Clinical trial NCT02927249
Conditions: Node Positive HER2 Negative Breast Cancer
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2016-12-08; Completion date: 2023-02-15
Enrollment: 3021 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies how well aspirin works in preventing the cancer from coming back (recurrence) in patients with human epidermal growth factor receptor 2 (HER2) negative breast cancer after chemotherapy, surgery, and/or radiation therapy. Aspirin is a drug that reduces pain, fever, inflammation, and blood clotting. It is also being studied in cancer prevention. Giving aspirin may reduce the rate of cancer recurrence in patients with breast cancer.

Detailed description:
This is a randomized double-blind placebo-controlled phase III trial of aspirin (300 mg daily) in early stage node-positive HER2 negative breast cancer patients. Patients will be randomized 1:1 within stratum defined by: Hormone Receptor status (HR positive vs HR negative), body mass index (\<30 vs ≥ 30 kg/m2) and stage (Stage II vs III).

The primary objective of this trial is to compare the effect of aspirin versus placebo upon invasive disease free survival (iDFS).

Primary objective To compare the effect of aspirin (300 mg daily) versus placebo upon invasive disease free survival (iDFS) in early stage node-positive HER2 negative breast cancer patients.

Secondary objectives

1. To compare the effect of aspirin versus placebo in early stage node-positive HER2 negative breast cancer patients upon:

   1. Distant disease-free survival
   2. Overall survival
   3. Cardiovascular disease (see Section11.3)
2. To compare the toxicity of aspirin versus placebo in early stage node-positive HER2 negative breast cancer patients.
3. To assess adherence to aspirin and placebo among early stage node-positive HER2 negative breast cancer patients.
4. To bank tumor and germline deoxyribonucleic acid (DNA), plasma and urine collected at baseline and sequential plasma and urine collected 2 years later for future measurement of inflammatory markers.
5. To determine if there are subgroups of participants characterized by lifestyle factors associates with greater inflammation for whom there is greater benefit of aspirin versus placebo upon iDFS.

Patients are followed up to 10 years after study enrollment.

Arms: arm 1: Patients receive aspirin PO QD for five years in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive placebo PO QD for five years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Placebo intervention 2: Aspirin
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
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Update #06 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A011502 
 
A RANDOMIZED PHASE III DOUBLE BLINDED PLACEBO CONTROLLED TRIAL OF 
ASPIRIN AS ADJUVANT THERAPY FOR HER2 NEGATIVE BREAST CANCER: THE ABC 
TRIAL 
 
Investigational agents: Aspirin and Placebo for Aspirin  
Supplied by: Bayer; Distributed by: McKesson 
 
ClinicalTrials.gov Identifier: NCT02927249 
Stand-alone Companion Study: Alliance A211601 
 
Study Chair 
 
 
 
 
 
 
Community Oncology Co-Chair 
 
 
 
 
 
Disease Committee Co-Chairs 
 
 
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
 
 
  
 
 
 
 
Protocol Coordinator 
Data Manager 
NRG Champion 
 
 
 
 
 
 
 
 
 
 
SWOG Champion 
ECOG-ACRIN Champion 
 
 
 
 
 
 
 
Participating NCTN Groups:  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN/ECOG-ACRIN Cancer Research Group, 
NRG/NRG Oncology, SWOG/SWOG; CCTG/Canadian Cancer Trials Group 


 
 
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Study Resources: 
Expedited Adverse Event Reporting 
 
 Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
 Biospecimen Management System 
 
 
Protocol Contacts: 
A011502 Nursing Contact 
 
 
  
 
 
Pharmacy Contact 
  
 
 
 
Alliance Biorepository at Washington University (WUSTL) 
 
 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at Washington University 
(WUSTL) 


 
 
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CONTACT INFORMATION 
For regulatory requirements 
For patient enrollments:  
For data submission 
Regulatory 
documentation 
must be submitted to the CTSU 
via the Regulatory Submission 
Portal. 
 (Sign in at 
and 
select 
the 
Regulatory 
> 
Regulatory Submission.)  
 
Institutions 
with 
patients 
waiting that are unable to use 
the Portal should alert the 
CTSU 
Regulatory 
Office 
immediately 
at 
 
to 
receive 
further 
instruction and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN). 
 
 
  
 
Contact the CTSU Help Desk 
with any OPEN related 
questions by phone or email : 
 
  
 
Data collection for this study will be 
done exclusively through Medidata 
Rave. Refer to the data submission 
section of the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website 
). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password. 
Supplies can be ordered by downloading and completing the CTSU Supply Request Form (available on 
the protocol-specific page on the CTSU website) and submitting it as instructed on the form. 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 
2. 
For non-clinical questions (i.e. unrelated to patient eligibility, clinical treatment, or data 
submission  
Contact the CTSU Help Desk by phone or e-mail:  
 
 
 
 
 


 
 
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A RANDOMIZED PHASE III DOUBLE BLINDED PLACEBO CONTROLLED TRIAL OF 
ASPIRIN AS ADJUVANT THERAPY FOR HER2 NEGATIVE BREAST CANCER: THE ABC 
TRIAL 
 
Eligibility Criteria (see Section 3.0) 
Histologic documentation of women or men with HER2 negative breast carcinoma (See Section 
3.2.1). 
If ER and PR negative, tumor must be node positive or >2 cm and node negative. 
Patients must be registered within 18 months of diagnosis. pN1mic is eligible.  
If ER and/or PR positive, tumor must be node positive and within 10 years of 
diagnosis. pN1mic is eligible.  (See Section 3.2.2.) 
Prior adjuvant treatment with chemotherapy and/or endocrine therapy, as determined by the treating 
physician, is allowed (see Section 3.2.3). 
Prior regular NSAID/aspirin use (defined as ≥ 5 days per week) at any dose (including baby aspirin) 
allowed if stopped for at least 30 days prior to study entry and throughout study period (see Section 
3.2.4). 
If ER and/or PR positive, tumor must be node positive and within 10 years of diagnosis. pN1mic 
is eligible.  
Patients must be > 18 and < 70 years of age. 
ECOG performance status 0-2. 
Patients with a prior history of gastric/duodenal ulcers documented on endoscopy can be enrolled 
(see Section 3.2.7). 
No history of GI bleeding (see Section 3.2.8). 
No history of prior stroke (hemorrhagic or ischemic). 
No concurrent anticoagulation with warfarin, heparin/heparin analogues, clopidogrel, direct 
thrombin inhibitors or direct Factor Xa inhibitors. 
No history of atrial fibrillation or myocardial infarction. 
No history of grade 4 hypertension (see 3.2.12). 
No chronic (duration >30 days) daily use of oral steroids. Inhaled or topical steroids are allowed. 
No known allergy to aspirin. 
No prior invasive malignancy of any type within the past 5 years (see Section 3.2.15). 
Concurrent enrollment on a non-chemotherapy treatment trial will be allowed, as long as that trial 
allows concurrent daily aspirin use. 
No history of metastatic breast cancer 
 
 
 


 
 
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Schema 
* Sites can use AJCC 7 or AJCC 8 because the anatomical staging remains unchanged between the versions.  
** For patients who either have hormone receptor negative breast cancer or who are ER+ and completed hormone 
therapy within 6 months prior to registration to A011502, please consider enrolling to the companion study, 
A211601. See Section 4.3. 
 
Patients who complete five years of study treatment will be followed annually until 10 years from 
registration. Patients who stop treatment before 5 years, will have a follow-up visit 6 months after end of 
protocol treatment and then annually until 10 years from registration. 
 
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 
 
R 
 
ARM 1 
 
A 
 
Aspirin 300 mg daily x 5 years 
HER-2 negative 
N 
 
 
 
D 
 
 
If hormone positive: Node positive 
within 10 years of diagnosis 
O 
M 
 
 
 
I 
Z 
E 
 
 
If hormone negative: Node positive 
or high risk (> 2 cm) node negative 
and with 18 months of diagnosis 
 
 
ARM 2 
Placebo daily x 5 years 
 
 
 
 
Stratification Factors 
 
 
 
Hormone Receptor status** 
1) Positive (either ER or PgR positive 
or unknown) 
 
 
 
2) Negative (both ER and PgR 
negative) 
 
 
 
Body Mass Index 
1) Less than 30 kg/m2 
 
 
 
2) Greater than or equal to 30 kg/m2 
 
 
 
Breast Cancer Stage*  
 
 
 
1) Stage I/II 
 
 
 
2) Stage III 
 
 
 
Time Since Diagnosis 
1) < 18 months 
2) > 18 months 
 
 
 


 
 
