 15 of cycle 1 
 
 
X 
X4 
Home glucose monitoring8 
 
 
As clinically indicated 
to manage AEs 
 
 
As clinically indicated to 
manage AEs 
HbA1c, cholesterol (fasting), 
triglycerides (fasting), HDL, 
LDL, amylase, lipase6 
X 
 
Day 1 cycle 2 then  
day 1 of every  
third cycle. 
 
 
X 
X4 
INR 
X 
 
 
 
 
 
 
Estradiol (only for pre-
menopausal patients on 
LHRH analog) 
X 
 
 
 
 
 
 
Disease Assessment 
 
 
 
 
 
 
 
CT/MRI chest, abdomen and 
pelvis 
 
Within 28 
days prior to 
enrollment 
Every 8 weeks for the 
first 18 months then 
every 12 weeks until 
PD 2 
 
 
X2 
(if applicable 
based on 
timing) 
X2 
(disease 
assessments 
required as per 
during protocol 
treatment 
schedule until 
PD) 
CT/MRI brain (only required 
if known brain metastases or 
otherwise clinically indicated) 
Clinical tumour 
measurements (if applicable) 
Whole Body Bone Scan 
 
Every 8 weeks for the 
first 18 months then 
every 12 weeks until 
PD if bone lesions are 
present at baseline and 
cannot be assessed by 
chest / abdomen / 
pelvis imaging 2 
 
 
table continues on following page … 
 
 

 
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Required Investigations 
Screening 
(within 7 
days prior to 
registration) 
Baseline 
During Protocol 
Treatment 
(1 cycle = 28 days) 
At disease 
progression 
24 months 
after 
enrollment 
After Protocol Treatment 
4 weeks after 
discontinuation 
of protocol 
therapy1 
Every 12 weeks2 
Other Investigations 
 
 
 
 
 
 
 
Pregnancy Test (pre-
menopausal patients only)7 
 
Within 3 
days prior to 
enrollment 
As clinically indicated 
ECG 
X 
 
As clinically indicated 
X 
As clinically 
indicated 
Patient Oral Drug 
Administration Diary 
 
 
Daily 
 
 
 
 
Correlative Studies 
 
 
 
 
 
 
 
Whole blood collected in 
STRECK tubes for cfDNA 
Stratification 
sample sent 
to 
Foundation 
Medicine 
following 
registration 
 
Days 1 and 15 of cycle 
1, day 1 of cycles  
2 and 3 and then prior 
to every 2nd cycle of 
treatment9 
X9 
 
X14 
 
PK Blood Collection 
 
 
Day 15 of cycle 110 
 
 
 
 
Archival tumour tissue11 
Confirm 
available 
prior to 
registration 
Submit 
within 4 
weeks 
following 
enrollment 
 
 
 
 
 
Digital anatomical images 
upload for radiomics analysis 
and central radiology review. 
 
All protocol mandated images must be uploaded to AGMednet13 
Adverse Events 
 
 
 
 
 
 
 
Adverse Events 
To assess 
patient for 
eligibility as 
per 4.1.7 
X 
Continuously 
X2 
Quality of Life 
 
 
 
 
 
 
 
EORTC QLQ-C30 and 
NCI PRO-CTCAE 
 
Within 7 
days prior to 
enrollment 
Day 1 of cycles 2-4 then 
at the time of imaging 
for disease assessment 
beginning with the 24 
week assessment 
 
 
X12 
X12 
(required only at 
the 12 week 
follow-up visit if 
patient 
discontinued 
protocol 
treatment prior to 
PD and/or with 
related toxicities 
≥ grade 3 and has 
not started new 
anti-cancer 
treatment) 
Health Economics 
 
 
 
 
 
 
 
EQ-5D-5L 
 
Within 7 
days prior to 
enrollment 
Day 1 cycle 3 then day 
1 every other cycle 
 
X12 
 
At 3, 12, 24, 
36, 48 and 60 
months of 
follow up12 
Resource Utilization 
Assessment 
 
 
Each cycle 
 
 
X12 
X12 
table continues on following page … 
 
 

 
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1. A cycle is considered to be completed 28 days after IM administration of fulvestrant. The 4 week follow up visit is expected 4 weeks after 
the end of the last cycle. 
2. Timing of disease assessment is calculated from date of enrollment. All patients will be seen at 4 weeks after the end of the last cycle date. 
Thereafter, patients will be followed every 12 weeks to document related ≥ grade 3 adverse events until resolved and survival status. For 
patients who discontinue protocol treatment with CR, PR, or SD ongoing, disease assessments must continue according to the protocol 
schedule until disease progression as per RECIST 1.1 criteria. Death report is required for all patients. 
3. Bloodwork Timing: Pre-treatment physical exam and blood draws may be done the day prior to treatment if necessary, and when treatment is 
to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). 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. Day 1 assessments 
are required on day 1 of cycle 1. 
4. Required every 12 weeks to follow ≥ grade 3 lab results related to protocol treatment until resolved. 
5. Fasting glucose is required for eligibility (random glucose is not acceptable). Please instruct patients to fast for a minimum of 8 hours prior to 
blood collection. Fasting glucose is also required at subsequent time points, however, if it is determined that the patient is not fasting, please 
collect random glucose. 
6. It is preferable that both amylase and lipase are assessed at the required time points. For sites where only 1 of these parameters is routinely 
measured, then either lipase or amylase is acceptable as long as the same investigation is performed throughout the duration of protocol 
treatment. 
7. Urine or serum pregnancy test is acceptable. An ultrasound may be required to rule-out pregnancy. 
8. For any patients who initiate home glucose monitoring as a result of treatment emergent hyperglycemia (see Section 7.3.2.2) a glucometer 
will be provided. Glucose values must be recorded in the Patient Glucose Monitoring Diary. 
9. Correlatives blood sample should be collected within 28 days of objective disease progression. PD blood samples should also be collected if 
patient meets the criteria for objective disease progression after discontinuation of protocol treatment but prior to the start of a new anti-
cancer treatment. On-treatment correlative blood samples can be taken at the same time as the pre-treatment blood draws (i.e. one day prior 
to day 1 of treatment where necessary). 
10. Blood collection for PK is required on cycle 1 day 15 pre- and post- study drug dosing. The post-dose blood sample must be collected 2-4 
hours after ipatasertib/placebo dose is taken. See Correlative Studies Manual for details. 
11. Tissue must be confirmed available prior to registration for ALL patients. Archival tissue must be submitted at the same time that the 
baseline CRF is submitted. Refer to Section 12.1. 
12. EORTC QLQ-C30, NCI PRO-CTCAE, EQ-5D-5L and Resource Utilization Assessment required until start of new anti-cancer treatment. 
13. AGMednet access is provided to each site at the time of local activation. 
14. Whole blood collection for cfDNA is required at the 4 week post-treatment follow up visit for all patients, including patients who have 
started a new anti-cancer treatment. 
 
5.1 
Follow-up for Ineligible Patients 
 
The follow-up requirements for patients determined to be ineligible after enrollment but who have 
received no protocol therapy include submission of the Baseline Report and End of Treatment 
Report plus an annual short follow up form for survival. Data submission for ineligible participants 
who have received at least one dose of protocol therapy should be followed according to the 
protocol to allow for treatment and adverse event assessment. 
 
 

 
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6.0 
ENTRY/ENROLLMENT PROCEDURES 
 
6.1 
Entry Procedures 
 
All registrations for screening/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/enrolling patients will be provided at the time of study 
activation and will also be included in the “EDC Data Management Guidebook”, posted on the 
MA.40 trial specific web-site. If sites experience difficulties accessing the system and/or 
registering/enrolling patients please contact the help desk (link in EDC) or the MA.40 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 serial 
number will be assigned after registration for screening and will remain the same following 
enrollment. 
 
The following information will be required at the time of registration for screening: 
• 
trial code (CCTG MA.40) 
• 
patient's initials (may be coded) 
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
tissue banking/optional consent version date 
• 
confirmation of the requirements listed in Sections 4.0 and 5.0, including dates of essential 
tests and actual laboratory values 
 
The following information will be required at the time of enrollment: 
• 
confirmation of the additional requirements listed in Sections 4.0 and 5.0, including dates of 
essential tests 
• 
stratification factors 
 
6.2 
Stratification 
 
Subjects will be stratified by: 
• 
PIK3CA/PTEN/ AKT1 status: altered versus wildtype/unknown. 
• 
Prior treatment duration with CDK4/6 inhibitor: < 6 months versus ≥ 6 months. 
 
6.3 
Study Enrollment 
 
There will be two steps for enrollment on this study, a registration for screening and an enrollment. 
Once the results of the cfDNA analysis for stratification are known, and all other eligibility criteria 
are confirmed, enrollment can take place. Both registration for screening and enrollment will be 
provided electronically. 
 
 

 
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At the time of registration for screening and enrollment, all data reported within the Patient 
Enrollment folder must be accurate, complete and verifiable against source documentation. If a 
system query is issued indicating that the patient is not eligible, registration and/or enrollment 
within the EDC system will not proceed. CCTG should be contacted for assistance if needed. Under 
no circumstances should inaccurate data be entered in order to permit registration for screening and 
enrollment.  
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws consent and requests that data 
collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting screening/enrollment. 
 
All enrolled patients are to be followed until death or until sites are informed by CCTG that further 
follow-up is no longer required. The follow-up requirements for ineligible patients are outlined in 
Section 5.1. 

 
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7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
enrollment. 
 
7.1 
Treatment Plan 
 
7.1.1 
Drug Administration 
 
Arm 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
1 
Ipatasertib 
400 mg 
PO 
Day 1-21 
1 cycle = 28 days 
Fulvestrant 
500 mg 
IM 
Day 1 
(+ day 15 of cycle 1 only) 
2 
Placebo 
matching 
PO 
Day 1-21 
1 cycle = 28 days 
Fulvestrant 
500 mg 
IM 
Day 1 
(+ day 15 of cycle 1 only) 
 
A drug administration diary must be completed by the patient for each cycle of treatment with 
ipatasertib/placebo. 
 
7.1.2 
Blinding / Un-blinding 
 
Blinding is critical to the integrity of this clinical drug trial. If there is a need to break the blind this 
must be discussed with the CCTG as per Appendix VIII. 
 
7.1.3 
Premedication 
 
All patients will be pre-medicated with: 
 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Loperamide 
2 mg 
PO 
Days 1-28 
Cycle 1 
BID 
 
See Section 7.3.2.1 for further details regarding premedication with loperamide. Loperamide will 
not be supplied or reimbursed. 
 
7.2 
Dose Adjustments 
 
Doses will be reduced or held for 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 v 5.0) (see Appendix IV). 
 
 

 
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Ipatasertib has been associated with identified risks including nausea, vomiting, diarrhea, 
stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, AST increased, ALT increased, 
dehydration, decreased appetite, erythema multiforme, and rash. Ipatasertib’s potential risks 
include hematologic or immunosuppressant effects, hyperlipidemia, hepatobiliary disorders, 
pneumonitis, colitis, and developmental toxicity.  
 
Fulvestrant is associated with identified risks including injection site reactions (including more 
severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy), 
hepatotoxicity, asthenia, joint and musculoskeletal pain (includes arthralgia, and less frequently 
musculoskeletal pain, back pain, myalgia and pain in extremity), nausea, hypersensitivity reactions, 
rash, hot flushes, headache, reduced platelet count, vomiting, diarrhea, anorexia, and urinary tract 
infections. 
 
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. 
 
7.2.1 
Dose Modification for Ipatasertib/Placebo 
 
Management of some adverse reactions may require temporary dose interruptions/delays, and/or 
dose reductions, or permanent discontinuation of ipatasertib/placebo as per dose reduction 
schedules (see below Table 1). If the patient does not tolerate the daily dosing of the 
ipatasertib/placebo, dosing with food may be used to alleviate gastrointestinal symptoms, including 
nausea, vomiting, and/or diarrhea. No more than two dose reductions of ipatasertib/placebo per 
patient will be allowed (see Table 1). The starting dose is 400 mg and two dose reductions are 
allowed, the first to 300 mg and the second to 200 mg. Dose re-escalation is not permitted for 
ipatasertib/placebo, regardless of the dose level. 
 
