Multicentre Study to Determine the Feasibility of Using an Integrated Consent Model to Compare Three Standard of Care Regimens for The Treatment of Triple-Negative Breast Cancer in the Neoadjuvant/Adjuvant Setting (REaCT-TNBC) OTT 15-04
Phase: PHASE4
Conditions: Breast Cancer
Sponsor: Ottawa Hospital Research Institute

Multicentre Study to Determine the Feasibility of using an Integrated Consent Model to 
Compare Three Standard of Care Regimens for The Treatment of Triple-Negative Breast 
Cancer in the Neoadjuvant/Adjuvant Setting (REaCT-TNBC) OTT 15-04 
 
 
 
Coordinating Centre:  
 
The Ottawa Hospital Cancer Centre 
 
Other Participating Centres: 
Kingston General Hospital (Andrew Robinson, PI) 
 
 
 
 
 
 
Qualified Investigator:  
 
John Hilton, MD, FRCPC 
 
 
 
 
 
The Ottawa Hospital Cancer Centre 
 
 
 
 
 
E-mail: jfhilton@toh.on.ca 
 
Study Team: Mark Clemons, Sasha Mazzarello, Dean Fergusson, Andrew Robinson (Kingston 
General Hospital) 
 
Funding provided by: Internal funding 
 
 
 
 
 
Protocol Version May 4, 2016 
 
 

Protocol Version May 4, 2016 
 
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PROTOCOL SIGNATURE PAGE 
 
My signature below confirms that I have reviewed and approved this protocol, and agree that it 
contains all necessary details for carrying out the study as described. I will conduct this protocol 
as outlined therein, and according to Good Clinical Practice and all applicable local regulations 
 
 
 
 
 
 
 
 
 
 
Qualified Investigator (Please Print) 
 
 
 
 
 
 
 
 
 
 
 
Qualified Investigator Signature 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 

Protocol Version May 4, 2016 
 
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Table of Contents 
 
1 
BACKGROUND ..................................................................................................................... 4 
2 
OBJECTIVES .......................................................................................................................... 7 
2.1 
Primary objective ............................................................................................................. 7 
2.2 
Secondary objective ......................................................................................................... 7 
3 
STUDY DESIGN .................................................................................................................... 7 
4 
METHODS .............................................................................................................................. 7 
5 
CONSENT PROCESS ............................................................................................................ 8 
6 
ELIGIBILITY ........................................................................................................................ 11 
6.1 
Inclusion Criteria ............................................................................................................ 11 
6.2 
Exclusion Criteria ........................................................................................................... 11 
7 
RANDOMIZATION ............................................................................................................. 11 
8 
DATA COLLECTION .......................................................................................................... 11 
9 
OUTCOMES ......................................................................................................................... 12 
9.1 
Primary Outcome ........................................................................................................... 12 
9.2 
Secondary outcome ........................................................................................................ 13 
10 
RISKS ................................................................................................................................ 13 
11 
SAFETY REPORTING ..................................................................................................... 13 
12 
MONITORING .................................................................................................................. 13 
13 
CRITERIA FOR FEASABILITY SUCCESS ................................................................... 13 
14 
PREMATURE WITHDRAWAL ...................................................................................... 14 
15 
SAMPLE SIZE AND STATISTICAL ANALYSIS ......................................................... 14 
16 
References .......................................................................................................................... 15 
 
 