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Table of Contents 
 
Section 
Page 
1.0 
BACKGROUND .............................................................................................................................. 8 
1.1 
Rationale for Selected Approach and Trial Design ........................................................................ 8 
1.2 
Relevance for a Randomized Trial ................................................................................................. 9 
1.3 
Epidemiological Data: Prospective Observational Studies ............................................................ 9 
1.4 
Clinical Trials in Cardiovascular Disease, Gastrointestinal Cancer, and Breast Cancer .............. 11 
1.5 
Randomized Controlled Trials for Breast Cancer Treatment ....................................................... 12 
1.6 
Compliance and Adherence to Aspirin in Prior RCT’s ................................................................ 12 
1.7 
Non-Protocol Use of Aspirin/NSAIDs from RCT’s .................................................................... 13 
2.0 
OBJECTIVES ................................................................................................................................ 13 
2.1 
Primary Objective......................................................................................................................... 13 
2.2 
Secondary Objectives ................................................................................................................... 13 
3.0 
PATIENT SELECTION ............................................................................................................... 14 
3.1 
On-Study Guidelines .................................................................................................................... 14 
3.2 
Eligibility Criteria......................................................................................................................... 14 
4.0 
PATIENT REGISTRATION/RANDOMIZATION ................................................................... 16 
4.1 
Investigator and Research Associate Registration with CTEP ..................................................... 16 
4.2 
Cancer Trials Support Unit Registration Procedures ................................................................... 17 
4.3 
Patient Registration Requirements ............................................................................................... 19 
4.4 
Patient Registration/Randomization Procedures .......................................................................... 19 
4.5 
Stratification Factors and Treatment Assignments ....................................................................... 20 
5.0 
STUDY CALENDAR .................................................................................................................... 21 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................... 22 
6.1 
Data Collection and Submission .................................................................................................. 22 
6.2 
Lifestyle Measures of Inflammation ............................................................................................ 23 
6.3 
Specimen Collection and Submission .......................................................................................... 24 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 26 
7.1 
Study Treatment ........................................................................................................................... 26 
7.2 
Adherence ..................................................................................................................................... 27 
7.3 
Disease Recurrence and New Invasive Disease ........................................................................... 27 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING ............................................ 27 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care........................................... 27 
8.2 
Dose Modifications ...................................................................................................................... 29 
8.3 
Unblinding Procedures ................................................................................................................. 31 
9.0 
ADVERSE EVENTS ..................................................................................................................... 32 
9.1 
Routine Adverse Event Reporting ................................................................................................ 32 
9.2 
CTCAE Routine Reporting Requirements ................................................................................... 33 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) ................................................................... 33 
10.0 
DRUG INFORMATION ............................................................................................................... 36 
10.1 Aspirin or Aspirin-Matched Placebo ............................................................................................ 36 
10.2 Shipment of Study Drug Supply Directly to the Study Participant .............................................. 39 
11.0 
MEASUREMENT OF EFFECT .................................................................................................. 39 
11.1 Evaluation of Breast Cancer Outcomes ........................................................................................ 39 
11.2 Definitions of Analysis Variables ................................................................................................ 40 


 
 
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11.3 Evaluation of Cardiovascular Outcomes ...................................................................................... 40 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................... 40 
12.1 Duration of Treatment .................................................................................................................. 40 
12.2 Patient Follow-up ......................................................................................................................... 41 
13.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 41 
13.1 Study Design ................................................................................................................................ 41 
13.2 Sample Size, Accrual Time and Study Duration .......................................................................... 41 
13.3 Primary Endpoint Analysis .......................................................................................................... 42 
13.4 Study Monitoring and Interim Analysis ....................................................................................... 43 
13.5 Statistical Section for Lifestyle Measures of Inflammation ......................................................... 45 
13.6 CDUS Reporting .......................................................................................................................... 46 
13.7 Inclusion of Women and Minorities ............................................................................................. 47 
14.0 
COMPANION STUDY ................................................................................................................. 48 
14.1 Life Style Measures of Inflammation ........................................................................................... 48 
15.0 
BIOSPECIMEN COLLECTION ................................................................................................. 50 
15.1. Rationale ....................................................................................................................................... 50 
15.2. Biomarker selection ...................................................................................................................... 50 
16.0 
REFERENCES .............................................................................................................................. 51 
APPENDIX I 
 LIFESTYLES MEASURES OF INFLAMMATION ............................................. 55 
APPENDIX II A011502 STUDY MEDICATION LOG ........................................................................ 63 
 


 
 
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1.0 
BACKGROUND 
1.1 
Rationale for Selected Approach and Trial Design 
Multiple lines of evidence including preclinical and epidemiologic studies and clinical trial data 
present a compelling case for the potential of aspirin as adjuvant therapy.  However, in order to 
become part of routine clinical care, a randomized placebo-controlled trial is crucial to 
definitively evaluate the risks and benefits for breast cancer survivors. 
Selection of the aspirin dose was chosen to balance optimal therapeutic dose with potential 
toxicity. In the observational Nurses’ Health Study (NHS) there was reduced breast cancer 
mortality among those who consumed aspirin as infrequently as 2-5 times per week, but there 
was a significant linear trend (p<0.001) indicating greater survival benefit with daily use. 
Although NHS did not assess dose, 35% took aspirin for heart disease prevention (likely 81 mg 
daily) whereas others took it for muscle or joint pain, headache, backache, menstrual cramps, or 
other reasons (likely 325 mg) [1]. One large meta-analysis and one large pooled analysis looking 
at cancer mortality among randomized trials of aspirin for cardiovascular and other diseases 
have been published. In the pooled data, subjects allocated to aspirin had a reduced risk of cancer 
with distant metastasis, mainly due to a reduced risk of metastatic adenocarcinoma (RR=0.52, 
95% CI=0.35-0.75). Total survival and cancer survival rates were higher among those 
randomized to aspirin whether it was low-dose (<300mg) or high dose (>300mg) [2]. A meta-
analyses of 11 studies also observed a significant reduction in cancer mortality with aspirin (RR 
0.77 (95% CI 0.63-0.94). Of these studies, approximately 75% of subjects took 75-100 mg daily 
and 25% took > 200 mg daily [3]. However, most studies showing efficacy of aspirin in 
prevention of colorectal cancer prevention studies utilized 325 mg daily or higher. A pooled 
analysis of aspirin chemoprevention trials for colorectal adenoma found no difference between 
higher (300+ mg daily) versus lower (≤160 mg daily) in terms of overall reduction of adenoma, 
but higher dose aspirin appeared to reduce risk of advanced adenomas, more than lower dose 
aspirin [4]. A randomized, placebo-controlled trial among 861 hereditary colorectal cancer 
carriers found a decreased risk of cancer incidence with aspirin 600 mg daily compared to 
placebo (IRR 0.56 (95% CI 0.32-0.99) after accounting for multiple primary tumors in some 
individuals) [5]. In contrast, a previous study of lower dose aspirin in the primary prevention 
setting (the Women’s Health Study) found no association with breast cancer incidence among 
39,876 women aged 45 or older randomized to placebo or aspirin 100 mg every other day [6]. 
Therefore, although some data support the possible benefit of low dose aspirin (< 100 mg daily), 
other studies suggest a higher dose may be necessary with no clear consensus.  
The primary effect of low dose aspirin (< 100 mg) is anti-platelet and anti-thrombotic. However, 
the higher dose of > 300 mg daily is required to affect inflammatory pathways. In addition, 
several other possible mechanisms including inhibition of mTOR, PI3K, and nuclear factor 
kappa-light-chain-enhancer of activated B cells (NF-kB) would also most likely need higher 
doses. Given the resources devoted to this study, the best scientific strategy would be to begin 
at the higher dose which would cover multiple possible mechanisms of actions with allowances 
for toxicity rather than including only the 81 mg dose and risk missing an effect. Unlike 
cardiovascular disease, the optimal dose for cancer prevention is unknown. If the current study 
utilized low dose aspirin and did not find an effect at the end of the study period, the scientific 
question would still remain as to whether higher dose (>300 mg daily) would be effective. 
However, if the higher dose were ineffective in terms of cancer recurrence, this would be 
considered the definitive study. 
A three arm study of placebo versus low dose (< 100 mg) versus higher dose (> 300 mg) with 
sufficient power for a primary endpoint of recurrence would necessitate a sample size of at least 


 
 