Table 1: Dose Reductions for Ipatasertib/Placebo 
 
Dose Level 
Total Daily Ipatasertib/Placebo dose 
Starting dose 
400 mg 
First dose reduction 
300 mg 
Second dose reduction 
200 mg 
Third dose reduction 
Discontinue 
 
7.2.2 
Dose Modification for Fulvestrant 
 
Dose reductions for fulvestrant are not required. Injections may be delayed at the discretion of the 
investigator to manage toxicity related to fulvestrant as described below and as per the most recent 
Product Monograph. 
 
7.2.3 
Treatment Hold and Discontinuation 
 
Protocol treatment may be temporarily held in patients who experience toxicity considered to be 
related to study drug. If corticosteroids are initiated for treatment of the toxicity, they must be 
tapered to ≤ 10mg/day oral prednisone or equivalent before ipatasertib/placebo can be resumed, if 
clinically appropriate.  
 
 

 
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If treatment with ipatasertib/placebo must be held due to toxicity, treatment with fulvestrant should 
continue according to the schedule provided in Section 7.1.1. If ipatasertib/placebo has been 
withheld for > 56 consecutive days (2 cycles) because of treatment-related toxicity, the patient 
should be permanently discontinued from treatment with ipatasertib/placebo. If, in the judgment of 
the investigator, the patient is likely to derive clinical benefit from resuming ipatasertib/placebo 
after a hold of > 56 consecutive days, study drug may be re-started at the dose level approved by 
CCTG. 
 
If treatment with fulvestrant must be held, treatment with ipatasertib/placebo may continue 
according to the schedule provided in Section 7.1.1 provided the duration of the hold for fulvestrant 
is less than 2 weeks. Dose holds for fulvestrant extending beyond 2 weeks must be discussed with 
CCTG before treatment can proceed.  
 
Ipatasertib/placebo and/or fulvestrant treatment may be temporarily held/interrupted for reasons 
other than toxicity (e.g., surgical procedures) with approval from CCTG. If a scheduled fulvestrant 
dose coincides with a holiday or inclement weather or other conditions that preclude dosing, dosing 
should commence on the nearest following date, and, generally, subsequent dosing of both agents 
can continue on a new 28-day schedule on the basis of the new IM injection date. 
 
In cases where treatment with ipatasertib/placebo is discontinued due to toxicity, patients may 
continue to receive treatment with fulvestrant at the discretion of the investigator. Patients who 
permanently discontinue treatment with fulvestrant should also discontinue treatment with 
ipatasertib/placebo except in cases where the patient is considered to be deriving benefit from 
ipatasertib/placebo monotherapy. These cases must be approved by CCTG before treatment can 
proceed. 
 
7.3 
Adverse Event Management Guidelines 
 
Guidelines for management of specific adverse events are provided in the subsections below. 
 
Management of adverse events related to fulvestrant should be made according to the most recent 
Product Monograph/approved label, with the exception of management of hepatotoxicity as 
outlined in Section 7.3.2.7. 
 
7.3.1 
Management of Hematologic Toxicities 
 
The likelihood of hematological toxicities related to ipatasertib/placebo and fulvestrant is very low, 
therefore, specific dose modifications for hematologic toxicities are not provided. For toxicities 
≥ grade 3, management according to Section 7.3.2.8 should be considered. 
 
7.3.2 
Management of Non-hematologic Adverse Events 
 
Toxic effects will be graded using the NCI Common Terminology Criteria for Adverse Events 
Version 5.0 (CTCAE v5.0) (Appendix IV) 
 
7.3.2.1 Diarrhea Management Guidelines 
 
All patients will be pre-medicated with loperamide 2 mg BID upon start of study treatment through 
the first cycle. Loperamide will not be supplied or reimbursed. After the first cycle, continued 
treatment with loperamide is encouraged for the remainder of the study or as needed. The 
prophylaxis dose of loperamide may be adjusted as necessary based on clinical judgement and per 
local guidance. Patients should be educated on the symptoms and importance of early reporting of 
diarrhea to receive instructions on treatment and prevention of dehydration so that patients can be 
promptly and appropriately managed. 
 
 

 
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Dose reductions of ipatasertib/placebo for diarrhea should only occur if the symptoms persist 
despite treatment with adequate anti-diarrheal medications. For diarrhea occurring after cycle 2 that 
persists for more than 5 days despite treatment with anti-diarrheal agent(s) and/or withholding 
dosing of ipatasertib / placebo, imaging to rule out colitis and/or a stool culture for infectious 
workup should be obtained. 
 
Table 2: Diarrhea Management Guidelines 
 
Severity of Diarrhea 
Management Guidelines 
Grade 1 
Increase of < 4 stools per day 
over baseline; mild increase in 
ostomy output compared to 
baseline 
 Continue ipatasertib/placebo at the current dose level. 
 Manage with loperamide 4 mg initially and then 2 mg every 4 hours 
or after every unformed stool until 12 hour diarrhea-free interval. 
 Dietary modifications, such as avoiding lactose-containing foods and 
eating small meals and hydration with 8-10 glasses per day of clear 
liquid such as broth or low-calorie drinks with electrolytes. 
Grade 2 
Increase of 4-6 stools per day 
over baseline; moderate 
increase in ostomy output 
compared to baseline; limiting 
instrumental ADL 
 Manage with loperamide as early as possible at 4 mg initially and 
then 2 mg every 4 hours or after every unformed stool until 12 hour 
diarrhea-free interval. 
 Dietary modifications such as avoiding lactose-containing foods and 
eating small meals and hydration with 8-10 glasses per day of clear 
liquid such as broth or low-calorie drinks with electrolytes. 
 For non-infectious diarrhea lasting more than 48 hours despite 
optimal loperamide treatment, manage with second-line anti-
diarrheal agents, including, but not limited to Lomotil, codeine or 
octreotide or as per institutional guidelines. 
 Hold ipatasertib/placebo until diarrhea improves to ≤ grade 1. 
Ipatasertib/placebo can be resumed at the same dose or one dose 
lower per investigator evaluation upon improvement to ≤ grade 1. 
 For recurrent grade 2 diarrhea, reduce ipatasertib/placebo by one dose 
level. 
Grade 3 
Increase of ≥ 7 stools per day 
over baseline; hospitalization 
indicated; severe increase in 
ostomy output compared to 
baseline; limiting self-care 
ADL 
 Rule out infectious etiology. 
 Treat as per grade 2 management guidelines and supportive care. 
 Hold ipatasertib/placebo until diarrhea improves to ≤ grade 1. 
Ipatasertib/placebo should be reduced by one dose level when 
treatment is restarted. 
 For recurrent grade 3 diarrhea, hold treatment as above and reduce 
ipatasertib/placebo dose by one additional dose level or permanently 
discontinue treatment as per investigator’s discretion. 
Grade 4 
Life threatening consequences; 
urgent intervention indicated 
 Management as per grade 3 guidelines. 
 Permanently discontinue ipatasertib/placebo. 
 
 
 

 
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7.3.2.2 Hyperglycemia Management Guidelines 
 
Patients should be instructed to report symptoms associated with hyperglycemia such as thirst, 
frequent urination and blurred vision. As clinically indicated, the work-up for hyperglycemia 
should include fasting (abstaining from food or drink for ≥ 8hrs) blood glucose, urinary glucose 
and ketones, arterial blood gas, serum bicarbonate, and hemoglobin A1C. Home glucose 
monitoring may be required based on the management guidelines below. Home glucose results may 
be used to trigger contact between patient and investigative site team and may lead to an 
unscheduled clinic visit to assess fasting glucose. Guidance for when to call the investigator/site 
staff (or designated endocrinologist, if applicable) should be provided to patients for hypoglycemia 
(e.g. random glucose value under 3.9 mmol/L) and hyperglycemia (e.g. random glucose value over 
11.1 mmol/L). Alternative thresholds may be selected as clinically indicated per investigator 
discretion or institutional guidance and noted in the source documents. Increased glucose 
monitoring may include more frequent laboratory assessments in addition to home glucose 
monitoring using a glucometer as described in Table 3. For any patients performing home glucose 
monitoring, instructions must be provided regarding use of the glucometer and the frequency of the 
monitoring according to institutional guidance. Home glucose results must be recorded on the blood 
glucose log and this should be reviewed at each clinic visit (and source data retained). Entry of 
blood glucose results into the patient’s eCRF will be limited to laboratory results only. 
 
In the event of ipatasertib/placebo treatment hold/interruption, anti-diabetic medications may need 
to be held or reduced (per investigator judgment) and glucose should be monitored closely to 
minimize the risk of hypoglycemia. 
 
Guidelines for hyperglycemia attributable to ipatasertib/placebo are outlined below (see Table 3) 
based on fasting glucose measurements assessed in the clinic, unless otherwise specified. This table 
is not meant to inform grading of adverse events, which should be conducted per NCI CTCAE v5.0. 
All events of hyperglycemia should be thoroughly evaluated for more common etiologies other 
than drug-induced effects. 
 
 
 

 
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Table 3: Hyperglycemia Management Guidelines 
 
Severity of Hyperglycemia 
Management Guidelines 
Fasting glucose value > ULN 
to 8.9 mmol/L 
 Continue treatment with ipatasertib/placebo at current dose. 
 Consider oral anti-diabetic medications (e.g. metformin). 
 Consider home glucose monitoring under supervision of the treating 
investigator. 
Fasting glucose value > 8.9-
13.9 mmol/L 
 Hold ipatasertib/placebo until fasting glucose values return to 
≤ 8.9 mmol/L. 
 Initiate home glucose monitoring under supervision of the treating 
investigator. 
 Start oral anti-diabetic medications (e.g. metformin). 
 If patient is already taking oral anti-diabetic medication, the dose of 
ipatasertib/placebo should be reduced by one dose level when 
treatment is re-started. 
 If the patient previously had not been receiving oral anti-diabetic 
medication, ipatasertib/placebo may be resumed at the previous dose 
level with initiation of oral anti-diabetic medication. 
Fasting or non fasting 
glucose value > 13.9 – 27.8 
mmol/L 
 Hold ipatasertib/placebo until fasting glucose values return to 
≤ 8.9 mmol/L. 
 Initiate home glucose monitoring under supervision of the treating 
investigator. 
 Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used. 
 Start (or increase dose of) oral anti-diabetic medications (e.g. 
metformin). If the patient is already on oral anti-diabetic medication, 
ipatasertib/placebo should be reduced by one dose level when 
treatment is re-started. 
 If the patient previously had not been receiving oral anti-diabetic 
medication, ipatasertib/placebo may be resumed at the previous dose 
level with initiation of oral anti-diabetic medication. 
 If fasting glucose value exceeds 13.9 mmol/L again, the dose of 
ipatasertib/placebo should be reduced by one dose level when 
treatment is re-started. 
Fasting or non-fasting 
glucose value > 27.8 
mmol/L; life-threatening 
consequences; urgent 
intervention indicated 
 Hold ipatasertib/placebo until fasting glucose values return to 
≤ 8.9 mmol/L. 
 Initiate home glucose monitoring under supervision of the treating 
investigator. 
 Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used. 
 Start (or increase dose of) oral anti-diabetic medications (e.g. 
metformin). 
 Assess for volume depletion and appropriate intravenous or oral 
hydration. 
 Assess for diabetic ketoacidosis according to local guidelines. 
 Reduce ipatasertib/placebo by one dose level when treatment is re-
started. 
 If fasting or non-fasting glucose value exceeds 27.8 mmol/L again, 
permanently discontinue ipatasertib/placebo. 
NOTE: For all cases, the patient should receive education on a diabetic diet 
 
 

 
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7.3.2.3 Nausea and/or Vomiting Management Guidelines 
 
In general, patients should be closely monitored for GI effects and patients should be managed as 
per institutional standard of care and protocol guidelines, including hydration if appropriate, to 
prevent renal insufficiency due to fluid depletion. Dose reductions for nausea and/or vomiting 
should occur only if the symptoms persist despite a minimum of two treatments with adequate 
(combination) anti-emetic treatment(s), including ondansetron and other anti-emetics (i.e. 
prochlorperazine or metoclopramide per institutional guidelines; see Table 4). 
 