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1 
BACKGROUND 
Disease of Interest 
Triple-negative breast cancer (TNBC) is a term applied to breast cancer cases that have 
<1% expression of the estrogen receptor (ER) and the progesterone receptor (PR) and do not 
over express HER2 [1, 2].  TNBC is diagnosed in 15-20% of breast cancer cases and tends to 
occur in younger women [3] and have biologically more aggressive high grade disease [4]. 
Clinically, patients with TNBC have a poorer prognosis compared to patients diagnosed with 
other breast cancer subtypes [5].  Because of the aggressive phenotype and due to observations 
that systemic chemotherapy offers significantly higher benefit in ER negative disease, current 
treatment guidelines from provincial and other organizations [6, 7] recommend that patients 
receive adjuvant systemic chemotherapy for any TNBC greater than 0.5 cm in greatest diameter 
or node positive independent of primary tumor size [8]. 
Currently, there is no world-wide standard recommended chemotherapy regimen for the 
management of TNBC in the neoadjuvant/adjuvant setting, with treatments varying from region 
and institution.  Although multiple adjuvant regimens have been tested in phase III trials, based 
on guideline recommendations, three chemotherapy regimens are most frequently prescribed for 
for TNBC in the province of Ontario: 
1. 
Dose dense AC-P (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 q2weeks x 
4 cycles followed by paclitaxel 175 mg/m2 q2weeks x 4 cycles) [9] 
2. 
Dose dense AC followed by weekly P (doxorubicin 60 mg/m2 plus cyclophosphamide 
600 mg/m2 q2weeks x 4 cycles followed by paclitaxel 80 mg/m2 weekly x 12 cycles) [10] 
3. 
FEC-D (5-FU 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 
q3weeks x 3 cycles followed by docetaxel 100 mg/m2 q3weeks x 3 cycles) [11] 
Although these regimens are widely used and effective, at the current time, they have never been 
compared head to head in patients with TNBC. Indeed, as all these chemotherapy regimens are 
funded in Canada, there is no pharmaceutical company interested in funding such a trial.  
Therefore, there is significant clinical equipoise regarding the best management of these patients. 

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Quite simply neither patients nor physicians know which is the best of these 3 standard of 
care regimens to receive for the most aggressive type of breast cancer. 
Issues Regarding Clinical Trial Design 
When new cancer treatments are developed, they are usually tested in randomized clinical trials 
(RCTs), where they are directly compared with either a placebo or an established treatment. The 
results of these usually pharmaceutical company funded trials establish the new treatments as 
being: better, worse or more commonly equivalent to established therapies. As a result, in 
clinical practice, physicians may be faced with multiple funded “standards of care”. The reason 
why comparative standard of care treatment trials are rarely conducted is multifactorial. One of 
the major barriers is expense. It is incredibly expensive to perform clinical trials as their 
regulatory oversight (patient consent, REB submission, contracts, drug costs, research 
coordination and management, data collection of multiple often superfluous endpoints, analysis) 
has been designed around trials of new agents or established agents for new indications. While 
these types of studies are also time-consuming, there are sometimes only modest differences 
between treatment arms. Given that these trials are usually pharmaceutical company funded, they 
can take many years to start and complete.  
As physicians do not know what the “best” treatment for patients is, genuine uncertainty 
(“clinical equipoise”) exists. Physicians will choose between different “standards” in their 
personal practice, using idiosyncratic decision making processes, without the physician or the 
patient knowing the optimal option. This is not good for patients, physicians and society as a 
whole. Determining the optimal treatment remains an important medical issue for patients, 
physicians and society. This study will survey opinions on a novel method to allow comparisons 
of established standard of care prophylactic treatment using the “integrated consent model” as 
part of a pragmatic clinical trial [12]. By integrating medical and clinical practices, physicians 
will be able to inform their patients about the RCT, akin to a typical conversation between the 
physician and patient, without written informed consent. This clinical interaction would then be 
documented, as ordinarily done in practice, in the patient’s electronic medical record. Medical 
and clinical practice will be intertwined with the patients’ welfare at the forefront of our best 
interests. 