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4500 subjects which would add considerably to the cost and duration of the study. Thus, this 
trial is a two arm study of higher dose aspirin (> 300 mg) versus placebo. 
Although this protocol was originally conceived using a starting dose of 325 mg daily with dose 
reductions to 81 mg, which are the commercially available doses in the United States, the 
protocol has been revised to a starting dose of 300 mg daily with per protocol dose reductions 
to 100 mg daily, which are the commercially available aspirin doses in Europe and other 
countries outside of the United States. This change is due to price and supply issues. The 
global/European division of Bayer was able to supply aspirin and placebo at a much less 
expensive price and faster timeline than the US division. For the published meta-analyses, 
pooled analyses, and USPTF evidence reviews for cardiovascular disease and cancer, all “low-
dose” (≤ 100 gm daily) studies were pooled together and studies using 300 or 325 mg daily were 
pooled together, because effects were considered equivalent. Furthermore, although multiple 
pharmacodynamics/pharmacokinetic studies have been done comparing 81/100 to 300/325 
demonstrating differences in activity, no published studies have evaluated differences between 
81 versus 100 or 300 versus 325, since these were not considered biologically significant dose 
differences. Therefore, from the scientific standpoint, the change from 325 to 300 mg will not 
impact the chances of finding an effect or the risk/benefit ratio. Finally, the 300/100 mg doses 
align with the doses in the UK Add-Aspirin study, which will facilitate future pooling of the 
analyses. 
1.2 
Relevance for a Randomized Trial 
Aspirin strongly merits a randomized trial, based on compelling in-vitro, in-vivo, and 
epidemiologic evidence of its potential to prevent recurrence and death among breast cancer 
survivors. Observational studies report up to 50% reduction in the risk of breast cancer 
recurrence and death with regular aspirin use. Before these findings could be considered 
standard of care, the benefits of aspirin need to be confirmed in a randomized controlled trial. 
If proven effective, adding aspirin following the completion of adjuvant chemotherapy and/or 
concurrently with hormonal therapy would improve survival. It is also possible that aspirin may 
be associated with higher compliance than hormonal therapy, which can be poorly tolerated. For 
example, about 50% of American women with hormone-positive tumors do not finish the 
recommended 5 years of hormonal therapy, sometimes due to side effects such as joint pains or 
menopausal symptoms and sometimes because of cost. Outside the US, aspirin’s low cost ($6 
per year) would make it a major aid in developing nations unable to access expensive therapies.  
All pertinent data (include phase 1-3 trial results, and any pilot or confidential data from 
companies that justify the use of the control and experimental arms). 
1.3 
Epidemiological Data: Prospective Observational Studies 
1.3.1 
Aspirin and breast cancer survival 
The 2010 results from Nurses’ Health Study (NHS), a prospective observational study, 
sparked tremendous interest in the potential for aspirin to improve breast cancer survival. 
Among 4,164 female registered nurses diagnosed with Stages I, II, or III breast cancer 
between 1976 and 2002, aspirin use after diagnosis was associated with a decreased risk of 
breast cancer death. The adjusted relative risks (RR) of death (95% confidence interval 
(CI)) for 1, 2-5, and 6-7 days of aspirin use per week compared to no use were 1.07 (0.70-
1.63), 0.29 (0.16-0.52), and 0.36 (0.24-0.54), respectively (p for trend <0.0001). The 
association for dichotomous aspirin use (yes/no) was a nearly 50% decrease in breast 
cancer death, RR (95%CI) = 0.51(0.41-0.65). This association did not differ appreciably 
by stage, menopausal status, body mass index (BMI), and estrogen receptor status. Results 
were similar for distant recurrence [1]. 


 
 
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Besides NHS, multiple other observational studies reported similar benefits for aspirin 
and/or NSAID’s and breast cancer survival. Prior to 2010, two prospective studies 
evaluated NSAID use and breast cancer survival. Blair et al reported a reduced risk of 
breast cancer death (RR, 95% CI = 0.53, 0.30-0.93) for aspirin use after diagnosis among 
591 postmenopausal women with breast cancer in the prospective Iowa Women’s Health 
Study. In that study, aspirin and non-aspirin NSAID use was combined, but use of aspirin 
only (43%) was much more common than use of non-aspirin NSAIDs only (10%) or use 
of both (27%) [7]. Among 2,292 women with early stage breast cancer in a breast cancer 
survivor cohort, current regular use of ibuprofen (RR 0.56 [95% CI 0.32-0.98]), but not 
aspirin (RR 1.09 [95% CI 0.74-1.61]), was associated with a reduced risk of recurrence [8].  
After our NHS study, three additional prospective observational studies of aspirin and 
breast cancer survival have been published. Among 1,024 breast cancer cases from a 
population-based case-control study followed for an average of 7 years, Li et al reported a 
non-statistically significant reduced risk of breast cancer death (RR=0.82, 95% CI, 0.54-
1.24) and total mortality (RR=0.89, 95% CI, 0.53-1.52) among those using aspirin [9]. A 
Scottish registry study of 4,627 women with breast cancer found that post diagnosis aspirin 
use (75 mg dose) was associated with a lower risk of breast cancer mortality (RR, 95% CI 
= 0.42, 0.31-0.55) and all-cause mortality (0.53, 0.45-0.63), after adjustment for age, stage, 
treatment and pre-diagnosis aspirin use [10]. Finally, a nested case-control study of 27,426 
women with breast cancer in the Swedish registry system was null for aspirin use assessed 
in most time periods, but reported a lower risk of death from breast cancer only when 
assessed within 6 months of death or the end of follow-up (RR, 95% CI=0.69, 0.56-0.86), 
which may reflect discontinuation of aspirin during terminal illness or confounding by 
indication. Aspirin use in this study was exclusively low-dose (75 or 160 mg) [11]. With 
the exception of the Swedish and Scottish registry data, detailed data on dose and duration 
were not available for the other studies, which may explain some of the differing results. 
Because non-aspirin NSAID use has also been hypothesized to improve breast cancer 
survival, the question arises whether protective associations seen with aspirin use may be 
attributable to concomitant NSAID use. The epidemiologic studies varied as to how non-
aspirin NSAID use was handled in the analyses, but most combined women who used ASA 
alone with those who used ASA and NSAIDs as ASA users and therefore the unique role 
of NSAIDs could not be determined. However, among the epidemiologic studies that 
showed a benefit of aspirin use and breast cancer mortality, a report by Blair et al from the 
Iowa Women’s Health Study was the only study that clearly separated ASA from NSAID 
users. Among those taking only aspirin, the HR (95% CI) for breast cancer death was 
0.53(0.30-0.93). Among those taking only non-aspirin NSAIDs, the HR was 0.67(0.28-
1.57). Among those taking both ASA and NSAID, the HR was 0.82(0.46-1.48) [7]. In 
addition, the pooled data from the aspirin randomized controlled trials (RCT’s) for 
cardiovascular disease (see Section 1.4.1) did not include non-aspirin NSAID use in their 
analyses. Most of the RCT’s discouraged off protocol aspirin and NSAID use, so non-
aspirin NSAID use is unlikely to have been a major confounder in the aspirin RCT’s 
showing a benefit of aspirin. 
In sum, the majority of prospective epidemiologic studies demonstrated an association 
between regular aspirin/NSAID use and improved breast cancer survival. 
1.3.2 
Aspirin/NSAIDs and breast cancer incidence 
Results of individual studies regarding aspirin/NSAIDs and breast cancer incidence were 
mixed and not as strong as the breast cancer survival data. However, meta-analyses of 
NSAID or aspirin use have generally found a 9-30% reduced risk of breast cancer incidence 


 
 
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[12-15]. It is likely that aspirin more strongly affects breast cancer metastasis than cancer 
initiation, so would be more effective as an adjuvant therapy, rather than for primary 
prevention. 
1.4 
Clinical Trials in Cardiovascular Disease, Gastrointestinal Cancer, and Breast Cancer 
1.4.1 
Clinical trials: Randomized trials in cardiovascular diseases 
In addition to the observational studies on aspirin and breast cancer survival, randomized 
trial data from cardiovascular disease have also demonstrated an effect of aspirin on cancer 
recurrence. Rothwell et al pooled data from 5 large randomized trials from the United 
Kingdom (UK) of aspirin to prevent vascular disease. The purpose of the pooled analysis 
was to examine the effect of aspirin on cancer metastases presenting during or after the 
trials’ follow-up. In the pooled data, subjects allocated to aspirin had a reduced risk of 
cancer with distant metastasis, mainly due to a reduced risk of metastatic adenocarcinoma 
(RR=0.52, 95% CI=0.35-0.75). In addition, patients with adenocarcinoma who did not 
have metastasis at initial diagnosis and who remained on aspirin up to or after diagnosis 
had a markedly reduced risk of metastasis during follow-up (RR=0.31, 95% CI=0.28-0.72). 
Examination of case-fatality by individual cancers was hampered by small numbers, but 
there was a suggestion of reduced case-fatality for breast cancer (RR=0.16, 95% CI=0.02-
1.19) [2]. Further corroboration was provided by a meta-analysis comparing data from 
observational studies to that from the UK randomized trials. The risk of breast cancer with 
distant metastases pooled from observational studies, (RR=0.58, 95% CI=0.20-1.71) was 
similar to that found in randomized trials, although due to small numbers it did not reach 
statistical significance [16]. These randomized data strongly implicate a role for breast 
cancer in preventing metastases, but need to be confirmed in a breast cancer clinical trial. 
The pooled data from the aspirin RCT’s for cardiovascular disease did not include non-
aspirin NSAID use in their analyses. Most of the RCT’s discouraged off protocol aspirin 
and NSAID use and as described below in Section 1.7, off study use was in the range of 
10-15%, so non-aspirin NSAID use is unlikely to have been a major confounder in the 
aspirin RCT’s showing a benefit of aspirin. 
1.4.2 
Randomized controlled trials of aspirin for gastrointestinal cancer treatment 
The largest amount of randomized cancer trial data pertains to patients with or at risk for 
colorectal cancer. The key studies are summarized below, since they provide insight on 
potential mechanism, dose selection, and toxicity in the setting of cancer prevention. For 
purposes of space and clinical relevance, studies on COX2 inhibitors and colorectal cancer 
will not be reviewed. 
1.4.2.1 Primary polyp prevention 
Four randomized trials including 2967 subjects evaluating aspirin for prevention of 
colorectal adenoma were combined in a meta-analysis [4]. All four studies included 
an arm with 300+ mg aspirin daily and two of the four studies also included a third 
arm (either 81 or 160 mg aspirin daily). There was a decreased risk of any adenoma 
with any dose of aspirin (RR 0.83 (95% CI 0.72-0.96)) compared to placebo which 
translated to an absolute risk reduction of 6.7%. There was no difference between 
higher (300+ mg daily) versus lower (≤160 mg daily) in terms of overall reduction of 
adenoma, but higher dose aspirin appeared to reduce risk of advanced adenomas, 
more than lower dose aspirin, arguing for the higher dose for the cancer prevention 
setting. 