Table 4: Nausea and Vomiting Management Guidelines 
 
Severity of Nausea 
and/or Vomiting 
Management Guidelines 
Grades 1 or 2 
 Provide maximum supportive care as needed. 
Grade ≥ 3 
 Hold ipatasertib/placebo until nausea and/or vomiting resolves to ≤ grade 2. 
 Provide maximum supportive care as needed. 
 If grade ≥ 3 nausea or vomiting recurs, ipatasertib/placebo should be reduced 
by one dose level when treatment is re-started. 
 
7.3.2.4 Rash Management Guidelines 
 
Ipatasertib/placebo should be permanently discontinued for rash associated with Stevens Johnson 
syndrome, toxic epidermal necrolysis, or other suspected severe hypersensitivity or allergic 
reaction. Dosage modification and symptom management guidelines for skin toxicity attributable 
to study treatment are shown in Table 5. 
 
Table 5: Rash Management Guidelines 
 
Severity of Rash 
Management Guidelines 
Grade 1 
 Continue ipatasertib/placebo at current dose. 
 Consider treatment with topical corticosteroids. 
Grade 2 
 Hold ipatasertib/placebo treatment until resolution to ≤ grade 1 or the toxicity is 
no longer clinically significant. 
 Treat rash with topical corticosteroids. 
 Consider treatment of rash with oral corticosteroids. 
 Reduce ipatasertib/placebo by one dose level for recurrent grade 2 rash. 
Grade 3 
 Hold ipatasertib/placebo treatment until resolution to ≤ grade 1 or the toxicity is 
no longer clinically significant. 
 Treat rash with topical and systemic corticosteroids. 
 Consider dermatological consultation. 
 If, within 28 days, the skin toxicity resolves to ≤ grade 1 or is no longer 
clinically significant within 28 days, following completion of steroid taper, 
ipatasertib/placebo may be resumed at one dose level below the previous dose. 
 If skin toxicity remains clinically significant continuously for 28 days, or grade 3 
rash recurs, permanently discontinue ipatasertib/placebo. 
Grade 4 
 Administration of systemic steroids (oral or intravenous) is recommended. 
 Consider dermatological consultation and skin biopsy. 
 Ipatasertib/placebo should be permanently discontinued. 
 
 

 
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7.3.2.5 Pneumonitis Management Guidelines 
 
Pneumonitis is not known to be causally related to ipatasertib, however, pneumonitis has been 
observed with drugs that target pathways similar to ipatasertib. Every effort should be made to 
determine the etiology of dyspnea and changes in pulmonary function (see Table 6). 
 
Table 6: Interstitial Lung Disease/Pneumonitis Management Guidelines 
 
Severity of 
ILD/Pneumonitis 
Management Guidelines 
Grade 1 
 Continue ipatasertib/placebo at current dose. 
 Perform CT scan. Repeat CT scan every 8 weeks until a return to baseline. 
Pulmonary function tests are suggested to establish a baseline. 
Grade 2 
 Prescribe corticosteroids, as clinically indicated, once infectious etiology is 
ruled out. Hold ipatasertib/placebo treatment while patient is treated with 
corticosteroids. 
 Perform CT scan and pulmonary function tests. Repeat CT scan every 4 weeks 
until a return to baseline. 
 If pneumonitis resolved to grade ≤ 1 after completion of steroid taper, 
ipatasertib/placebo may be resumed at either the previous dose or reduced by 
one dose level per investigator discretion. 
 For recurrent grade 2 pneumonitis, ipatasertib/placebo must be resumed at one 
dose level below the previous dose. 
 Discontinue ipatasertib/placebo if recovery to grade ≤ 1 is not evident within 
28 days. 
Grade 3 
 Prescribe corticosteroids, as clinically indicated, once infectious etiology is 
ruled out. Hold ipatasertib/placebo treatment while patient is treated with 
corticosteroids. 
 Perform CT scan and pulmonary function tests. Repeat CT scan every 4 weeks 
until a return to baseline. Bronchoscopy is also recommended. 
 If pneumonitis resolves to grade ≤ 1, following completion of steroid taper, 
reduce ipatasertib/placebo treatment by one dose level. 
 Discontinue ipatasertib/placebo if recovery to grade ≤ 1 is not evident within 
28 days. 
 For recurrent non-infectious grade 3 pneumonitis, ipatasertib/placebo should 
be permanently discontinued. 
Grade 4 
 Prescribe corticosteroids, as clinically indicated, once infectious etiology is 
ruled out. 
 Permanently discontinue ipatasertib/placebo. 
 Perform CT scan and PFTs. Repeat CT scan every 4 weeks until a return to 
baseline. Bronchoscopy is also recommended. 
 
7.3.2.6  Mucositis Management Guidelines 
 
Mouthwash such as magic mouthwash (if inaccessible, warm salt or bicarbonate water) should be 
used as supportive care per institution guidelines. Brushing teeth after meals, keeping lips 
moisturized with non-Vaseline products, and avoiding alcohol, spicy food, and smoking have all 
been shown to reduce pain and infection related to mucositis. Ranitidine or omeprazole may be 
helpful if patients have epigastric pain. Dosage modification guidelines for mucositis attributable 
to study treatment are outlined in Table 7. 
 
 

 
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Table 7: Mucositis Management Guidelines 
 
Severity of Mucositis 
Management Guidelines 
Grade 1 or 2 
 Manage with maximum supportive care. 
 If grade ≥ 2 mucositis recurs in subsequent cycles despite maximal 
supportive care, the dose of ipatasertib/placebo should be reduced by one 
dose level. 
Grade ≥ 3 
 Hold ipatasertib/placebo until recovery to ≤ grade 2. If mucositis resolves 
to ≤ grade 2, the dose of ipatasertib/placebo should be reduced by one dose 
level.  
 
7.3.2.7 Hepatotoxicity Management Guidelines 
 
Permanently discontinue ipatasertib/placebo for any patients who develop a concurrent elevation 
of ALT and/or AST to ≥ 3 x ULN and total bilirubin ≥ 2 x ULN and/or clinical jaundice in the 
absence of biliary obstruction or other causes responsible for the concurrent elevation, including 
patients having abnormal liver function tests that meet Hy’s law criteria. 
 
Table 8: Hepatotoxicity Management Guidelines 
 
Severity of LFT Elevation 
Management Guidelines 
Grade 1: 
AST or ALT > ULN – 3.0 x ULN if baseline 
was normal;  
1.5-3.0 x baseline if baseline was abnormal 
or 
Total bilirubin > ULN – 1.5 x ULN if baseline 
was normal; 
> 1.0 – 1.5 X baseline if baseline was abnormal 
 Continue ipatasertib/placebo and fulvestrant at 
current dose level. 
 Monitor LFTs according to protocol schedule 
Grade 2: 
AST or ALT > 3.0 – 5.0 x ULN if baseline was 
normal; > 3.0 – 5.0 x baseline if baseline was 
abnormal 
or 
Total bilirubin > 1.5 – 3.0 x ULN if baseline 
was normal;  
> 1.5 – 3.0 X baseline if baseline was abnormal 
 Continue ipatasertib/placebo and fulvestrant at 
current dose level. 
 The frequency of LFT monitoring should be 
increased as clinically indicated if the investigator 
judges that the laboratory abnormalities are 
potentially related to study medication. 
 
table continues on next page … 
 
 

 
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Severity of LFT Elevation 
Management Guidelines 
Grade 3: 
AST or ALT > 5.0 – 20.0 x ULN if baseline was 
normal;  
> 5.0 – 20.0 x baseline if baseline was abnormal 
or 
Total bilirubin > 3.0 – 10.0 x ULN if baseline 
was normal;  
> 3.0 – 10.0 x baseline if baseline was abnormal 
 Hold ipatasertib/placebo and fulvestrant. 
 On return of LFTs to ≤ grade 2, restart 
ipatasertib/placebo and fulvestrant at previous dose 
level. 
 Consider hepatology consult. 
 Following treatment resumption, monitor serum 
transaminases and bilirubin at a minimum every 
2 weeks for 3 months and monthly thereafter. 
 If another grade 3 event occurs, hold treatment with 
ipatasertib/placebo and fulvestrant. On return of 
LFTs to ≤ grade 2, restart ipatasertib/placebo 
reduced by one dose level. Fulvestrant may be 
resumed at the original dose. 
 Permanently discontinue treatment with 
ipatasertib/placebo and fulvestrant for further 
grade 3 occurrences. 
Grade 4: 
AST or ALT > 20.0 x ULN if baseline was 
normal;  
> 20.0 x baseline if baseline was abnormal 
or 
Total bilirubin > 10.0 x ULN if baseline was 
normal;  
> 10.0 x baseline if baseline was abnormal 
 Permanently discontinue treatment with 
ipatasertib/placebo and fulvestrant. 
 
7.3.2.8 Management of Other Clinically Significant Adverse Events 
 
If other Grade ≥ 3 toxicities not described above develop in patients, ipatasertib/placebo may be 
held at the discretion of the investigator. During this time, treatment may continue with fulvestrant. 
Grade ≥ 3 clinically significant toxicity should be monitored at least weekly. If the toxicity is 
deemed related to ipatasertib/placebo and resolves to Grade 1 or better in 2-4 weeks, the dose of 
ipatasertib/placebo should be reduced by one level per the suggested guidelines in Table 1. 
 
For Grade ≥ 3 toxicities associated primarily with laboratory abnormalities only (e.g. lipase, or 
amylase, or decreases in phosphorus without clinical or other evidence of pancreatitis), study 
treatment may continue without interruption and/or dose reduction at the discretion of the 
investigator per institutional guidelines. 
 
7.4 
Duration of Therapy 
 
Patients should continue protocol treatment until RECIST 1.1 defined progression or unacceptable 
toxicity/other treatment discontinuation criterion is met. See Section 10.0 for further details on 
protocol discontinuation criteria. 
 
 

 
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7.5 
Concomitant Therapy 
 
7.5.1 
Permitted 
• 
Medications required to treat adverse events, manage cancer symptoms, concurrent diseases 
and supportive care agents, such as pain medications, anti-emetics, anti-diarrheal medications 
(refer to section 7.3.2.1) as well as medical marijuana/cannabis oil/commercially procured 
marijuana, taking into account those not permitted below. 
• 
Bisphosphonates / denosumab are permitted for the treatment of hypercalcemia, osteoporosis 
and prevention of skeletal related events for patients with bone metastases. 
• 
LHRH agonists/antagonists are permitted only for pre-menopausal women as per eligibility 
criterion 4.1.2. 
• 
Moderate CYP3A4 inhibitors should be taken with caution as they can increase ipatasertib 
exposure (see Appendix VII). 
 
7.5.2 
Not Permitted 
• 
Strong CYP3A inhibitors: such as, but not limited to, atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandamycin, voriconazole, and/or grapefruit juice or grapefruit supplements (see Appendix 
VII). 
• 
Strong CYP3A inducers: such as, but not limited to, rifampin, carbamazepine, rifapentine, 
phenytoin, phenobarbital, and/or St. John’s wort or hyperforin (see Appendix VII). 
• 
CYP3A4 substrates with a narrow therapeutic index: such as, but not limited to, alfentanil, 
astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, ergot alkaloids ergotamine, and/or dihydroergotamine. 
• 
Herbal medications/preparations, dietary supplements that are potentially hepatotoxic or with 
known or potential drug interactions. 
• 
Administration of any other anti-cancer therapy is not permitted while the patient is receiving 
protocol therapy. Patients may be treated at the investigator’s discretion after discontinuation 
of protocol therapy. Specifically, with respect to concurrent radiation therapy while on protocol 
treatment: 
− 
Radiation therapy to a solitary non-target lesion (i.e. for symptomatic pain relief) may be 
permitted after consultation with CCTG 
− 
Radiation therapy to target lesions is not permitted while the patient is receiving protocol 
therapy. Patients who require radiation therapy to a target lesion would be considered to 
have met the criteria for disease progression and discontinuation of protocol treatment is 
required. 
• 
Systemic corticosteroids > 10 mg daily oral prednisone equivalent (except as stated in Section 7 
to treat a protocol treatment related adverse event or for pre-medication for contrast allergy as 
per local guidelines). 
 