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There is increasing attention being given to pragmatic clinical trials which commonly 
incorporate comparative effectiveness research – that is, comparing the safety and effectiveness 
of diagnostic, therapeutic or delivery systems – can help overcome these challenges. These 
studies, in addition to the ability to leverage patient data from electronic health records to 
increase sample size of trials at much lower costs, is enabling major national and international 
initiatives to generate the data needed to improve care [13]. Thus the Integrated Consent Model 
is being increasingly used internationally to improve patient care [12, 13]. We have already 
performed a highly successful feasibility study in Ottawa (approved through the local REB) 
using the Integrated Consent Model to randomise patients receiving TC chemotherapy between 
G-CSF and ciprofloxacin primary prophylaxis. These are both established and funded standard 
of care treatments. Feasibility has been demonstrated by successful REB approval, patient and 
physician engagement in the randomisation process, as well as the collection of results through 
established hospital datasets.  In addition, a second study using the Integrated Consent Model 
designed by our research team has received provincial IRB approval, demonstrating that this 
strategy is becoming widely accepted.  
This current proposal is similar as all three chemotherapy agents are widely and commonly 
used with no head to head data. All three consist of an anthracycline (i.e. Adriamycin or 
epirubin) in combination with cyclophosphamide for 8-12 weeks followed by a taxane (i.e. 
docetaxel or paclitaxel) for 8 to 12 weeks. The side effects are the same; nausea, vomiting, 
fatigue, febrile neutropenia, myalgias, mucositis, cardiotoxicity and leukaemia. All are given 
with standard and anti-emetics for the control of nausea/vomiting as well as concurrent 
haematopoeitic growth factor support to reduce the risk of febrile neutropenia.  
We surveyed oncologists who treat breast cancer at the Ottawa Hospital Cancer Centre.  
Universally (100% of replies), there was great interest in comparing dose-dense AC-P with FEC-
D; or a 3-arm study.  This compares well to an informal survey of medical oncologists from 
across Canada (n=27); when asked to only select one option, 41% would enroll patients on a 
TNBC study comparing dose-dense AC-P with FEC-D while 44% would prefer a study which 
evaluated all three of the above regimens (i.e. dose-dense AC-P, FEC-D of Dose dense AC 
followed by weekly P). 

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2 
OBJECTIVES  
2.1 
Primary objective 
To assess the feasibility and physician acceptance of performing a pragmatic multi-centre 
clinical trial with an Integrated Consent Model for evaluating different standards for  
neoadjuvant/adjuvant chemotherapy regimens for patients with curable TNBC. Feasibility will 
be reflected through composite endpoints including; physician engagement, accrual rates, 
physician compliance and satisfaction, and patient satisfaction.  
2.2 
Secondary objectives 
• Proportion of patients completing all their chemotherapy 
• Adverse effects requiring hospitalization/treatment delays (e.g. febrile neutropenia) 
3 
STUDY DESIGN 
This will be a multicenter-center open label randomized trial.  
4 
METHODS 
Investigators will approach potentially eligible breast cancer patients who are planned to receive 
chemotherapy to treat TNBC in the neoadjuvant/adjuvant setting. The physician will inform their 
patient about the RCT study, akin to a typical conversation between the physician and patient. 
Eligible and consented patients will be randomized using a permeated block design developed by 
The Ottawa Hospital’s Methods Centre to receive one of either: 
1. 
Dose dense AC-P (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 q2weeks x 
4 cycles followed by paclitaxel 175 mg/m2 q2weeks x 4 cycles) [9] 
2. 
Dose dense AC followed by weekly P (doxorubicin 60 mg/m2 plus cyclophosphamide 
600 mg/m2 q2weeks x 4 cycles followed by paclitaxel 80 mg/m2 weekly x 12 cycles) [10] 
3. 
FEC-D (5-FU 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 
q3weeks x 3 cycles followed by docetaxel 100 mg/m2 q3weeks x 3 cycles) [11] 
Patients will be stratified by lymph node status and neoadjuvant/adjuvant administration of 
chemotherapy. 

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In clinical practice, patients do not switch from regimen to regimen as each one is designed as 
comprehensive care for TNBC and essentially contain the same backbone (anthracycline/taxane).  
In addition, in Ontario, an alternative funding source would need to be found as funding is for 
only the initial primary regimen as per Cancer Care Ontario guidelines.  In these very rare 
situations when there needs to be a switch in therapy, it will be because of a compelling medical 
reason that prohibits the administration of an anthracycline or taxane.  In these situations, 
patients tend to use non-standard of care regimens not included in the study as determined by 
their primary oncologist.  As these issues are rare and the benefit of switching to a non-standard 
of care regimen uncertain, this will not be allowed in this study unless patient safety is of issue 
(this is not different from standard clinical practice).   
5 
CONSENT PROCESS 
In this study the investigator will obtain oral consent using the following prepared REB approved 
script. 
Multicentre Study to Determine the Feasibility of using an Integrated Consent Model to 
Compare Three Standard of Care Regimens for The Treatment of Triple-Negative Breast 
Cancer in the Neoadjuvant/Adjuvant Setting (REaCT-TNBC) OTT 15-04 
 