 
 
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1.4.2.2 Primary chemoprevention for colorectal cancer 
Although several randomized trials have evaluated aspirin for prevention of polyps, 
only one study published to date has colorectal cancer incidence as the primary 
endpoint. The Colorectal Adenoma/carcinoma Prevention Program (CAPP trial) 
randomized 861 carriers of Lynch syndrome to either aspirin 600 mg daily or placebo. 
At mean follow-up of 55.7 months and after accounting for multiple primary events 
in some subjects, there was a decreased incidence of colorectal cancer in the aspirin 
(IRR 0.56 (95% CI 0-.32-0.99). The effects were stronger for subjects who completed 
at least 2 years of treatment (IRR 0.37 [95% CI 0.18-0.78]) [5]. 
1.4.2.3 Adjuvant treatment for colorectal cancer 
An early underpowered study of only 66 subjects with colorectal cancer showed an 
improvement in overall survival for subjects randomized to aspirin 600 mg twice per 
day compared to placebo, but the difference was not statistically significant (HR 0.65 
(95% CI 0.02-18.06) [17]. Currently, the ASCOLT trial (Aspirin for Dukes C and 
High Risk Dukes B Colorectal Cancers - NCT00565708) is a randomized phase III 
trial began enrolling subjects in 2009 with either Duke’s C or high-risk Duke’s B with 
random assignment to 200 mg aspirin daily or placebo and continues to accrue. 
Primary endpoint is disease free survival with accrual goal of 1200. 
1.4.2.4 Adjuvant treatment for gastro-esophageal cancer 
1716 Chinese patients who had undergone resection of either squamous cell 
carcinoma of the esophagus of adenocarcinoma of the cardia were randomly assigned 
to aspirin or placebo. Five year overall survival was improved for those taken aspirin 
(51.2%) compared to those on placebo (41%) (p=0.04 for the difference) [18]. 
As summarized, the colorectal cancers studies that demonstrated a benefit generally 
evaluated doses of 300 mg+ daily, arguing for utilizing this dose in the cancer setting. 
1.5 
Randomized Controlled Trials for Breast Cancer Treatment 
In contrast to colorectal cancer, there are no randomized trials of aspirin for breast cancer 
treatment. 
1.6 
Compliance and Adherence to Aspirin in Prior RCT’s  
1.6.1 
Compliance 
Fortunately, there have been many large randomized controlled trials (RCT’s) of aspirin in 
the cardiovascular and gastrointestinal fields with robust data on adherence and study 
design. Regarding compliance, we have excellent estimates based upon prior aspirin 
RCT’s, such as the Women’s Health Study (WHS), a randomized trial of 10 years of 100 
mg aspirin QOD vs placebo for primary prevention of chronic disease among 39,876 
healthy women aged 45 or older. Average compliance (defined as taking > 2/3 of study 
medication) was 76.1% overall at 5 years and over the 10 year study was high and similar 
for both arms: 73.7% (placebo) vs 72.5% (ASA) [19]. Similar to WHS, regular monitoring 
will be done by telephone to monitor adherence and off study use of aspirin/NSAIDs. 
However, the WHS was for primary prevention and among breast cancer survivors, 
adherence should be even higher. A more comparable study may be a meta-analysis of 4 
aspirin trials (n= 1121 subjects) to prevent colorectal adenomas among high-risk subjects 
which showed even higher rates of adherence – 81% (placebo) vs 84% on aspirin (mean 
trial durations 3-4 years) [4]. Therefore, we anticipate that adherence should be similar 
among breast cancer survivors and across placebo and aspirin arms. 


 
 
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1.7 
Non-Protocol Use of Aspirin/NSAIDs from RCT’s 
We also have robust estimates for cross-in/cross-out (e.g. off study use of aspirin/NSAIDs) from 
prior studies. In WHS, non-trial use of aspirin of >4 days per month at 5 years was 11.6% and 
averaged across the 10 year trial was similar in both groups – 13.0% (placebo) vs 12.7% (aspirin) 
[19]. In the Colon Polyp Prevention trial, off study use of aspirin/NSAIDs of  > 4 days per month 
was 3.8% during the 1st year and 9.3% at study end (roughly 3-4 years) across both study arms 
[20]. In the Japanese Primary Prevention Project (n=14,464), an open label randomized trial of 
100 mg aspirin daily vs no aspirin, off protocol use of any aspirin or antiplatelet agent was 
similar in both arms at 5 years (10.5% on aspirin and 10.4% on placebo) [21]. As can be seen 
from these other aspirin RCT’s across a range of settings and study populations, all had cross-
in/cross-out rates in the 10-15% range so we assume similar estimates among breast cancer 
survivors. None of these studies provided data on whether subjects who crossed-in/out differed 
from those who did not. Therefore, we acknowledge that there will be some cross-in/cross-out, 
but this should be low and more importantly, non-differential across aspirin and placebo arms. 
We have adopted the design of the other studies and will monitor non-trial aspirin/NSAID use 
and encourage subjects to use acetaminophen for symptoms if needed. For our proposal, 
compliance and cross-in/cross-out rates will be monitored every 6 months and will be submitted 
to the Data Safety and Monitoring Board for review. Similar to the other published aspirin 
RCT’s and adjuvant hormonal therapies, we did not include stopping rules based upon non-
compliance or cross-in/cross-out. However, we will monitor this closely and will reconsider if 
compliance is poor or cross-in/cross-out is unexpectedly high. Finally, it should be noted that 
all of the large aspirin RCT’s allowed prior regular aspirin/NSAID users to enroll as long as 
they stopped use prior to study entry. 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To compare the effect of aspirin (300 mg daily) versus placebo upon invasive disease free 
survival (iDFS) in early stage HER2 negative breast cancer patients. 
2.2 
Secondary Objectives 
2.2.1 
To compare the effect of aspirin versus placebo in early stage HER2 negative breast 
cancer patients upon: 
a) Distant disease-free survival 
b) Overall survival 
c) Cardiovascular disease (see Section11.3) 
 
2.2.2 
To compare the toxicity of aspirin versus placebo in early stage HER2 negative 
breast cancer patients. 
2.2.3 
To assess adherence to aspirin and placebo among early stage HER2 negative breast 
cancer patients. 
2.2.4 
To bank tumor and germline deoxyribonucleic acid (DNA), plasma and urine 
collected at baseline and sequential plasma and urine collected 2 years later for 
future measurement of inflammatory markers. 
2.2.5 
To determine if there are subgroups of participants characterized by lifestyle 
factors associates with greater inflammation for whom there is greater benefit of 
aspirin versus placebo upon iDFS. 
 
 


 
 
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3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements. 
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
• 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
• 
Patients who cannot swallow oral formulations of the agents. 
• 
• 
For women of reproductive potential, a member of the study team should discuss 
with them the potential risks of taking the study treatment during pregnancy in order to 
help them determine whether or not they would like to use an appropriate method of 
birth control, which are described in the model consent form. 
3.2 
Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday 1week later would 
be considered Day 7. 
___ 
3.2.1 
Histologic documentation of women or men with HER2 negative breast 
carcinoma and free of recurrence. If neoadjuvant therapy was received, either initial 
clinical stage (determined by physical and or radiologic examination) or post-operative 
pathologic stage can be used for eligibility purposes, with the higher stage determining 
eligibility. Histologic documentation of node positivity is required for ER/PR positive 
tumors. 
 
Bilateral or synchronous breast cancers are allowed, as long as both cancers are HER2 
negative and at least one of the cancers meets eligibility. 
___ 
3.2.2 
If ER and PR negative, tumor must be node positive or >2 cm and node negative. 
Patients must be registered within 18 months of diagnosis. pN1mic is eligible.  
 