 

 
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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for Adverse Events 
 
All enrolled patients will be evaluable for baseline adverse events and adverse events on treatment 
from the time of their first treatment.. 
 
8.1.2 
Evaluable for Response 
 
All enrolled patients will be included in the analyses of response. Those 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]. 
 
8.1.3 
Evaluable for Quality of Life Assessment 
 
All enrolled patients who have completed the quality of life questionnaire are evaluable for quality 
of life analyses. 
 
8.1.4 
Evaluable for Health Economics Assessment 
 
All enrolled patients are evaluable for health economics analyses. All patients who have completed 
the health utility questionnaire will be evaluable for cost-utility analyses. 
 
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 
[Eisenhauer, 2009]. 
 
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. 
 
 

 
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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. 
 
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 
 
8.2.5.1 Patients with Measurable Disease 
 
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 
< 10mm and considered CR). Residual lesions (other than nodes < 10 mm) thought to be non-
malignant should be further investigated (by cytology specialized imaging or other techniques as 
appropriate for individual cases [Eisenhauer, 2009] before CR can be accepted. 
 
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. 
 
 

 
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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 appears to have increased by at least 73% in volume, or in select instances 
where tumour burden has increased sufficiently to require urgent intervention (e.g. radiation for 
spinal cord compression or drainage of a fluid collection). Modest increases in the size of one or 
more non-target lesions are NOT considered unequivocal progression. If the evidence of PD is 
equivocal (target or non-target), treatment may continue until the next assessment, but if confirmed, 
the earlier date must be used. 
 
Table 1: Integration of Target, non-Target and New Lesions into Response Assessment: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
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 progression”. 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. 
 
8.2.5.2 Patients with Non-Measurable Disease Only 
 
Patients with only non-measurable (but evaluable) disease, may only have an overall RECIST 1.1 
response of CR, non-CR/non-PD or PD as follows: 
 
 

 
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Complete Response (CR): disappearance of non-target lesions. Residual lesions 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. 
 
Non-CR/Non-PD: persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): the appearance of new lesions and/or unequivocal progression of non-
target lesions. 
 
Table 2: Integration of Non-Target and New Lesions into Response Assessment for patients with 
only non-measurable, evaluable, lesions: 
 
Non-Target Lesions* 
New Lesions 
Overall 
Response 
Best Overall Response for this 
category also requires 
CR 
No 
CR 
 
Non-CR/Non-PD 
No 
Non CR/ 
Non-PD 
Documented at least once > 4 weeks 
from baseline 
Not all evaluated 
No 
NE 
 
Unequivocal PD** 
Yes or No 
PD 
No prior CR or non-CR/non-PD 
Any 
Yes 
PD 
* 
Note that these lesions should be recorded under the "Non-Target" lesions table on the CRFs. 
** 
Unequivocal progression in non-measurable lesions will be accepted as disease progression. 
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 progression”. 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. 
 
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 enrollment 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”. 
 
 

 
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8.5.1 
Clinical Lesions 
 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10mm as 
assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging 
is preferred. 
 
8.5.2 
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. 
 
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 (SAEs) defined as per ICH guidelines (see below) and other adverse 
events must be reported 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. 
 
Adverse Event Reporting 
 
Adverse event reporting for this trial will be as follows: 
• 
All adverse events will be captured on the case report form as follows: 
− Baseline: all adverse events experienced within 14 days prior to start of protocol treatment. 
− During protocol treatment and up to 4 weeks after discontinuation of protocol treatment: 
all adverse events. 
− During follow up: all ≥ grade 3 AEs which are new or ongoing and related to protocol 
therapy until complete resolution. 
 
• 
Adverse Events of Special Interest (AESI), applicable to ipatasertib/placebo and fulvestrant, 
will require expedited reporting using the AESI report (if not serious) or SAE report (if serious). 
AESIs which are not SAEs must also be reported according to the timelines outlined in 
Section 9.2. AESIs collected for this trial are as follows: 
− Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law. 
− Grade ≥ 3 hepatotoxicity. 
− Grade ≥ 3 ALT/AST elevations. 
− Suspected transmission of an infectious agent by the study drug, defined as any organism, 
virus or infectious particle (e.g. prion protein transmitting/transmissible spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product. This term 
applies only when a contamination of the study drug is suspected. 
− Grade ≥ 3 diarrhea. 
− Grade ≥ 3 fasting hyperglycemia. 
− Grade ≥ 2 pneumonitis. 
− Grade ≥ 2 colitis/enterocolitis. 
− Grade ≥ 3 rash. 
− Erythema multiforme. 
 
 

 
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9.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events which are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 9.2 for reporting instructions). These include 
events occurring from the first protocol treatment administration until 30 days after last 
protocol treatment administration and at any time afterwards. Note: adverse events which occur 
prior to the start of protocol therapy must only be reported as serious adverse events if they are 
directly related to a study specific procedure. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information contained in the investigator brochure or product monograph. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol agent cannot reasonably be ruled out. 
• 
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 MA.40 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 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
MA.40 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
 

 
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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 MA.40 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) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 4.1.12. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy. 
 
9.3.2 
Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants, and 
female partners of male participants. Pregnancies occurring up to 2 years after the last dose of study 
drug must also be reported. 
 
The investigator should report the pregnancy within 24 hours of learning of the pregnancy using 
the CCTG Pregnancy Reporting Form available from the trial webpage, under the “Toolbox” link. 
The Pregnancy Reporting Form should be updated to provide the outcome of the pregnancy. 
 
 Information from the trial participant’s pregnant partner can only be collected following informed 
consent. A copy of the signed signature page of the pregnancy follow-up consent must be submitted 
to CCTG. Centres that require additional informed consent to collect information about the 
pregnancy from a trial participant must submit a copy of the signed signature page of the pregnancy 
follow-up consent to CCTG. 
 
All follow-up reports must be submitted to CCTG in a timely manner. All documents must be sent 
to the CCTG safety desk (Fax: 613-533-2812/Email: safety-desk@ctg.queensu.ca). 
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
 

 
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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 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 30 days following the exposure. 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 (Fax: 613-
533-2812/Email: 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. 
 
9.3.4 
Blinded Studies and Patient Unblinding 
 
Centre requests for participant unblinding as a result of a pregnancy or exposure are acceptable. 
However, the usual unblinding rules (see Appendix VIII) must be followed. 
 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which a causal relationship with protocol treatment cannot be ruled out). 
 
9.5 
CCTG Responsibility for Reporting Serious Adverse Events to Breast Cancer Trials Australia 
 
The CCTG will provide expedited reports from Australia and New Zealand of SAEs for those 
events which meet the regulatory requirements for expedited reporting, i.e. events which are BOTH 
serious AND unexpected, AND which are thought to be related to protocol treatment (or for which 
a causal relationship with protocol treatment cannot be ruled out) to the MA.40 trial team at Breast 
Cancer Trials (BCT) for reporting to other regulatory authorities. 
 
9.6 
CCTG Reporting Responsibility to Hoffman-La Roche Ltd. 
 
Hoffman La-Roche Ltd. will be notified of all protocol reportable serious adverse events, adverse 
events of special interest, special situation reports and instances of exposure to study drug during 
pregnancy or lactation within agreed timelines. 
 
 

 
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9.7 
Hoffman-La Roche Reporting Responsibilities 
 
Hoffman La-Roche Ltd. shall notify CCTG of individual safety reports from other studies using 
ipatasertib, which may affect the overall safety profile of the study and which they have reported 
to Health Canada. 
 
9.8 
Reporting Safety Reports to Investigators 
 
For Canadian Sites: 
CCTG will notify Investigators of all Safety Reports including all serious adverse events that are 
unexpected and related (i.e. possibly, probably, or definitely) to protocol treatment (SUSARs) from 
this trial as well as Safety Updates (single reports or line listings). 
 
The reports will be posted to the CCTG trial MA.40 web-based safety monitoring utility, available 
on the CCTG trial webpage, under the “Toolbox” link. Relevant safety reports requiring REB 
submission that are not submitted at the time of initial REB approval should be submitted to the 
REB as soon as possible (suggest within 30 days of the date of local activation). REB submissions 
greater than 90 days from the date of local activation will be regarded as delinquent and a major 
deficiency will be assigned. Centres being activated later in the life of the study only need to submit 
the latest version of the IB/PM and safety reports as described above. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the Safety Report such as protocol and/or informed consent 
changes. Safety reports that are not mandated by CCTG to be submitted to the REB are marked as 
“NR” (not required) in the safety report monitoring utility. However, local policy may still require 
REB submission of this information.  
 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
MA.40 web based safety monitoring utility and documentation of REB submission must be retained 
in the study binder on site. The REB submission template provided by CCTG can be used to assist 
with tracking, submission, filing and monitoring. 
 
 

 
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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. 
 
Note: Efforts must 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 
Therapy After Protocol Treatment is Stopped 
 
If patients discontinue protocol treatment due to adverse events or progression of disease, any 
further non-protocol treatment is at the discretion of the investigator. 
 
10.3 
Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy (4 weeks after the end date 
of the last cycle) then every 12 weeks thereafter. For patients who discontinue protocol therapy 
with CR, PR or SD ongoing, disease assessments will continue during follow up as per the protocol 
schedule until disease progression. New or ongoing adverse events experienced during follow up 
which are ≥ grade 3 and related to protocol therapy must be documented until complete resolution. 
A Death Report will be required for all patients. 
 
 

 
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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Central Data Review 
 
The CCTG Central Data Review process is a critical part of CCTG’s quality assurance program. 
As part of this trial, limited critical data will be collected by CCTG, including de-identified surgical 
reports, digital images and reports and pathology reports to allow central data review and 
confirmation of eligibility (disease under study) and primary outcomes (including date of 
progression). These reviews and confirmations will be performed by experts (e.g. CCTG Central 
Office, Trial Committee) and are critical to ensuring the accuracy of the data and consistency of 
conclusions drawn, thus reducing bias. 
 
The collection of this critical data involves uploading documents through the electronic Supporting 
Document Upload Tool (SDUT) data capture linked system. See Appendix III (Documentation for 
Study) for details of supporting document requirements for this trial and for requirements for the 
redaction of personal identifiers. Although it remains the centres responsibility to ensure adequate 
redaction of any information provided to CCTG, submitted source documents are reviewed prior 
to acceptance at CCTG; in the case of incomplete redaction, documents are removed and the site 
assigned a violation and required to resubmit. 
 
All patients will provide written informed consent for submission of source documents, and the 
rationale and documents to be collected will be detailed in the informed consent document. 
 
11.2 
Central Radiology Review 
 
A radiology review of all cases by a third party is planned to confirm response to treatment. The 
upload of digital images and clinical photography of skin lesions is required to conduct this review. 
The reviewer will be blinded to study treatment allocation. Details of electronic upload of imaging 
files will be provided to sites by the third party. 
 
11.3 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
 

 
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12.0 
CORRELATIVE STUDIES 
 
Collection and immediate shipment of time sensitive samples (e.g. cfDNA for stratification) MUST 
occur after registration. This is to ensure that the stratification samples are labelled with a CCTG 
patient ID, which is required for return and entry of results.  
 
A detailed Correlative Studies Manual will be provided on the MA.40 trial specific website, which 
will include details regarding sample preparation, handling and shipping. 
 