“Our discussion today is a new approach of informing and consenting patients to participate in 
this study. The traditional approach is to provide a paper copy of the detailed information sheet 
and consent form for you to sign. Using this new integrated model for consenting we will have a 
discussion and you may give a verbal consent to participate or not to participate. I will document 
our discussion and your decision in your progress note that is part of your health record. 
 
As we've talked about, you will be receiving chemotherapy for your breast cancer. Currently, 
there are a number of different approved regimens which are used throughout the world to treat 
your type of breast cancer.   
1. 
Dose dense AC-P (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 q2weeks x 
4 cycles followed by paclitaxel 175 mg/m2 q2weeks x 4 cycles)  

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2. 
Dose dense AC followed by weekly P (doxorubicin 60 mg/m2 plus cyclophosphamide 
600 mg/m2 q2weeks x 4 cycles followed by paclitaxel 80 mg/m2 weekly x 12 cycles)  
3. 
FEC-D (5-FU 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 
q3weeks x 3 cycles followed by docetaxel 100 mg/m2 q3weeks x 3 cycles)  
In clinical practice, patients do not switch from regimen to regimen as each one is designed as 
comprehensive care for TNBC and essentially contain the same backbone (anthracycline/taxane).  
In addition, in Ontario, an alternative funding source would need to be found as funding is for 
only the initial primary regimen as per Cancer Care Ontario guidelines.  In these very rare 
situations when there needs to be a switch in therapy, it will be because of a compelling medical 
reason that prohibits the administration of an anthracycline or taxane.  In these situations, 
patients tend to use non-standard of care regimens not included in the study as determined by 
their primary oncologist.  As these issues are rare and the benefit of switching to a non-standard 
of care regimen uncertain, this will not be allowed in this study unless patient safety is of issue 
(this is not different from standard clinical practice).  
 Because all of these regimens represent standards of care, I can treat you with any one of these 
different chemotherapy regimens.   Because we really don't know if one is better than the other, 
some of the Oncologists at The Ottawa Hospital Cancer Centre are doing this study by randomly 
assigning (like pulling a name out of a hat, so that we can obtain an unbiased answer) 
participants to one of the standards of care and then comparing results over a period of 1 year. 
We are also looking at how feasible it is for study doctors to enter participants on this study 
using this integrated consent model. If you choose to participate there won't be any special 
procedures or visits and you will receive a copy of this document for your reference. If you do 
participate and decide to stop your participation in the study you may do so but it will not be 
feasible to switch you to one of the other regimens offered in this study as this is not permitted 
by Cancer Care Ontario, even if one does not participate in this study. If this occurs, potential 
treatment options will be discussed with you by your treating oncologist as the options will be 
very specific to your medical situation. 
At the end of the study, there will be a satisfaction survey for you to complete,  

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There are no additional risks to participating in this study, as all three regimens are standard of 
care. The Cancer care Ontario toxicity sheets for the risks for anthracyclines and taxanes are 
included as appendices. 
Your participation in this study is voluntary.  If you choose not to participate, your decision will 
not affect the care you receive at this institution at this time, or in the future.   You will not have 
any penalty or loss of benefits to which you are otherwise entitled to.  
You may withdraw from the study at any time without any impact on your current or future care 
at this institution. 
Information that identifies you will be released only if it is required by law.  All information 
collected during your participation in this study will be identified with a unique study number 
(for example participant # AB01), and will not contain information that identifies you.  
Documents or samples leaving the Ottawa Hospital Cancer Centre will only contain the coded 
study number.  A Master List provides the link between your identifying information and the 
coded study number. This list will only be available to Dr. J. Hilton and his staff and will not 
leave this site.  The Master List and coded study records will be stored securely.  You will not be 
identified in any publications or presentations resulting from this study. 
All research-related records will be kept for 10 years after termination of the study.  No 
identifiable information will leave this institution.   The Ottawa Hospital Science Network 
Research Ethics Board (OHSN-REB) and the Ottawa Hospital Research Institute, may review 
your relevant study records for audit purposes. 
If you have any questions about this study please refer to your list of contact numbers to reach 
me. The OHSN-REB has reviewed this protocol. The Board considers the ethical aspects of all 
research studies involving human participants.  If you have any questions about your rights as a 
study participant, you may contact the Chairperson at   613-798-5555, extension 16719 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov.  This 
website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
Do you have any questions?” 