If ER and/or PR positive, tumor must be node positive and within 10 years of diagnosis. 
pN1mic is eligible.   
___ 
3.2.3 
Prior adjuvant treatment with chemotherapy and/or endocrine therapy, as 
determined by the treating physician, is allowed. The last dose of chemotherapy or 
radiation therapy must be at least 30 days prior to study registration. Concurrent 
hormonal therapy is allowed. 
___ 
3.2.4 
Regular NSAID/aspirin use at any dose (including baby aspirin) (defined as ≥ 5 
days per week) is allowed if aspirin and/or NSAIDs are stopped for 30 days prior to study 


 
 
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entry and throughout the study period. Participants will be encouraged to use 
acetaminophen for minor pain and fever. 
___ 
3.2.5 
Age > 18 and < 70 years of age. 
___ 
3.2.6 
ECOG performance status 0-2. 
___ 
3.2.7 
Patients with a prior history of gastric/duodenal ulcers documented on endoscopy 
can be enrolled as long as the ulcers did not cause bleeding requiring a blood 
transfusion/major intervention. 
For patients who are Helicobacter pylori positive, a course of Helicobacter pylori 
eradication treatment must have been completed. 
___ 
3.2.8 
No history of GI bleeding requiring a blood transfusion, endoscopic or operative 
intervention. 
___ 
3.2.9 
No history of any prior stroke (hemorrhagic or ischemic). 
___ 
3.2.10 No concurrent anticoagulation with warfarin, heparin/heparin analogues, 
clopidogrel, direct thrombin inhibitors, or direct factor XA inhibitors. 
___ 
3.2.11 No history of atrial fibrillation or myocardial infarction. 
___ 
3.2.12 No history of grade 4 hypertension, defined as hypertension resulting in life-
threatening consequences (e.g., malignant hypertension, transient or permanent 
neurologic deficit, hypertensive crisis). 
___ 
3.2.13 No chronic (duration >30 days) daily use of oral steroids. Inhaled or topical 
steroids are allowed. 
___ 
3.2.14 No known allergy to aspirin. 
___ 
3.2.15 No prior invasive malignancy of any type within the past 5 years except for 
current diagnosis of breast cancer, and any prior diagnosis of basal or squamous cell 
carcinoma of the skin. 
 
Prior history of in situ carcinoma is allowed. 
 
Patients with a prior history of any type of breast cancer greater than 5 years from study 
screening may participate in this study. 
___ 
3.2.16 Concurrent enrollment on a non-chemotherapy treatment trial will be allowed, as 
long as that trial allows concurrent daily aspirin use.  
___ 
3.2.17 No history of metastatic breast cancer.   
 


 
 
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4.0 
PATIENT REGISTRATION/RANDOMIZATION 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
  
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 


 
 
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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 
   
4.2 
Cancer Trials Support Unit Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 


 
 
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Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.1 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
Protocol Organization (PO) on the protocol. One way to search for a protocol is listed 
below. 
• 
Log in to the CTSU members’ website 
) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select Alliance, 
and protocol number A011502. 
• 
Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.) 
4.2.2 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 
 in order to 
receive further instruction and support. 
4.2.3 
Checking Site’s Registration Status  
Site registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 


 
 
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4.3 
Patient Registration Requirements 
• 
Informed consent: The patient must be aware of the neoplastic nature of their disease 
and willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, 
and discomforts. Current human protection committee approval of this protocol and a 
consent form is required prior to patient consent and registration. 
• 
Patient completed booklets: Patient Life Style Measures of Inflammation booklets are 
to be ordered prior to the registration of any patients. Patient completed booklets can be 
ordered by downloading and completing the CTSU supply request form (located under 
the site registration documents section of the A011502 CTSU site) and submitting the 
form via the Regulatory Submission Portal on the CTSU website (the portal is located 
under the Regulatory tab). Samples of the booklets are found in Appendix I, which are 
to be used for reference and IRB submission only. They are not to be used for patient 
completion. 
• 
The Alliance Prevention Committee study, A211601: “Evaluation of mammographic 
breast density effect of aspirin: A companion study to Alliance study A011502,” is a 
separate stand-alone companion protocol available to all institutions participating in 
Alliance A011502. All eligible patients enrolling to this study should be approached and 
invited to participate in Alliance A211601. Registration to A211601 may take place 
after a patient has been randomized to A011502. 
4.4 
Patient Registration/Randomization Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 


 
 
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Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
For any additional questions, contact the CTSU 
Help Desk at 
  
4.5 
Stratification Factors and Treatment Assignments 
Patients will be stratified by Hormone Receptor (HR) status, enrollment time, stage (Stage I/II 
vs Stage III), and body mass index as below: 
Hormone Receptor Status and enrollment time: 
1) Positive (either ER or PgR positive or unknown) and < 18 month since diagnosis 
2) Positive (either ER or PgR positive or unknown) and > 18 months since diagnosis 
3) Negative (both ER and PgR negative) 
  
 
Breast Cancer Stage  
1) Stage I/II 
2) Stage III 
NOTE: Sites can use AJCC 7 or AJCC 8 because the anatomical staging remains 
unchanged between the versions.  
Body Mass Index 
 
 
 
 
 
 
1) Less than 30 kg/ m2 
 
 
 
 
 
2) Greater than or equal to 30 kg/m2  
 
 
 
 
 


 
 
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5.0 
STUDY CALENDAR 
The Pre-study testing interval is a guideline only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
Pre-Study Testing Intervals  
• 
To be completed ≤ 28 DAYS before registration: History and physical. 
 
Prior to 
Registration/ 
Randomization 
Every 6 months 
from start of 
study treatment 
+/- 28 days* 
At End of 
protocol 
Treatment 
Post treatment 
follow-up 
Tests & Observations 
 
 
 
 
History and Progress Notes  
X 
X 
X (4) 
X 
Physical Examination 
X 
X 
X (4) 
X 
Weight, BMI 
X(1) 
X (1) 
 
 
PS 
X 
X 
X 
 
Height 
X 
 
 
 
Pulse, Blood Pressure 
X 
X 
 
 
Adverse Event Assessment 
X 
X 
X 
 
Patient Medication Diary 
 
X (2) 
 
 
Evaluation of Disease 
Recurrence or new invasive 
disease 
 
X (3) 
X (4) 
X (4) 
For patients who agree to participate 
Lifestyle Measures of 
Inflammation assessments 
and Registration Fatigue 
and Uniscale Assessment 
See Section 6.2 
Tissue, Blood and Urine 
samples for Future use 
See Section 6.3.  (5) 
*The first 6-month visit should be timed from the start of treatment. Subsequent visits should be timed 
based on the date of the previous visit. 
1. BMI to be calculated at baseline and at 24 months. 
2. The Patient Medication Log must begin the day the patient starts taking the study medication and must 
be completed per protocol and returned to the treating institution at each 6 month visit (see Section 7.0). 
3. Patients should be evaluated for disease recurrence every 6 months while receiving study treatment 
according to Section 11.1. 
4. Patients who complete five years of study treatment will be followed annually (+/- 28 days) until 10 
years from registration. Patients who stop treatment before 5 years without an invasive disease event 
will have a follow-up visit 6 months (+/- 28 days) after end of protocol treatment and then followed 
annually (+/- 28 days) until 10 years from registration. Patients who stop treatment before 5 years due 
to an invasive disease event may receive treatment at physician discretion and will be followed annually 
(+/- 28 days) until 10 years from registration. All patients will be followed for all invasive disease 
events (locoregional and distant recurrence and new primaries in breast and non-breast sites) and 
survival for a maximum of 10 years from registration. 
5. Sample should be drawn after consent, prior to the start of treatment.  


 
 
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6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data Collection and Submission 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration 
type. 
Refer to 
 for registration types and 
documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
using their CTEP-IAM username and password and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study 
name in iMedidata instead of the Rave EDC link; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC link 
will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at 
or 
by contacting the CTSU Help Desk at 
 
 A Schedule of Forms is available on the Alliance study webpage, within the Case Report Forms 
section. The Schedule of Forms is also available on the CTSU site within the study-specific 
Education and Promotion folder, and is named Time & Events. 
Patient completed questionnaire booklets for this study are to be ordered prior to the registration 
of any patients (see ). Samples of questionnaire booklets are available in Appendix I for 
reference and IRB submission only. They are not to be used for patient completion. Booklets 
must be given to patients to complete and patients should be instructed to return the booklets to 
site staff in person and site staff will enter patient into Rave. 


 
 
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6.1.1 
Supporting documentation 
This study requires supporting documentation for: 
1) Eligibility, which includes the pathology report (including node positivity or tumor 
size >2.0 cm and node negative) with histologic documentation of pathologic staging, 
date of diagnosis and ER, PR, HER2 status (see Section 3.2.1).  
2) Disease recurrence. 
3) New invasive primary. 
These pathology reports and any additional supporting documentation must be uploaded 
into RAVE at the time of Registration/Randomization and at the time of diagnosis of 
disease recurrence or new primary. 
6.1.2 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
6.2 
Lifestyle Measures of Inflammation 
Measures 
Baseline (After agreement to 
participate, prior to drug 
start date) 
At the end of 24 months of 
study treatment 1  
Modified Parffenbarger 
Questionnaire 
X 
X 
Sleep Quality Index (PSQI) 
X 
X 
Center for Epidemiologic Studies-
Depression Scale (CES-D) 
X 
X 
Perceived Stress Scale (PSS) 
X 
X 
Brief Pain Index 
X 
X 
1. Patients who discontinue study treatment before 24 months will be asked to complete the 
measure at the concurrent 24-month study visit. 


 
 
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6.3 
Specimen Collection and Submission  
All participating institutions must ask patients for their consent to participate in the collection 
of specimens planned for A011502 future analysis, although patient participation is optional. 
For patients who consent to A011502 biospecimen banking (consent question #1) tissue, blood, 
and urine will be collected at the following time points for these studies. Sites are required to 
provide their own materials for biospecimen collection (blood vacutainer tubes and urine 
specimen containers) and shipping (IATA-compatible biospecimen shipping boxes with cold 
packs, where necessary.  
 