Correlative samples will be used for research purposes only and will not be sold. Patients will not 
be identified by name. The identification of samples may include a patient study number assigned 
at the time of registration to the trial, a surgical/ histology number, patient initials and year of birth. 
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 
 
In the course of genetic testing for this study, there is a chance that “clinically relevant incidental 
findings” may occur; these refer to unanticipated discoveries made in the course of research but 
that are outside of the scope of the research [TCPS2 2014] being conducted. These findings could be 
inherited changes that might predispose a person to particular cancers or other diseases, and may 
be passed on in families. 
 
As the genetic testing for this study will be conducted in a certified laboratory the results will be 
considered validated. 
 
During the informed consent process, participants will be told about the remote possibility of 
clinically relevant incidental findings being discovered, and given the opportunity to make 
informed choices about whether they wish to receive this information. 
 
If a clinically relevant incidental finding is discovered during the testing for this study and a 
participant consented to learning about the results, the enrolling institution will be responsible for 
following local SOPs with regard to confirming the result, ensuring genetic counseling is available, 
obtaining REB approval (if required) and contacting the study participant. 
 
12.1 
Protocol-Mandated Correlative Studies 
 
The goal of the correlative studies component of the trial is to genomically profile the emergence 
of clinical resistance to ipatasertib treatment. The objective is to capture quantifiable genomic, 
epigenomic and proteomic longitudinal alterations, that when integrated with response data will 
facilitate the development of prognostic and predictive biomarkers related to ipatasertib sensitivity. 
 
Pharmacokinetic studies will also be conducted. 
 
 

 
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Blood Collection (Mandatory) 
 
The submission of whole blood is mandatory for participation in this trial. Whole blood will be 
collected at the following time points: 
• 
at the time of patient registration for stratification 
• 
on days 1 and 15 of cycle 1  
• 
on day 1 of cycles 2 and 3 then prior to every 2nd cycle of treatment 
• 
at the time of objective disease progression 
• 
4 weeks after discontinuation of protocol treatment 
 
Blood samples for stratification will be analyzed by Foundation Medicine using the 
FoundationOne® Liquid platform. Following analysis of the stratification sample by Foundation 
Medicine, an alteration report will be provided to the investigator. The expected turnaround time 
for the report is 14 days from the date that the sample is received by Foundation Medicine. The 
investigator will be responsible for entering the alteration result for stratification and enrollment 
based on the report provided. 
 
The following alterations will be considered alteration positive for stratification: 
• 
AKT1 alterations that result in an amino acid substitution at the E17, L52 or Q79 residues 
• 
PIK3CA alterations that result in an amino acid substitution at the R88, G106, K111, G118, 
N345, C420, E453, E542, E545, Q546, M1043, H1047 or G1049 residues 
• 
PTEN dominant negative SNV (C124S, G129E, R130X) or homozygous deletion (copy 
number of 0) 
 
cfDNA samples from baseline, on treatment, at the time of disease progression, and at 4 weeks 
post-treatment will be evaluated using established targeted sequencing methods and technologies 
such as Foundation One® Liquid and the OICR MA.38 (NCT02630693) bespoke panels. The 
MA.38 panel was specifically designed to address key signaling features in CDK4/6 pathway 
resistance (e.g. CCNE1) not currently included on Foundation One® Liquid. Further features 
specific to PIK3CA pathway assessment (potentially including TSC1/2, HK & NRAS) may 
mandate a similar approach in MA.40. These techniques allow for significant genomic depth to 
confidently identify tumour-derived mutations whose variant allele fraction in tumours are ≥ 0.2%. 
Included in this approach is an assessment of tumour mutational burden (TMB) and microsatellite 
instability.  
 
Specifically, 
PFS 
will 
be 
compared 
between 
patients 
exhibiting 
altered/mutant 
PI3K/PTEN/AKT1-3 cfDNA and those with unaltered cfDNA, relative to treatment. In addition, 
using the cfDNA samples collected during treatment, alterations of cfDNA and emergence of 
“novel” mutations (for example PIK3CB, which is mutated in 1-2% of breast cancers) will be 
identified and assessed with respect to therapeutic response and potentially requiring a “bespoke” 
cfDNA panel. cfDNA analysis performed upon progression or end of treatment will be employed 
to identify patterns of genomic alterations and possible underlying mechanisms associated with 
resistance to ipatasertib (and fulvestrant). 
 
 

 
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DNA and RNA will be isolated from blood-derived exosomes for genomic and transcriptomic 
analysis, respectively, and proteins will be extracted for characterization using mass spectrometry 
based techniques. Exosomal contents at baseline will be evaluated to identify potential prognostic 
and predictive genomic/transcriptomic/protein features and key pathways linked to ipatasertib 
sensitivity. Samples collected during treatment will be used to assess emergence of “novel” 
exosomal alterations with respect to therapeutic response, and those collected at progression will 
be useful in identifying alterations associated with resistance to ipatasertib (and fulvestrant). 
 
Pharmacokinetics (Mandatory) 
 
Blood samples will be collected to enable pharmacokinetic correlations with response and safety. 
Blood samples will be collected on all patients pre- and post-ipatasertib dose (2-4 hours) on day 15 
of cycle 1. Please refer to the correlative studies manual for further details regarding collection and 
processing of the pharmacokinetic samples. 
 
Tumour Tissue Collection (Mandatory) 
 
The submission of a representative block of the diagnostic tumour tissue is mandatory for 
participation in this trial. One tumour block is requested from the most recent biopsy or resection. 
Tumour tissue from a metastatic lesion is preferred, however tissue from the primary site is also 
acceptable. Where local centre regulations prohibit submission of blocks of tumour tissue, cores 
(two 2 mm cores of tumour from the block) or 20 slides of representative tumour tissue may be 
substituted instead. 
 
Where no previously resected or biopsied tumour tissue exists or is found to be of inadequate 
amount or quality, an additional biopsy of the metastatic or primary tumour will be required for the 
patient to be considered eligible for the study. 
 
Dual DNA/RNA extraction will be performed on the diagnostic FFPE tumour material. We will 
perform quantitative expression profiling using technologies such as the NanoString gene 
expression profiling or RNA sequencing. Both technologies enable highly sensitive and 
reproducible digital profiling of RNA from small amounts of FFPE material. We will evaluate 
expression of key cancer pathways and processes. Employing state-of-the-art analytical methods, 
including machine learning, we will identify prognostic and predictive transcriptomic features and 
key pathways linked to ipatasertib sensitivity. Tumour FFPE samples will also be evaluated for 
genomic aberrations using NGS platforms and concordance between alterations in the primary 
tumour and the cfDNA alterations detected above will also be evaluated. 
 
With respect to PTEN, a key mediator of sensitivity to CDK4/6 inhibitors and potential effector of 
ipatasertib sensitivity, expression will be evaluated by RNAseq and possibly traditional IHC. 
Targeted methylSeq will also be utilized as promoter methylation is a common cause of reduced 
PTEN protein expression in numerous cancer types. PTEN expression (low vs non-low) will also 
be incorporated into the analysis of progression free survival described above (altered/mutant 
PI3K/PTEN/AKT1 vs unaltered), however, this will be evaluated for exploratory purposes outside 
of the parameters defined for stratification by the FoundationOne® Liquid platform. 
 
As an extension of the PTEN promoter methylation analysis, additional methylation profiling will 
be implemented using a targeted sequencing panel to identify clinically relevant epigenomic 
features. This approach uses the bisulfite method for identifying specific methylation patterns 
within a DNA or FFPE DNA sample. With low DNA input (10-20ng), (the panel provides high 
accuracy and can detect methylation status of a minimum of 38 targets. 
 
 

 
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Genomic/transcriptomic changes within the primary tumour FFPE material will also be evaluated 
for possible associations with time on CDK4/6 inhibitor treatment, since all patients will have 
received CDK4/6 based therapy before enrollment. Critical effectors of CDK4/6 inhibitor 
sensitivity such as Rb, CCNE and CCND1 will be a focus of this evaluation and this will be 
reflected in the techniques used for analysis. 
 
Proteomic characterization will be performed on FFPE tumour tissue using IHC and NanoString’s 
GeoMx® digital spatial profiling to evaluate possible correlations with progression free survival. 
The DSP platform allows the interrogation of multiple proteins within multiple defined areas 
(tumour vs stroma). We will evaluate changes in expression of key immune cell types including T 
cells, B cells and macrophages, checkpoint molecules and immune function. Other possible 
platforms for proteomic analysis will also be considered, including mass spectrometry/cytometry. 
 
Digital Imaging Collection (Mandatory) 
 
Digital images from all time points must be uploaded in order to conduct the central radiology 
review and radiomics analysis. Images must be de-identified according to local SOPs prior to 
upload. If de-identification of images is not possible, please contact CCTG. For the radiomics 
analysis, mathematical methods will be applied to derive information including gray-level 
intensity, pixel inter-relationships and spectral properties of the images which may be imperceptible 
to the human visual system [Davnall 2012]. The goals of the planned radiomic analyses include 
prognostication of outcome, prediction of response to endocrine therapy and ipatasertib and 
characterization of patterns of resistance to therapy, independent of traditional imaged based 
methods of estimation of tumour response/progression using RECIST 1.1. 
 
A detailed manual will be provided by the third party reviewer, which will include details regarding 
image upload. 
 
12.2 
Optional Banking 
 
Banking of Tumour Tissue 
 
Mandatory submission of tumour tissue has been described above. The subsequent banking of any 
remaining tissue is not mandatory for participation in the study, but the participation of all centres 
is strongly encouraged. Blocks will be carefully banked as part of the CCTG tissue/tumour bank at 
Queen’s University in Kingston, Ontario. 
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 
 
Biomarker Research on Tumour Tissue and Blood Samples 
 
As researchers become aware of new prognostic and predictive information related to ipatasertib 
activity, additional research outside of the planned assays may be applicable. Patients will be asked 
to consent to the use of tumour tissue and blood samples for additional assays not listed in the 
protocol. The results of this research will be used to better understand how patients are affected by 
the study treatments. This is not mandatory for participation in the study, but the participation of 
all centres is strongly encouraged. No additional sample collection is required for this purpose and 
the samples used will have already been sent to the CCTG tissue/tumour bank at Queen’s 
University in Kingston, Ontario. 
 
 

 
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Banking of Digital Images 
 
Mandatory upload of de-identified digital images and clinical photography of skin lesions for 
central radiology review and radiomics analysis has been described above. The subsequent banking 
of the digital images is not mandatory for participation in the study, but the participation of all 
centres is strongly encouraged. Digital images will be collected by a third party and then transferred 
to CCTG for banking following central review. Images from patients who have consented to 
banking will be stored indefinitely at Queen’s University in Kingston, Ontario. 
 
Proposals to use the banked digital images for research purposes may be submitted to CCTG. A 
scientific review process of any proposals to use the digital images will take place and any proposals 
approved will have undergone ethics approval. 
 
 

 
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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
The primary objective of this trial is to compare progression-free survival (PFS) in the intent to 
treat (ITT) population consisting of enrolled patients with ER+/HER- advanced/metastatic breast 
cancer and treated with ipatasertib and fulvestrant versus placebo and fulvestrant after progression 
on first line CDK 4/6 inhibitor plus AI treatment. 
 
A key secondary objective is to compare PFS between the two treatment arms in the subgroup with 
PIK3CA/AKT1/PTEN altered status. Other secondary objectives include response rate, duration of 
response, clinical benefit rate, overall survival, time to commencement of subsequent systemic 
therapy or death, quality of life, health economics and safety comparisons between the two 
treatment arms in the ITT population. 
 
Eligible subjects will be randomized at 1:1 ratio to one of the following two treatment groups: 
ipatasertib + fulvestrant (experimental arm) or placebo + fulvestrant (control arm). Subjects will be 
stratified by: 1) PIK3CA/PTEN/AKT1 alteration status: altered versus wildtype/unknown, 2) prior 
duration of treatment with CDK 4/6 inhibitor: < 6 months versus ≥ 6 months. 
 