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If the patient agrees to participate the physician will dictate in the progress note they have had 
the above conversation with the patient. There will be no need for the patient to sign an informed 
consent form.  
6 
ELIGIBILITY 
6.1 
Inclusion Criteria 
• Histologically confirmed primary TNBC breast cancer 
• Planned for chemotherapy 
• ≥18 years of age 
• Able to provide verbal consent 
6.2 
Exclusion Criteria 
• Metastatic disease 
• Contraindication to one or more of the chemotherapy agents being evaluated in the study 
7 
RANDOMIZATION 
Each site investigator will be able to randomize participants through either their handheld device, 
their office desk top or by calling the study coordinator (CRA). Each site will have a site code 
preceding the study number and for each site the study number will be continuous. Patients will 
be stratified by the goal of therapy (adjuvant or neoadjuvant and presence of lymph nodes). The 
physician must dictate that the verbal consent and eligibility review has taken place prior to 
randomization. The investigators will then forward the randomization conformation email 
indicating the selected study drug to their CRA along with the participant’s medical record 
number.  
8 
DATA COLLECTION 
Once the patient has been randomized, the study CRA will collect participant information 
treatment assignment, treatment received, and adverse effects requiring hospitalization or 
treatment delays.  This data will all recorded in real-time via electronic health records. From a 
study standpoint only the CRA will access this information. Data not available at the time of visit 

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will be collected from the dictated physician note. CRAs will complete the paper case report 
forms (CRF) and for external sites fax the de-identified source documents and CRFs to Dr. 
Hilton within the timeframes noted on the CRFs. CRFs will also have the contact fax number 
listed.  
Participant data to be collected over the treatment period: 
• Treatment assignment 
• Treatment received 
• Adverse effects requiring hospitalization/treatment delays  
If the patient is randomized and either the patient or physician refuses the randomization 
selection, reasons for this will be recorded.  Once assigned to a particular treatment arm, patients 
will not be permitted to switch to an alternative treatment arm offered in the protocol; this is 
consistent with Cancer Care Ontario guidelines for treatment standard of care. If physicians 
choose to break the protocol, they must inform the patient as to why the allocated selection 
should not be used from the randomization process. We will monitor the charts to ensure that this 
reason has been recorded.  Treatment options at this point would be regarded as non-standard of 
care and will be left to the discretion of their treating physician.  Patients will still be analyzed in 
the arm that they were assigned despite breaking with protocol treatment (as per intention to treat 
principles).  Patient satisfaction will be assessed using a survey, developed by the study team, 
following completion of their chemotherapy. 
9 
OUTCOMES 
9.1 
Primary Outcome  
Feasibility of performing this study will be measured with composite endpoints: 
1. Percentage of patients who receive chemotherapy in the neoadjuvant/adjuvant setting for 
TNBC compared to the number of participants who after being approached subsequently agree to 
randomization. 
2. Optional Participant satisfaction survey. Overall participant satisfaction will be determined 
using the participant survey. 