After consent 
signed, prior to 
treatment start 
At the end of 24 
Months of study 
treatment 1 
Storage/ 
Shipping 
conditions  
Submit 
to: 
Tissue 
 
1 Paraffin block from resection for 
patients undergoing upfront 
surgery * 
OR 
1 Paraffin block for patients with 
residual disease after neoadjuvant 
chemotherapy* 
OR 
1 Paraffin block from initial 
diagnostic biopsy for patients who 
under-went neoadjuvant 
chemotherapy with complete or 
near complete pathologic response* 
X 
 
 
Ambient/ship 
overnight 
WUSTL 
 
Blood 
Whole blood 
 
 
 
 
EDTA tube Whole blood* 
One 10 mL K2 
or K3 EDTA 
lavender top 
anticoagulant 
vacutainer tube 
One 10 mL K2 or K3 
EDTA lavender top 
anticoagulant 
vacutainer tube 
Cool pack/ship 
over night 
WUSTL 
* See Sections 6.3.4 and 6.3.5    1 Patients who discontinue study treatment will be asked to provide the whole blood 
and spot urine samples at the concurrent 24-month visit. 
Urine 
Spot Urine 
 
Cool 
pack/ship 
over night 
 
Spot Urine* 
Two 15 ml falcon tubes with10ml of 
urine per tube 
Two 15 ml falcon tubes 
with10ml of urine per tube 
WUSTL 
6.3.1 
Specimen submission using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA 
THIS SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL: 
using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS webpage to access the on-line user manual, FAQs, 
and training videos. To report technical problems, such as login issues or application errors, 
please contact: 
For assistance in using the 
application or questions or problems related to specific specimen logging, please contact: 
 


 
 
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After logging collected specimens in BioMS, the system will create a shipping manifest. 
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All blood and urine specimens must be labeled with the protocol number (A011502), 
Alliance patient number, patient’s initials, date and type of specimen collected (e.g., urine, 
whole blood). 
Any surgical pathology tumor block or unstained slides submitted MUST be accompanied 
by a corresponding de-identified surgical pathology report labeled with the protocol 
number (A011502) and Alliance patient number. 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in 
the shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Ship specimens on Monday through Thursday only. Shipping by overnight service to 
assure receipt is encouraged. Do not ship specimens on Fridays or Saturdays. 
All specimens should be sent to the following address: 
Alliance Biorepository at Washington University 
 
 
 
 
 
6.3.2 
Collection of tissue, blood and urine 
For patients who consent to participate in the optional specimen collection and banking, 
tumor blocks will be banked for future analyses and potential correlative studies. 
6.3.3 
Collection of paraffin blocks 
Paraffin blocks of primary tissue obtained from archival tumor specimens should be sent 
to the Alliance Biorepository at Washington University (WUSTL) within 30 days of patient 
registration/randomization.  
The Alliance has instituted special considerations for the small percentage of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of hospitals 
whose policies prohibit release of any block. If, due to institutional policy, a block cannot 
be sent, three unstained slides, cut at 4-6 micron in thickness and mounted on charged glass 
slides will be requested. Slides should be labeled as follows: Each slide must be labeled 
with the specimen surgical pathology number and block number either via your institutions 
standard method for labeling clinical slides or using a permanent marker. Please DO NOT 
use sticky labels. The labeling of study number, patient ID, patient Initials, sample type, 
and collection time is no longer required on slides. 
The goal of the Alliance Biorepository at Washington University is to provide investigators 
with quality histology sections for their research while maintaining the integrity of the 
tissue. For this reason, it is preferred that the Alliance Biorepository at Washington 
University bank the block until the study investigator requests thin sections. Please contact 
the Alliance Biorepository at Washington University if additional assurances with your 
hospital pathology department are required. 


 
 
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Be certain to include a de-identified surgical pathology report, which includes the surgical 
pathology case number and tissue block identifier that matches the submitted block or 
labeled slides. 
For patients who are simultaneously enrolled to another Alliance trial (e.g. A011401) at 
the same time as this study, and there is insufficient tissue available to be submitted 
separately for both studies, please prioritize the tissue for the current A011502 study and 
ship the tissue to the Alliance Biorepository at Washington University in St. Louis. Please 
select “not collected” in BioMS for the other trial to which the patient may be enrolled (e.g. 
A011401) for tissue submission, select “other” as the reason for not collecting the 
specimen, and note in the comments area that tissue has been submitted to for A011502 
study, along with the A011502 participant ID. 
For any questions regarding tissue submission for patients enrolled on any Alliance studies, 
please contact Melissa McKenna email: mlmckenna@wustl.edu. Phone: 
 
6.3.4 
Blood sample submission 
Collect 10 mL of venous blood in one K2 or K3 EDTA lavender top anticoagulant 
vacutainer tube. The tubes should be inverted approximately 8-10 times to mix the 
EDTA.  Refrigerate sample until shipping. The sample should be placed in a biohazard bag 
and shipped according to IATA guidelines the same day as the blood is drawn on a cold 
pack by overnight courier service to the Alliance Biorepository at Washington University. 
Blood samples will be processed into plasma and buffy coat for long term storage by the 
Alliance Biorepository at Washington University (WUSTL). 
6.3.5 
Urine sample submission 
Spot urine collection should follow institutional standard procedures. For each collection, 
20 mls of urine should be transferred into two 15 ml falcon tubes (10 ml per tube) or any 
equivalent collection container, and be shipped overnight with a cold pack to the Alliance 
Biorepository at Washington University. Ensure that the collection containers are sealed, 
fluid-tight, and that lids will not become insecure during transit. 
Urine samples will be stored as 2 ml aliquots in LN2 vapor until retrieved for correlative 
science assays. 
Label blood and urine samples with the following identification: 
• 
1) 
Specimen procurement date and time 
• 
2) 
Alliance patient number 
• 
3) 
Alliance study number (A011502) 
• 
4) 
Specimen type: Whole blood; spot urine. 
7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 28 days of registration/randomization. This is a double blinded, 
placebo controlled trial. Patients will be randomized with equal probability to receive treatment 
with aspirin or placebo. 
7.1 
Study Treatment 
Agent 
Dose 
Route 
Day 
Aspirin/Placebo 
One 300 mg tablet 
Oral 
Daily x 5 years 
 


 
 
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After registration, blinded, patient-specific supplies of aspirin/placebo are to be ordered by the 
site by completing the drug order form (see Section 10.0). 
Patients should be given a six-month supply of study drug in order to correspond with study 
visit schedule in Section 5.0. 
7.2 
Adherence 
Since patients will take oral medications at home without direct supervision, we will monitor 
drug compliance until the discontinuation of aspirin/placebo using A011502 Study Medication 
Logs (Appendix II). At study entry the patient will receive the Medication Log and be instructed 
on how to take the medication and how to use the Log. The patient will bring the Log to each 
visit where it will be reviewed with a member of the study team. The patient will then be given 
a new Log to record study medication until the next visit. If a patient cites reasons other than 
drug side effects for not taking the required medication, the reasons for missed doses will be 
reviewed and the importance of taking all doses on schedule will be reinforced. The study team 
member will document the patient-reported dosage in the patient’s medical record and determine 
if the patient was compliant for that study period and document compliance on the appropriate 
study forms. Compliance is defined as patient self-report of taking 80% of study tablets. 
Non-protocol use of aspirin and NSAIDs will also be monitored every 6 months along with 
study drug compliance. 
7.3 
Disease Recurrence and New Invasive Disease 
Upon disease recurrence or new invasive second primary, except for basal or squamous cell 
carcinoma of the skin, protocol treatment will be discontinued and treatment will then be at the 
discretion of the treating physician. 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose must be recorded in the medical 
records. 
8.1.2 
Antiemetics may be used at the discretion of the attending physician. Analgesics and/or 
antiemetics received from the first day of study treatment administration until 30 days 
after the final dose must be recorded in the medical records. 
8.1.3 
Proton pump inhibitors (PPIs) may be used at the discretion of the treating study 
physician. 
*For patients who require a PPI, US sites only may order the PPI through the Alliance 
while funding is available. Instructions for ordering the PPI are located on the A011502 
study pages on the Alliance and CTSU websites. 
8.1.4 
Non-protocol use of aspirin and/or NSAIDs is discouraged. However, non-protocol 
use of these medications will not result in removal from study, but must be noted on 


 
 
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the appropriate study form. Instead, use of acetaminophen for treatment of aches, 
pains, and fevers is encouraged. 
8.1.5 
Concomitant endocrine therapy  
Patients with hormone receptor (ER and/or PR) positive disease should receive a minimum 
of 5 years of standard endocrine therapy (experimental agents/regimens are not permitted).  
Endocrine therapy should begin following completion of neoadjuvant chemotherapy and 
surgery, either before, during or after radiation therapy at discretion of oncologist. 
Selection of the agents is at the treating physician’s discretion. 
8.1.6 
Study drug should be held while on lovenox or other daily anticoagulation 
medications. 
8.1.7 
Co-enrollment in other clinical trials 
Patients are able to co-enroll on these studies only if they have completed radiation, 
chemotherapy or surgery and meet all other A011502 eligibility criteria. For the studies 
listed below, you do not need to ask for a separate confirmation from the A011502 Study 
Chair. However, for those studies that are NOT listed, please contact the study Protocol 
Coordinator at the email or phone number listed on the cover page of this protocol. 
 