13.2 
Primary Endpoints and Analyses 
 
The primary endpoint is progression-free survival (PFS) defined as time from randomization to 
disease progression or death from any cause, whichever occurs first. Disease progression will be 
investigator assessed using the RECIST 1.1 criteria [Eisenhauer, 2009] CCTG or its designee will 
collect and store all tumour measurement images on all enrolled patients throughout the study to 
enable an independent review of imaging scans and an assessment of disease progression. If a 
patient has not progressed or died at the time of final analysis, PFS will be censored on the date of 
the last visit with adequate disease assessment. Lack of tumour assessments post-randomization 
will lead to censoring at the date of randomization. Progression documented between scheduled 
visits will be assigned to the date of the clinical lesion evaluation indicating progression. Death 
before first PD assessment, including death between adequate assessment visits, will lead to the 
assignment of progression to the date of death. Death or progression after more than one missed 
visit will lead to the censoring of data at the date of last visit with adequate assessment. 
 
The primary PFS comparison between treatment arms will be performed on data derived from the 
ITT population. All patients will be included in the primary PFS efficacy analyses according to the 
arm of randomization, regardless of the actual treatment received. The PFS survival experiences of 
subjects in both treatment arms will be described by the Kaplan-Meier method. Stratified two-sided 
log-rank tests adjusting for stratification factors as defined in the protocol will be the primary 
method to compare PFS between experimental and control arm. As an exploratory analysis, a Cox 
proportional hazards model will be used to identify and adjust for factors significantly related to 
progression free survival. 
 
A pre-specified secondary analysis for PFS in the PIK3CA/PTEN/AKT1 altered status subset will 
be tested using a hierarchical testing procedure [Hung, 2007]. If the result for PFS in the ITT patient 
population is significant at a 0.05 level, then PFS will be tested in the PIK3CA/PTEN/AKT1 altered 
status subset under the same 0.05 significance level. If this criterion for the PFS comparison is not 
met in the ITT population, no further testing for the PFS comparison will be performed in the 
PIK3CA/PTEN/AKT1 altered status subgroup. 
 
 

 
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13.3 
Secondary Endpoints and Analyses 
 
All efficacy endpoints will be compared between arms in the ITT population with exploratory 
analyses in the PIK3CA/PTEN/AKT1 altered status and/or wildtype/unknown. 
 
Response rate (RR) per RECIST 1.1 is defined as the number of responders (complete response 
and partial response) as a percentage of all the randomized patients. The 95% confidence intervals 
for the response rate will be calculated for each arm. The difference of response rate between two 
arms and the corresponding 95% confidence interval will be obtained by the asymptotic normal 
approximation. 
 
Duration of Response (DoR) will be calculated for patients with a best response of CR or PR as per 
RECIST 1.1 criteria. DoR is measured from the date of first evidence of CR or PR to the date of 
objective progression or the date of death due to any cause, whichever is earlier. A Kaplan-Meier 
analysis of duration of response will be performed to describe the experience of both treatment 
arms. 
 
Clinical Benefit Rate (CBR) will be calculated for patients with a best overall response of CR, PR 
or SD (≥ 6 months) as per RECIST 1.1 criteria as a percentage of all randomized patients. The 95% 
confidence intervals for the CBR will be calculated for each treatment arm. The difference of CBR 
between the two treatment arms and the corresponding 95% confidence interval will be obtained 
by the asymptotic normal approximation. 
 
Overall Survival (OS), defined as time from randomization to the time when death from any cause 
is documented, will be analysed similar to PFS. 
 
Time to commencement of subsequent line of systemic therapy or death (TSST) is defined as time 
from randomization to the time of subsequent treatment commencement or death, whichever comes 
first. TSST will be censored at the date of last known alive without commencement of subsequent 
line of systemic therapy. TSST will be analyzed similar to the PFS endpoint using the time-to-event 
methods such as the KM curves and stratified long-rank test. 
 
The safety population will consist of patients who received at least one dose of study treatment, 
and will be based on the actual treatment received if this differs from randomized treatment 
assignment. All subjects will be evaluated for toxicity from the time of their first dose of study 
medication. Toxicities will be graded using the CTCAE version 5.0. The incidence of toxicities by 
treatment will be summarized by type of adverse event and severity. A Fisher’s Exact Test will be 
used to compare selected toxicities between two arms. 
 
Quality of Life and Health Economics analyses are defined in Sections 13.7 and 13.8. 
 
 

 
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13.4 
Sample Size and Duration of Study 
 
The statistical assumptions for the control arm are based on the median PFS of 4.8 months in the 
control arm of FAKTION (though no prior CDK 4/6 inhibitor exposure in this trial) and the median 
PFS of 5.6 months in the control arm of SOLAR-1 (6% prior CDK 4/6 inhibitor exposure). Thus 
we assume an H0 median PFS of 4.5 months for the placebo + fulvestrant arm. Assuming a 
projected hazard ratio (HR) of 0.60 of benefit and thus a projected median PFS of 7.5 months in 
the ipatasertib and fulvestrant arm (H1 median PFS of 7.5 months) with an α = 0.05 (2-sided) and 
92% power, a total of 250 randomized patients (ITT population) will be required. The duration of 
enrolment will be 24 months with 30 additional months for follow-up for the secondary and overall 
survival end points. A total of 175 events will be required to trigger the final analysis for PFS, 
which is estimated to occur 6 months after the final patient is enrolled. If PFS is significant for the 
ITT population at 0.05 level, then the pre-specified secondary analysis for the altered subgroup will 
be conducted. Assuming that the incidence rate of mutations is 45% and two-sided alpha = 0.05, 
the power to detect a hazard ratio of 0.50 (median PFS 3.5 months versus 7.0 months) will be 87% 
with a total of 79 PFS events. 
 
For the secondary endpoint of OS, it is estimated that 76 deaths will have occurred at the time of 
the final PFS analysis. This will provide 34% power to establish an OS benefit with an assumed 
HR of 0.70 for OS. This projection is based on an estimated median OS in the control arm of 30 
months and a projected median OS of 42.86 months in the ipatasertib + fulvestrant arm.  
 
An additional OS analysis is planned when 155 deaths are observed. This will provide 60% power 
to establish an OS benefit with an assumed HR of 0.70 for OS (duration of follow-up of 30 months). 
These projections are based on an estimated median OS in the control arm of 30 months and a 
projected median OS of 42.86 months in the ipatasertib + fulvestrant arm. 
 
13.5 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators’ meetings. 
 
The CCTG Data Safety Monitoring Committee (DSMC) will review progress and safety data 
(including SAEs and fatal SAEs) bi-annually. 
 
13.6 
Interim Analysis 
 
No interim analysis is planned for this study. 
 
13.7 
Quality of Life Analysis 
 
Scoring of the EORTC QLQ-C30 will be done according to the scoring manual. Missing 
questionnaires will be calculated and the proportion of expected questionnaire completion at each 
time point will be reported. Management of missing data within questionnaires will follow the 
scoring manual. Standard CCTG statistical analysis for QOL/PRO will be done [Osoba, 2005] 
 
For the PRO-CTCAE, item responses are scored from 0 to 4 and there are no guidelines on how to 
combine the scores for a symptom nor for the longitudinal analysis. Developers recommend that 
the data should be reported at least descriptively at a minimum and along with the CTCAE grades 
for the corresponding period. The proportion of missing data should also be summarized 
(https://healthcaredelivery.cancer.gov/pro-ctcae/faqs.html). 
 
 

 
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For the main QOL analysis, we will compare the difference in overall QOL between baseline and 
8 weeks between the 2 treatment arms. We hypothesized that if there is improved PFS in the 
combination arm of ipatasertib and fulvestrant, there will be no worsening in overall QOL. 
 
With a sample size of 200 patients (based on an estimate of 20% non-compliance to questionnaire 
completion), we will have a 80% power with a 2-sided alpha error of 5% to detect an effect size of 
0.40 for the difference in overall QOL on the EORTC QLQ-C30 at 8 weeks.  
 
We will not adjust for multiple comparisons for the other comparisons of other EORTC QLQ-C30 
subscales or PRO-CTCAE symptoms. 
 
The mean and standard deviation of each QOL domain/item score at baseline and mean and 
standard deviation of QOL change score from baseline at each assessment time will be calculated. 
Then Wilcoxon Rank-Sum test will be used to compare the two treatment arms in terms of change 
in QOL score at each assessment time from baseline. 
 
The profile of change scores over time for diarrhea, rash, fatigue and pain between the treatment 
arms will be compared using a generalized linear mixed model. The presence of a treatment by 
time interaction will be tested if the interaction effect is significant, treatment differences will be 
tested at each time point. 
 
Four specific symptoms/toxicities from the PROCTC AE will be compared between the treatment 
arms: diarrhea, rash, fatigue and pain. These will be compared using the Fisher’s exact test.  
 
13.8 
Health Economics Analysis 
 
We will embed an economic evaluation nested within the trial framework to determine the 
incremental costs and benefits (life years, quality adjusted life years) across the two treatment arms. 
This analysis will be performed from both a health system and a societal perspective. 
 
The economic evaluation will estimate the model outcomes within the trial period, and a subsequent 
modelled analysis will be performed to estimate the costs and outcomes beyond the period of the 
trial over the estimated lifetime of the study participants. Additional data inputs from the modelled 
analysis that are unavailable through the trial will be estimated from the published literature and 
from expert consultation. Cox proportional hazards regression will be used to estimate survival 
endpoints to allow for the adjustment of different follow-up and survival among participants. 
Uncertainty will be characterized using 95% confidence intervals and non-parametric 
bootstrapping methods. Due to the potential that time-preference could drive both the costs and 
benefit, a standard discount rate of 5% will be applied to both and will be subject to sensitivity 
analysis. The discount rate as well as other potential drivers of costs and benefit will additionally 
be evaluated in one-way sensitivity analyses. 
 
 

 
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Cost estimates will be based on both the health system and societal resources utilized by subjects 
in the trial. Health system resources will be identified as, but not limited to, clinic visits, treatments 
(radiation, surgery), physician encounters, hospitalizations related to treatment and complications, 
emergent visits and diagnostics. These resources will be based on the trial protocol and data 
collected during the trial itself. Societal resources will be identified as, but not limited to, lost 
productivity related to treatment (e.g. time off work, change in status), and any significant out-of-
pocket subject expenses (e.g. medications, travel, parking). These resources will be based on patient 
specific data collected alongside the quality of life portion of the study. Health system and societal 
resources will be quantified over the course of the trial to generate utilization information by 
patients in each study arm, which will be valued with health system unit costs (e.g. formularies, 
public sources) and societal unit costs (e.g. income). We will generate an average cost per study 
subject by treatment arm to estimate an overall mean cost per study arm. 
 
If the efficacy results are different between the two treatment arms, we will conduct a cost 
effectiveness analysis, evaluating both incremental costs and clinical outcomes (e.g., survival). If 
there is no significant clinical benefit, we anticipate that there will be differences in QOL between 
the two treatment arms and will conduct a cost-utility analysis. This cost-utility analysis will 
estimate the quality adjusted life years (QALY) gained from treatment with ipatasertib and 
fulvestrant compared to fulvestrant alone. This will be determined by combining the health 
preference value of each health state and the time frame in which one experiences that health state 
in both study arms. Health preferences will be measured with the EQ-5D-5L, which is a well-used 
and standardized measure of health status for economic analyses (https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf). The EQ-5D-5L will be collected 
alongside the study QOL instrument. 
 
The budget impact of introducing ipatasertib will be estimated by assessing the cost per patient and 
the number of patients per year. 
 
Sensitivity analyses will be conducted on the estimated costs and benefit to test the robustness of 
the incremental ratios calculated. 
 
 

 
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14.0 
PUBLICATION POLICY 
 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
14.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group and Hoffman La-Roche 
Ltd. 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. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
• 
In the event of a separate paper dealing with the economic outcomes, the first author will 
generally be the Health Economics Coordinator on the trial committee. 
• 
In the event of a separate paper dealing with the correlative studies outcomes, the first author 
will generally be the Correlative Sciences Chair on the trial committee. 
 
14.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
“A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions).” 
 