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9.2 
Secondary outcome 
1. 
Percentage of participants who complete study treatment compared to the percentage who 
discontinue their treatment while on study (compliance) will be calculated using the sites 
chemotherapy treatment records and data from New Patient Registration. 
2.  
Rate of adverse effects requiring hospitalization/treatment delays 
10 RISKS 
There are no additional risks associated with this study as all arms are standard of care 
treatments. 
11 SAFETY REPORTING 
For the purpose of this feasibility study SAE reporting is not required. Adverse events specific to 
the secondary (i.e. hospitalizations) outcome will be captured on the CRFs. 
12 MONITORING 
Monitoring will be performed remotely at The Ottawa Hospital Cancer Centre by their internal 
monitor for investigator initiated studies. The de-identified source documents and CRFs will be 
reviewed according to the approved monitoring plan. 
13 CRITERIA FOR FEASIBILITY SUCCESS 
The following criteria were established a priori and needed to be met to deem this feasibility trial 
successful:  
1) Over 50% of appropriate patients approached agree to participate in the RCT,  
2) Over 50% of physicians who agree at study commencement to participate in the study do 
indeed approach patients for the study.  
 

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14 PREMATURE WITHDRAWAL 
Participants have the right to withdraw from the study treatment at any time for any reason 
Investigator has the right and obligation to withdraw subjects from the study treatment in the 
event of: 
• 
Intercurrent illnesses which would, in the judgment of the investigator, affect assessment 
of clinical status to a significant degree, and require discontinuation of protocol therapy 
• 
Any toxicity that would produce further harm if continued on the protocol 
• 
Request by the participant  or  of their legally authorized representative (consent 
withdrawal) 
• 
Non-compliance to the study protocol or logistic consideration 
• 
Participant  is lost to follow-up 
15 SAMPLE SIZE AND STATISTICAL ANALYSIS  
As this is a feasibility study there is no pre-defined sample size. We would anticipate that around 
35 patients will be entered within one year of study commencement. 
Study results will be presented descriptively.  
 
 

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16 References  
 
1. 
Hammond, M.E., et al., American Society of Clinical Oncology/College of American Pathologists 
guideline recommendations for immunohistochemical testing of estrogen and progesterone 
receptors in breast cancer (unabridged version). Arch Pathol Lab Med, 2010. 134(7): p. e48-72. 
2. 
Wolff, A.C., et al., Recommendations for human epidermal growth factor receptor 2 testing in 
breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical 
practice guideline update. J Clin Oncol, 2013. 31(31): p. 3997-4013. 
3. 
Trivers, K.F., et al., The epidemiology of triple-negative breast cancer, including race. Cancer 
Causes Control, 2009. 20(7): p. 1071-82. 
4. 
Livasy, C.A., et al., Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. 
Mod Pathol, 2006. 19(2): p. 264-71. 
5. 
Lin, N.U., et al., Clinicopathologic features, patterns of recurrence, and survival among women 
with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer, 2012. 
118(22): p. 5463-72. 
6. 
Gandhi, S., et al., Adjuvant chemotherapy for early female breast cancer: a systematic review of 
the evidence for the 2014 Cancer Care Ontario systemic therapy guideline. Curr Oncol, 2015. 22: 
p. S82-94. 
7. 
Gradishar, W.J., et al., Breast cancer version 3.2014. J Natl Compr Canc Netw, 2014. 12(4): p. 
542-90. 
8. 
Berry, D.A., et al., Estrogen-receptor status and outcomes of modern chemotherapy for patients 
with node-positive breast cancer. JAMA, 2006. 295(14): p. 1658-67. 
9. 
Bonilla, L., et al., Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review 
and meta-analysis of randomized controlled trials. J Natl Cancer Inst, 2010. 102(24): p. 1845-54. 
10. 
Sparano, J.A., et al., Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med, 
2008. 358(16): p. 1663-71. 
11. 
Roche, H., et al., Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-
positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol, 2006. 24(36): p. 5664-71. 
12. 
Kim, S.Y. and F.G. Miller, Informed consent for pragmatic trials--the integrated consent model. N 
Engl J Med, 2014. 370(8): p. 769-72. 
13. 
Sugarman, J. and R.M. Califf, Ethics and regulatory complexities for pragmatic clinical trials. 
JAMA, 2014. 311(23): p. 2381-2.