Trials for which co-enrollment is allowed: 
Trials involving everolimus, palbociclib, PARP inhibitors, such as: 
AFT-05 PALLAS: PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III 
Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant 
Endocrine Therapy Alone for Hormone Receptor Positive (HR+) / Human Epidermal 
Growth Factor Receptor 2 (HER2)-Negative Early Breast Cancer (PALLAS). 
Alliance A011401: Randomized Phase III Trial of Evaluating the Role of Weight Loss in 
Adjuvant Treatment of Overweight and Obese Women with Early Breast Cancer. 
SWOG S1207: Phase III Randomized, Placebo-Controlled Clinical Trial Evaluating the 
Use of Adjuvant Endocrine Therapy +/- One Year of Everolimus in Patients with High-
Risk, Hormone Receptor-Positive and HER2/Neu Negative Breast Cancer. e3 Breast 
Cancer Study-Evaluating Everolimus with Endocrine Therapy. 
 


 
 
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Trials for which co-enrollment is allowed after completion of radiation and 
chemotherapy: 
Per Section 3.2.3, all adjuvant treatment with chemotherapy and/or radiation must be 
completed at least 30 days prior to registration. A patient may enroll on A011502 after they 
have completed radiation therapy and/or chemotherapy on the following trials provided 
that they meet all other eligibility criteria.  
Surgery trials: 
ALLIANCE A011202: A Randomized Phase III Trial Comparing Axillary Lymph Node 
Dissection to Axillary Radiation in Breast Cancer Patients (cT1-3 N1) Who Have Positive 
Sentinel Lymph Node Disease After Neoadjuvant Chemotherapy. 
Radiation trials:  
NRG B51: A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy Chest wall 
and Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT in Patients with 
Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to 
Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy. 
Chemotherapy Trials: 
ECOG EA1131: A Randomized Phase III Post-Operative Trial of Platinum Based 
Chemotherapy vs. Observation in Patients with Residual Triple-Negative Basal-Like 
Breast Cancer Following Neoadjuvant Chemotherapy after the completion of carboplatin 
or capecitabine. 
NRG BR-003: A Randomized Phase III Trial of Adjuvant Therapy Comparing 
Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel with or Without 
Carboplatin for Node-Positive or High-Risk Node-Negative Triple-Negative Invasive 
Breast Cancer 
8.2 
Dose Modifications 
8.2.1 
Dose Levels 
Dose 
Level 
Drug Name 
Dose 
0* 
Aspirin 
300 mg 
-1 
Aspirin 
100 mg 
 
*Dose level 0 refers to the starting dose. 
If dose reduction below level -1 is required, permanently discontinue protocol therapy. 
8.2.2 
Hematologic Adverse Events 
8.2.2.1 Grade 1 bleeding 
For grade 1 bleeding, one level dose reduction will be allowed at physician discretion.  
8.2.2.2 Grade 2 bleeding 
For grade 2 bleeding, one level dose reduction will be required.  
For recurrent Grade 2 bleeding after dose reduction, discontinue protocol therapy. 


 
 
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8.2.2.3 Grade 3 and 4 gastrointestinal bleeding or active gastrointestinal ulceration 
Grade 3and 4 GI bleeding will require that the patient be permanently removed from 
protocol treatment. 
8.2.2.4 Other grade 1 and 2 non-bleeding related gastrointestinal toxicity 
A proton pump inhibitor will be prescribed for the patient at the discretion of the 
treating physician. Alternatively, at the discretion of the treating physician, one level 
dose reduction may be performed. 
8.2.3 
Cardiovascular toxicities and thrombotic events 
8.2.3.1 For grade 3 or 4 cardiac ischemia/infarction or thrombosis: Permanently 
discontinue protocol therapy. 
8.2.3.2 For grade 1 toxicity, no change in study drug dosage is required. 
For grade 2 toxicity, reduce to dose level -1, at physician discretion. If dose is 
reduced, patients should continue at this dose for the duration of study treatment. 
8.2.4 
Intracranial hemorrhage: Permanently discontinue protocol therapy for any grade 
intracranial bleeding. 
8.2.5 
Macular Degeneration: Permanently discontinue protocol therapy for any grade 
macular degeneration considered related to aspirin/placebo. 
8.2.6 
Tinnitus or hearing loss: Permanently discontinue protocol therapy for any grade  
considered related to aspirin/placebo. 
8.2.7 
Dermatologic toxicities: Permanently discontinue protocol therapy for Stevens-
Johnson syndrome or toxic epidermal necrolysis. 
8.2.8 
Other non-hematologic toxicities attributed to aspirin/placebo 
For other grade 3 or 4 non-hematologic toxicities considered related to aspirin/placebo, 
interrupt aspirin/placebo, for a maximum of 28 days until toxicity improves to ≤ grade 2, 
then resume aspirin/placebo, with one dose reduction.  
For recurrence of the same grade 3 or 4 non-hematologic toxicity considered related to 
aspirin/placebo, or if toxicity does not improve after 28 days, permanently discontinue 
aspirin/placebo. 
For persistent grade 2 non-hematologic toxicity considered related to aspirin/placebo that 
the patient finds unacceptable, interrupt aspirin/placebo for a maximum of 28 days until 
toxicity improves to ≤ grade 1, then resume aspirin/placebo at the previous dose.  
For recurrence of unacceptable grade 2 non-hematologic toxicity considered related to 
aspirin/placebo, or if grade 2 toxicity does not improve after 28 days, permanently 
discontinue aspirin/placebo. 
8.2.9 
Holding study drug for surgical procedures 
Since aspirin can be associated with an increased risk of post-operative bleeding, some 
surgical procedures require stopping aspirin before and after a procedure. If the treating 
physician or surgeon determines that aspirin would be held for a procedure, then the study 
drug should be held for the same period of time. The total period that the study drug can 
be held for surgical procedures should not exceed 28 consecutive days. 


 
 
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8.3 
Unblinding Procedures  
Unblinding can be done only in cases of an emergency where knowledge of the treatment arm 
affects immediate medical management. Most medical emergencies and events attributed to 
study therapy can be adequately managed without knowledge of the treatment arm. 
Follow the directions below for emergency unblinding procedures. Please note that if a treatment 
assignment is unblinded, the patient must discontinue protocol therapy, but will continue to be 
followed per Section 12.2. 
Emergency Unblinding Procedures:  
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at least 
possibly related to the investigational agent and for which unblinding would influence treatment 
decisions; or 2) medication error, such as accidental overdose. Expected adverse events are 
listed in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 
 
  
The institution must provide the following information to the Alliance Executive Officer:  
• Alliance study ID (i.e., “A011502”)  
• Alliance patient ID number (e.g., “999999”)  
• Patient initials (e.g., “L,FM”)  
• Institution name  
• Name and telephone number of treating physician  
• Name and contact information of person requesting the unblinding procedure  
• Name and contact information of person to inform of treatment assignment  
• Reason for emergency unblinding  
Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation.  
After the Executive Officer deems unblinding is warranted, the treatment assignment will be 
provided to the contact person at the treating site.  
 
 


 
 
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9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using 
the terminology and grading categories defined in the NCI’s Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03. However, CTCAE v5.0 must be used for serious AE 
reporting through CTEP-AERS as of April 1, 2018. The CTCAE is available at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Attribution to protocol 
treatment for each adverse event must be determined by the investigator and reported on the 
required forms. Please refer to the section on AE reporting procedures. NCI Guidelines: Adverse 
Event Reporting Requirements for further details.  
9.1 
Routine Adverse Event Reporting   
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Adverse Events: Solicited 
form is used for routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment. 
• 
 
• 
CTCAE v 4.03 Term 
• 
CTCAE v4.0 Organ Class 
(SOC) 
• 
Gastrointestinal 
bleeding 
• 
Gastrointestinal disorders 
• 
Intracranial 
hemorrhage 
• 
Nervous system disorders 
• 
Epistaxis 
• 
Respiratory, 
thoracic 
and 
mediastinal disorders 
• 
Hematuria 
• 
Renal and urinary disorders 
• 
Dyspepsia 
• 
Gastrointestinal disorders 
• 
Gastritis 
• 
Gastrointestinal disorders 
• 
Bruising 
• 
Injury, 
poisoning 
and 
procedural complications 
 
 


 
 
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9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to 
the Alliance Statistics and Data Center. Questions about routine reporting should be directed 
to the Data Manager. 
 
*Combinations of CTCAE Grade & Attribution Required for Routine AE Data 
Submission on Case Report Forms (CRFs) 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 days of 
the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the patient’s last 
treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS)  
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their 
Institutional Review Board if a patient has a reportable serious adverse event. The descriptions 
and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5 will be utilized for AE reporting beginning April 1, 2018. A copy of the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
 
All appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note: All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the system 
organ class (SOC) “General disorders and administration site conditions.” Evidence that the death 
was a manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be submitted. 
 