14.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following the analysis of study results the 
draft is not substantially complete, 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, language, linguistic proficiency, age, religion, race, national or ethnic origin, 
colour, disability (except incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, 
or criminal record, unless there is a valid reason (i.e. safety) for the exclusion. 
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs. 
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately. 
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs. 
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable). 
 
Subjects who were competent at the time of enrollment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation. 
 
 

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

 
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Obtaining Consent for Exposure Reporting 
 
Information from and/or about the subject (i.e. the exposed individual) should not be collected from 
and/or about 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 and/or from them.  
 
A trial-specific consent form for “Exposure Follow-up” can be found on the trial webpage. The 
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 a refusal or withdrawal of 
permission to provide information related to the exposure. 
 
Obtaining Consent for Research on Children 
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian. 
 
For reporting an exposure, the parent/guardian is required to sign an “Exposure Follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
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. 
 
 

 
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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. 
 
For international participating regions, local regulatory guidance should be followed with respect 
to duration of records retention, unless otherwise contractually dictated. 
 
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 
 
This trial is registrational and will be conducted under the intensive monitoring program. 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. 
 
Participating centres may be subject to an inspection by regulatory authorities and audits by CCTG, 
Hoffman-La Roche Ltd. or by the Group responsible for oversight of participating centres. Audits 
may only be conducted after consultation with CCTG. 
 
 

 
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2002;13:444−51. 
 
 

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

 
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APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Distribution for Canadian sites 
 
Details of drug distribution, supply and control/accountability are provided in the MA.40 Pharmacy 
Information Manual available on the MA.40 trial website. 
 
Ipatasertib/placebo and fulvestrant are supplied by Roche to the CCTG distributor Bay Area Research 
Logistics (BARL) and will be distributed by BARL to participating sites in Canada. 
 
A start up supply of ipatasertib/placebo and fulvestrant will be distributed to the activated site 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. Sites should allow for 5 working days for drug 
shipments to arrive. 
 
Investigational product should be stored in a secure area according to local regulations and under the storage 
conditions stipulated on the investigational product label. 
 
Resupply 
 
For re-supply of fulvestrant, sites should submit a Request for Drug Shipment Form (available on the 
MA.40 website). This form should be submitted directly to BARL as per the instructions provided on the 
form. Once received, BARL will process the request and initiate shipment of re-supply. Sites should allow 
for 5 working days for shipment to arrive. 
 
Ipatasertib/placebo stock will be re-supplied automatically as treatment kits are used. 
 
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 MA.40 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 by the monitor and a drug destruction log has been issued. 
Documentation of destruction must be kept on file in the site pharmacy and is subject to on site 
monitoring/audit. 
 
Drug Destruction of Expired Medication 
The CCTG Study Coordinator must be contacted prior to destruction of expired medication to ensure an 
extension of expiry date is not expected. Expired trial medication may be destroyed per local policy, AFTER 
accountability and reconciliation has been completed by the monitor and a drug destruction log has been 
issued. 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 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. 
At the end of the study, it must be possible to reconcile delivery records with records of usage/returned 
stock by completion of the study drug accountability forms. Any discrepancies must be accounted for. At 
the end of the study, after the monitor has completed drug accountability, a copy of the drug accountability 
forms and drug destruction forms will be kept with the centre files. 
 
** PLEASE NOTE ** 
DRUG FROM THIS SUPPLY IS TO BE USED 
ONLY FOR PATIENTS ENROLLED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite 
pharmacy, provided separate drug accountability records are maintained in each pharmacy and appropriate 
storage is available. Investigational agent may NOT however, be transferred to pharmacies or physicians 
outside the participating centre. 
 
 

 
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APPENDIX III - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of enrollment. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except quality 
of life and health utility questionnaires. Quality of Life and Health Economics Questionnaires will be 
completed on paper by the patient and the answers will be entered into the EDC system by centre staff.  
 
For details of accessing the EDC system and completing the on-line Case Report Forms please refer to the 
“CCTG EDC Generic Data Management Guidebook” posted on the MA.40 area of the CCTG web-site 
(www.ctg.queensu.ca). 
 
The ELECTRONIC CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Required at 
To be completed 
electronically 
Supporting Documentation * 
Mandatory Submission 
To be uploaded immediately after the 
report they refer to has been submitted 
electronically 
Submission On 
Request 
To be uploaded 
immediately after 
request 
Patient Registration 
Prior to registration 
(for stratification) 
At the time of 
registration (for 
stratification) 
• Consent forms** 
• Diagnostic pathology report, 
including ER and HER2 result 
• Baseline radiology reports (e.g. 
CT/MRI chest/abdomen/pelvis, 
bone scan) and/or clinical 
photographs of skin lesions (if 
applicable) 
• Tumour Measurement Worksheet 
• Foundation Medicine genomic 
alteration report from post-
registration analysis 
• ECG report 
• Radiology report 
or clinical 
evidence of 
progression on 
prior CDK 4/6 
inhibitor + AI 
Patient Enrollment 
Prior to enrollment 
At the time of patient 
enrollment/assignment 
to treatment 
Baseline Report 
At the time of 
enrollment 
Within 2 weeks after 
enrollment 
Correlative Studies 
Report 
(Tumour, Blood, 
Digital Images) 
Continuous 
running-log folder 
Update prior to each 
shipment of tumour 
and blood samples. 
Prior to each upload of 
digital images**** 
 
 
Concomitant 
Medications Report 
Continuous running log folder 
 
 
Treatment Report 
Each cycle of 
treatment 
Within 2 weeks after 
completion of each 
cycle 
When applicable: 
Radiology reports from each disease 
assessment (CT/MRI 
chest/abdomen/pelvis, bone scan), 
and/or clinical photographs of skin 
lesions (if applicable), Tumour 
Measurement Worksheet, Patient 
Oral Drug Administration Diary, 
Home Blood Glucose Diary (if 
applicable) 
• ECG report 
End of Treatment 
Report 
At the time of 
permanent 
discontinuation of 
protocol treatment. 
Within 2 weeks after 
permanent 
discontinuation of 
protocol treatment 
 
 
Relapse/Progression 
Report 
At the time of 
objective disease 
progression 
Within 2 weeks of 
knowledge of 
progression 
 
 
 
Table continues on next page … 
 
 

 
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Electronic Folder 
Required at 
To be completed 
electronically 
Supporting Documentation * 
Mandatory Submission 
To be uploaded immediately after the 
report they refer to has been submitted 
electronically 
Submission On 
Request 
To be uploaded 
immediately after 
request 
Follow-up Report 
At each follow up 
visit prior to disease 
progression  
Within 2 weeks after 
visit 
Radiology reports from each disease 
assessment (CT/MRI 
chest/abdomen/pelvis, bone scan), 
and/or clinical photographs of skin 
lesions (if applicable), 
Tumour Measurement Worksheet, 
Home Blood Glucose Diary (if 
applicable)  
• ECG report 
Short Follow-up 
Report 
At each follow-up 
visit after disease 
progression 
Within 2 weeks after 
visit 
Home Blood Glucose Diary (if 
applicable) 
• ECG report 
Death Report 
At the time of patient 
death 
Within 2 weeks after 
knowledge of death 
When applicable: 
Autopsy/post-mortem report/hospital 
discharge summary 
 
Withdrawal of 
Consent 
At the time patient 
has withdrawn 
consent to participate 
in the clinical trial 
AND for further data 
submission 
Within 2 weeks of 
consent withdrawal 
Signed and date clinic note or letter 
to document patient’s withdrawal of 
consent. 
 
AESI report 
At the time of the 
event 
Initial report due 
within 1 working day 
of knowledge of the 
event. Updated report 
required within 10 days 
of the event 
 
All relevant test 
reports, admission 
and discharge 
summaries/notes and 
other documentation 
if requested 
SAE Report*** 
At the time of the 
event 
Initial report due 
within 1 working day 
of knowledge of the 
event. Updated report 
required within 10 days 
of the event 
 
All relevant test 
reports, admission 
and discharge 
summaries/notes and 
other documentation 
if requested 
* 
Scan and upload in the EDC Supporting Document Upload Tool (SDUT) – please refer to the slide set on the MA.40 web page for 
guidance. Source documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, and/or serious 
adverse events. Supporting documents should be uploaded immediately  after the report they refer to has been submitted electronically.  
EDC forms submitted without supporting documentation are not considered submitted and may be reflected in the Centre Performance 
Index (CPI) for Canadian sites. All relevant patient identifiers  and any other prohibited personal information must be fully and completely 
blacked out on all source documentation, as per national and local privacy protection regulations and requirements. Acceptable methods 
include: 
• Fully opaque sticker placed over the identifiers prior to scanning. 
• Electronic black box placed over identifiers in PDF document that is subsequently printed and then scanned (NOTE: do not send the 
unprotected PDF file with black boxes included as these can be moved/removed easily after opening the document). 
• Fully opaque black marker. Please ensure that the information under the marker cannot still be seen on the scanned document (often 
markers are translucent and the identifiers can in fact be seen after scanning). 
• Electronic stripping of identifiers prior to upload 
For quality assurance purposes, supporting documents must include the participant’s trial code, CCTG patient serial number, and participant 
initials or a two/three letter code assigned by your centre. 
** 
Required for Canadian centres: it is acceptable to submit only the signature page(s) of the main consent and only the check box 
page(s)/signature page(s) of the optional consent provided that the version date of the consent form is indicated. Centres are expected to 
redact (black out) the participant’s name and signature on the submitted copy, leaving only a portion visible (e.g. initials or loops) to 
confirm that a person has signed but that cannot identify that individual. 
*** See Section 9.0 Serious Adverse Event Reporting for details. 
**** For details regarding DICOM image upload, please see Digital Imaging Collection Manual posted on the MA.40 web page. 
 
 

 
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The collection of the following information will NOT be done through the EDC system. Instead submit as 
follows: 
 
Data  
Required at 
Collection /Submission 
Comments 
EORTC QLQ-C30 
NCI PRO-CTCAE 
 Baseline 
 Day 1 of cycles 2-4 then at the time of 
imaging for disease assessment 
beginning with the 24 week assessment 
 4 week post-treatment visit 
 At 12 week follow-up visit if patient 
discontinued protocol treatment prior to 
PD and/or with related grade ≥ 3 
toxicities 
 No longer required once patient has 
started a new anti-cancer treatment 
Patient to complete on 
paper; site to enter data 
into EDC system within 
corresponding folders. 
Retain paper 
questionnaires at 
the site. 
EQ-5D-5L 
 Baseline 
 day 1 of every other cycle beginning with 
cycle 3 
 24 months after enrollment 
 at 3, 12, 24, 36, 48 and 60 months of 
follow up. 
 No longer required once patient has 
started a new anti-cancer treatment 
Patient to complete on 
paper; site to enter data 
into EDC system within 
corresponding folders. 
Retain paper 
questionnaires at 
the site. 
 
 
 

 
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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 - QUALITY OF LIFE (AND HEALTH UTILITY) ASSESSMENT(S) 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life and health utility measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data and health utility can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
This study will use three patient-reported questionnaires: 
 
Quality of Life: 
• 
EORTC QLQ-C30, a widely used, cancer specific health-related quality of life questionnaire which 
will be used to capture the multidimensionality of quality of life in advanced breast cancer. 
 
Adverse Events: 
• 
PRO-CTCAE, a validated questionnaire which will provide a patient self-report of adverse events 
 
Health Economics: 
• 
EQ-5D-5L, a health utility instrument 
 
Instructions for Administration of a Quality of Life Questionnaire 
 
1. Preamble 
 
Quality of life and/or health utility data are collected for research purposes, and will usually not be used 
for the patient’s individual medical care. The assessment is in the form of a self report questionnaire. 
Therefore, it must be completed by the patient only, without translation, coaching or suggestions as to 
the "correct" answer by relatives or health care personnel. 
 
 

 
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The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-enrollment (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life and/or health utility questionnaire should be given to the patient before being seen 
by the doctor, and prior to treatment, as required by the schedule in the protocol (up to 3 days prior to 
treatment is acceptable). If the patient does not have a doctor visit scheduled, or if it was not possible 
for the patient to complete the questionnaire before being seen by the doctor, s/he should still complete 
the questionnaire prior to treatment. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire and/or health utility should be given to the patient before being seen 
by the doctor, on follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. In that 
case, you may express sympathy that things are below par, but state that this is exactly the information we 
require if we are to understand more about how quality of life is affected. You may also remind them that 
it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better! 
 
5. What If . . . 
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
 

 
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There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient. 
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over 
the phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible. 
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion. 
 
6. Waiving the Quality of Life and/or Health Utility Component 
 
The only time that we will not require a patient to complete the quality of life and/or health utility 
questionnaires is if s/he cannot comprehend either English or French (or other languages that the 
questionnaire may be available in). In other words, if the assistance of a translator is required to 
comprehend the questions and reply, the questionnaires should not be completed. Translation of the 
questions is not acceptable. Please indicate on questionnaire. 
 
 

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

 
 
Quality of Life Questionnaire – ENGLISH 
 
CCTG Trial: MA.40 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to enrollment (within 7 days) 
During protocol treatment: 
 Day 1 cycle 2      Day 1 cycle 3      Day 1 cycle 4      24 week disease assessment    32 week disease assessment 
 40 week disease assessment      _____ week disease assessment 
Off Treatment: 
 4 weeks post-treatment 
 week 12 follow-up 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:     home     clinic     another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
      yyyy            mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 

This box to be completed by the clinical research associate:            Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.40 
Page 1 of 3 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (MA.40) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:            Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.40 EORTC QLQ-C30 
Page 2 of 3 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:            Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.40. EORTC QLQ-C30 
Page 3 of 3 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
Please check to make sure you have answered all the questions. 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 
 
 

 
 
NCI PRO-CTCAE Questionnaire – ENGLISH 
 
CCTG Trial: MA.40 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to enrollment (within 7 days) 
During protocol treatment: 
 Day 1 cycle 2      Day 1 cycle 3      Day 1 cycle 4     24 week disease assessment    32 week disease assessment 
 40 week disease assessment      _____ week disease assessment 
Off Treatment: 
 4 weeks post-treatment 
 week 12 follow-up 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:     home     clinic     another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy           mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 
 

This box to be completed by the clinical research associate:            Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.40 
Page 1 of 2 
Please go on to the next page 
NCI PRO-CTCAETM Item Library Version 1.0 
NCI PRO-CTCAE - MA.40 
 
As individuals go through treatment for their cancer they sometimes experience different symptoms and side effects. For 
each question, please check or mark an X in the one box that best describes your experiences over the past 7 days... 
 
1. 
In the last 7 days, how OFTEN did you have BLOATING OF THE ABDOMEN (BELLY)? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
1a. In the last 7 days, what was the SEVERITY of your BLOATING OF THE ABDOMEN (BELLY) at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
2. 
In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA/DIARRHOEA)? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
 
3. 
In the last 7 days, how OFTEN did you have PAIN IN THE ABDOMEN (BELLY AREA)? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
3a. In the last 7 days, what was the SEVERITY of your PAIN IN THE ABDOMEN (BELLY AREA) at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
3b. In the last 7 days, how much did PAIN IN THE ABDOMEN (BELLY AREA) INTERFERE with your usual or 
daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
4. 
In the last 7 days, how OFTEN did you LOSE CONTROL OF BOWEL MOVEMENTS? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
4a. In the last 7 days, how much did LOSS OF CONTROL OF BOWEL MOVEMENTS INTERFERE with your usual 
or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
5. 
In the last 7 days, did you have any RASH? 
 Yes 
 No 
 
6. 
In the last 7 days, what was the SEVERITY of your DRY SKIN at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
7. 
In the last 7 days, how OFTEN did you have PAIN? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
Almost constantly 
7a. In the last 7 days, what was the SEVERITY of your PAIN at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
7b. In the last 7 days, how much did PAIN INTERFERE with your usual or daily activities? 
 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
 
 

This box to be completed by the clinical research associate:            Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.40 
Page 2 of 2 
NCI PRO-CTCAETM Item Library Version 1.0 
 
8. 
In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF ENERGY at its 
WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
8a. In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY INTERFERE with your 
usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
Do you have any other symptoms that you wish to report? 
 Yes 
 No 
Please list any other symptoms: 
 
 
 
 
 
 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
Thank you for completing this questionnaire! 
 
Please check to make sure you have answered all the questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
 
 

 
 
EQ-5D-5L 
 
Health Utilities Questionnaire – ENGLISH 
 
CCTG Trial: MA.40 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to enrollment (within 7 days) 
During protocol treatment (required after every second cycle): 
 Day 1 cycle 3      Day 1 cycle 5      Day 1 cycle 7      Day 1 cycle 9      Day 1 cycle _____ 
 24 months after registration  
Off Treatment – (required at 3, 12, 24, 36, 48 and 60 months of follow up): 
 3 months     12 months    24 months    36 months    48 months    60 months 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:     home     clinic     another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy           mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 
 

This box to be completed by the clinical research associate:            Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.40 
Page 1 of 2 
Please go on to the next page 
 
© 2009 EuroQol Group EQ-5D-5L™ 
EQ-5D-5L Questionnaire 
 
CCTG : MA.40 
 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems in walking about 
 
I have slight problems in walking about 
 
I have moderate problems in walking about 
 
I have severe problems in walking about 
 
I am unable to walk about 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 

 
CCTG Trial MA.40 
Page 2 of 2 
 
 
© 2009 EuroQol Group EQ-5D-5L™ 
The worst health 
you can imagine 
 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please check to make sure you have answered all questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you. 
 
YOUR HEALTH TODAY = 
10
0 
20
30
40
50
60
80
70
90
100 
5 
15
25
35
45
55
75
65
85
95
The best health you 
can imagine 

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

 
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APPENDIX VII - EXAMPLES OF STRONG AND MODERATE CYP3A INHIBITORS AND STRONG 
CYP3A INDUCERS 
 
This table is to provide examples and is not intended to be a complete list; names may vary in different 
locations. 
 
Strong CYP3A inhibitors 
Moderate CYP3A inhibitors 
Strong CYP3A inducers 
VIEKIRA PAK1* 
erythromycin* 
rifampin* 
indinavir* 
fluconazole* 
mitotane* 
tipranavir* 
darunavir 
avasimibe 
ritonavir* 
dronedarone* 
rifapentine 
cobicistat* 
crizotinib* 
apalutamide 
ketoconazole* 
atazanavir 
phenytoin* 
idelalisib* 
letermovir 
carbamazepine* 
troleandomycin* 
GSK2647544 
enzalutamide* 
telaprevir* 
aprepitant* 
St John's Wort3* 
danoprevir* 
casopitant 
lumacaftor 
elvitegravir* 
amprenavir 
rifabutin 
lopinavir* 
faldaprevir 
phenobarbital 
itraconazole* 
imatinib* 
 
voriconazole* 
verapamil* 
 
mibefradil 
netupitant 
 
LCL161 
nilotinib 
 
clarithromycin* 
grapefruit juice2 
 
posaconazole* 
tofisopam* 
 
telithromycin* 
cyclosporine* 
 
grapefruit juice2 
ACT-178882 
 
conivaptan* 
ciprofloxacin* 
 
nefazodone* 
magnolia vine (Schisandra sphenanthera)  
nelfinavir* 
isavuconazole 
 
saquinavir* 
cimetidine* 
 
ribociclib 
FK1706 
 
diltiazem* 
clotrimazole* 
 
boceprevir* 
fluvoxamine* 
 
1  VIEKIRA PAK = paritaprevir/ritonavir + ombitasvir + dasabuvir 
2  The effect of grapefruit juice varies widely among brands and is concentration, dose, and preparation-dependent. Studies 
have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g. high dose, 
double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g. low dose, single strength) 
3  The effect of St. John’s wort varies widely and is preparation-dependent. 
*  Drugs listed in FDA website 
 
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm 
 
This table is prepared to provide examples of clinical inhibitors and inducers of CYP3A. Data were collected based 
on a search of the University of Washington Drug Interaction Database 
 
 

 
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APPENDIX VIII - BLINDING / UNBLINDING 
 
Ipatasertib and matching placebo are identical in appearance as are the bottles in which they are provided. 
Blinding is critical to the integrity of this clinical drug trial. However, in the event of a medical emergency 
in an individual subject, in which knowledge of the investigational product is critical to the subject's urgent 
management, the blind for that subject may be broken by the treating physician. Before breaking the blind 
of an individual subject's blinded treatment, the Investigator should have determined that the information 
is necessary, i.e. that it will alter the subject's immediate management. In many cases, particularly when the 
emergency is clearly not investigational product related, the problem may be properly managed by 
assuming that the subject is receiving active product without the need for unblinding (i.e. almost all urgent 
situations can be managed by discontinuing study drug). 
 
If a patient is unblinded, they are considered to be off ipatasertib/placebo treatment. Therefore the need to 
break the blind must first be discussed and approved by the CCTG. For any treatment code unblinding, the 
reason and parties involved must be documented in the patient’s medical record. Treatment identification 
information should be kept confidential. 
 
Please note: Requests to unblind for information only or to permit participation in other clinical trials will 
not be considered until the trial has been unblinded and reported. 
 
Unblinding Procedure: 
 
To unblind the treatment for a patient you must contact CCTG. 
 
From 8am-4pm (EST): Please send an email to the Study Coordinator or Senior Investigator including the 
trial code, patient identification, patient initials, last treatment kit (if applicable) and the reason for the 
unblinding request. Once approval is obtained from the Senior Investigator, authorized personnel at CCTG 
will unblind the patient and send the unblinding information via email to the Investigator who requested 
the unblinding. 
 
From 4pm-8am (EST) and statutory holidays: Please phone the following number as appropriate: 
North America calls:  
833-896-9955 Toll Free 
International calls:  
613-507-3861 
Note that the country code for Canada is “1”. 
 
You will be required to provide basic information regarding the trial code, patient identification, last 
treatment kit (if applicable), and the reason for the unblinding request as well as contact information of the 
caller (and the Investigator/treating physician to whom the information is to be relayed if different from the 
caller). The unblinding information will be conveyed to the Investigator by phone and may also be followed 
with a confirmation email or fax. 
 
 

 
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APPENDIX IX - 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 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. 
 

 
PROTOCOL ADMINISTRATIVE UPDATE #2: 2023-APR-19 
 
CCTG TRIAL: MA.40 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Lisa Gallinaro 
Study Coordinator, CCTG 
Email: lgallinaro@ctg.queensu.ca 
613-533-6430 
613-533-2941 
Dr. Wendy Parulekar 
Senior Investigator, CCTG 
Email: wparulekar@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Stephen Chia 
Study Chair 
Email: schia@bccancer.bc.ca 
604-877-6000 
604-877-6107 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for 
details of reportable events. 
Dr. Wendy Parulekar 
Senior Investigator, CCTG 
or: 
Lisa Gallinaro 
Study Coordinator, CCTG 
613-533-6430 
613-533-2941 
DRUG ORDERING 
(Canadian Sites) 
See Appendix II for full details. 
Fulvestrant 
Manual re-supply via: 
Bay Area Research Logistics 
 
Email: barl@barl.ca 
905-527-1938 
905-527-1196 
Ipatasertib/placebo: 
Automatic re-supply via Mango : 
Lisa Gallinaro 
Study Coordinator, CCTG 
Email: lgallinaro@ctg.queensu.ca 
613-533-6430 
613-533-2941 
REQUESTS FOR 
UNBLINDING 
During office hours (8 am-4 pm EST): 
Lisa Gallinaro 
Study Coordinator, CCTG 
Email: lgallinaro@ctg.queensu.ca 
or: 
Dr. Wendy Parulekar 
Senior Investigator, CCTG 
Email: wparulekar@ctg.queensu.ca 
613-533-6430 
613-533-2941 
After office hours (4 pm-8 am EST) and statutory holidays: 
 
North American calls (toll free): 833-896-9955 
International calls: 613‐507-3381 
Note that the country code for Canada is “1”.