 


 
 
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9.3.1 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE ≤ 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
• 
Grade 1 
Timeframes 
• 
Grade 2 
Timeframes 
• 
Grade 3 
Timeframes 
• 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 


 
 
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2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
NOTE: Deaths clearly due to progressive disease should be reported via CTEP AERS 
• 
Expedited AE reporting timelines defined: 
• 
➢ 
“24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS 
report ≤ 5 calendar days of the initial 24-hour report. 
• 
➢ 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
≤ 10 calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with 
an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Grade 3/4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse events 
that precipitate hospitalization or prolong an existing hospitalization must be reported via CTEP-
AERS. 
• A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
▪ 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
▪ 
Myelodysplastic syndrome (MDS)  
▪ 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms as outlined in the protocol.  
• A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
unless otherwise specified.  
• 
All new malignancies must be reported via CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment. All new malignancies should be reported, i.e. solid 


 
 
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tumors 
(including 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. Whenever possible, 
the CTEP-AERS reports for new malignancies should include tumor pathology, history or prior 
tumors, prior treatment/current treatment including duration, any associated risk factors or 
evidence regarding how long the new malignancy may have been present, when and how the new 
malignancy was detected, molecular characterization or cytogenetics of the original tumor (if 
available) and of any new tumor, and new malignancy treatment and outcome, if available. 
• 
Treatment expected adverse events include those listed in Section 10.0 and in the package insert. 
• 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, 
the Pregnancy Information Form should be completed and submitted, along with any additional 
medical information (form is available on the CTEP website at
 The 
potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS report. 
In CTCAE v5.0, pregnancy loss is defined as “Death in utero,” and any pregnancy loss should 
be reported expeditiously as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 event under 
the Pregnancy, puerperium perinatal conditions SOC, as currently CTEP-AERS recognizes this 
event as a patient death. 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
10.0 
DRUG INFORMATION 
10.1 
Aspirin or Aspirin-Matched Placebo 
Aspirin/Placebo is IND exempt as used in this trial. This exemption has been determined by 
attestation that neither the investigator nor sponsor intends to seek a new indication for use or 
to support any other significant change in the labeling or product advertising for aspirin. This 
investigation will use an approved route of administration and dosage of aspirin and has no 
factors that increase the risk of the product. This investigation will be in compliance with 21CFR 
parts 56, 50, and 312.7 and neither the investigator nor the sponsor will promote or represent 
that aspirin is safe or effective for the context that is under investigation in this study. This 
investigation will not commercially distribute or test market the study agent, and will not 
unnecessarily prolong an investigation. 
Procurement 
Aspirin/placebo is an investigation agent supplied by Bayer and distributed by McKesson. Use 
the order form that is provided on the A011502 study page of the Alliance and CTSU web sites 
to order Aspirin/placebo. McKesson will ship a maximum of 2-year supply per shipment per 
patient to the site. 
At the end of the trial, any expired or remaining supplies of study drug should be destroyed 
according to institutional procedure. 
Formulation 
Aspirin/placebo is supplied as matching tablets in 300 mg and 100 mg strength in 200 count 
bottles. Please see drug order form for further details regarding supply. 
Aspirin 300mg tablets contain: 300mg acetylsalicylic acid, 30 mg powdered cellulose, 30mg 
maize starch, with coating of methacrylic acid-ethylacrylate copolymer, polysorbate 80, sodium 
laurilsulfate, talc, and triethyl citrate. Appearance is round coated white tablet 10mm in diameter 
and 407mg in weight. 


 
 
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Placebo 300mg tablets contain: 36mg calcium hydrogen phosphate dihydrate, 72mg 
microcrystalline cellulose, 15mg anhydrous citric acid, 198mg lactose monohydrate, 1mg 
magnesium stearate, 36mg maize starch, and 2mg colloidal anhydrous silica, with coating of 
methacrylic acid-ethylacrylate copolymer, talc, and triethyl citrate. Appearance is round coated 
white tablet 10mm in diameter and 407mg in weight. 
Aspirin 100mg tablets contain: 100mg acetylsalicylic acid, 10 mg powdered cellulose, 10mg 
maize starch, with coating of methacrylic acid-ethylacrylate copolymer, polysorbate 80, sodium 
laurilsulfate, talc, and triethyl citrate. Appearance is round coated white tablet 7mm in diameter 
and 137mg in weight.  
Placebo 100mg tablets contain: 12mg calcium hydrogen phosphate dihydrate, 24mg 
microcrystalline cellulose, 5mg anhydrous citric acid, 66mg lactose monohydrate, 0.4mg 
magnesium stearate, 12mg maize starch, and 0.67mg colloidal anhydrous silica, with coating of 
methacrylic acid-ethylacrylate copolymer, talc, and triethyl citrate. Appearance is round coated 
white tablet 7mm in diameter and 137mg in weight. 
Storage and Stability 
Store aspirin and placebo at room temperature 20° to 25°C (68° to 77°F), with excursions 
permitted to 15°C to 30°C (59°F to 86°F).” 
Administration 
Aspirin should be administered with food or full glass of water to minimize GI distress. Do not 
crush enteric coated tablets. 
Reconciliation 
Utilize the NCI oral DARF for documentation. Forms should be study specific and patient 
specific due to the double blind nature of the trial. 
Drug Interactions 
Aspirin is a minor substrate of CYP2C9. Inhibitors and inducers of CYP2C9 may alter aspirin 
exposure. Aspirin has the potential to have the following drug interactions:  
Angiotensin converting enzyme (ACE) inhibitors: The hyponatremic and hypotensive effects 
of ACE inhibitors may be diminished by concomitant administration of aspirin. 
Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum 
concentrations of acetazolamide (and toxicity) due to indirect effects on the renin-angiotensin 
conversion pathway. 
Anticoagulant/Antiplatelet therapy: Patients on concomitant anticoagulant and antiplatelet 
therapies are at increased risk of bleeding with concomitant aspirin due to competition at the 
renal tubule for secretion. 
Anticonvulsants: Salicylates can displace protein-bound phenytoin and valproic acid, leading 
to decreases in phenytoin and valproic acid concentrations. 
Beta blockers: The hypotensive effects of beta blockers may be diminished with concomitant 
aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and 
salt/fluid retention. 
Diuretics: Diuretic effectiveness may be diminished with concurrent aspirin due to inhibition 
of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. 
Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow 
toxicity, especially in the elderly or renally impaired. 


 
 
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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Concomitant administration of NSAIDs 
and aspirin may lead to increased bleeding or decreased renal function. Avoid concurrent use. 
Oral Hypoglycemics: Moderate aspirin doses may increase the effectiveness of oral 
hypoglycemic agents causing hypoglycemia. 
Uricosuric Agents: (Probenecid and Sulfinpyrazone): Salicylates antagonize the uricosuric 
action of uricosuric agents. 
Pharmacokinetics 
Absorption: Immediate, rapid and completely absorbed from gastrointestinal tract. 
Distribution: Widely distributed to all tissues and fluids in the body including the central 
nervous system (CNS) and breast milk and fetal tissues. The highest concentrations are found 
in the plasma, liver, renal cortex, heart and lungs. The protein binding of salicylate is 
concentration-dependent, i.e. non-linear.  
Metabolism: Hydrolyzed to salicylate (active by esterases in GI mucosa, red blood cells, 
synovial fluid and blood; metabolism of salicylate occurs primarily by hepatic conjugation; 
metabolic pathways are saturable. 
Excretion: Urine (75% as salicyluric acid, 10% as salicylic acid). 
T1/2: Parent drug 15 to 20 minutes; Salicylates 3 hours. 
Adverse Events 
Cardiovascular: Cardiac arrhythmia, edema, hypotension, tachycardia. 
Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, fatigue, 
headache, hyperthermia, insomnia, lethargy, nervousness, Reye’s syndrome. 
Dermatologic: Skin rash, urticarial. 
Endocrine & Metabolic: Acidosis, dehydration, hyperglycemia, hyperkalemia, hypernatremia 
(buffered forms), hypoglycemia (children). 
Gastrointestinal: Gastrointestinal ulcer, duodenal ulcer, dyspepsia, epigastric distress, gastritis, 
gastrointestinal erosion, heartburn, nausea, stomach pain, vomiting. 
Genitourinary: Postpartum hemorrhage, prolonged gestation, prolonged labor, proteinuria, 
stillborn infant. 
Hematologic & Oncologic: Anemia, blood coagulation disorder, disseminated intravascular 
coagulation, hemolytic anemia, hemorrhage, iron deficiency anemia, prolonged prothrombin 
time, thrombocytopenia. 
Hypersensitivity: Anaphylaxis, angioedema. 
Neuromuscular & Skeletal: Acetabular bone destruction, rhabdomyolysis, weakness. 
Otic: Hearing loss, tinnitus. 
Renal: Increased blood urea nitrogen, increased serum creatinine, interstitial nephritis, renal 
failure (including cases caused by rhabdomyolysis), renal insufficiency, renal papillary necrosis 
Respiratory: Asthma, bronchospasm, dyspnea, hyperventiliation, laryngeal edema, 
noncardiogenic pulmonary edema, respiratory alkalosis, tachypnea. 
Miscellaneous: Low birth weight. 


 
 
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Postmarketing and/or case reports (Limited to important or life-threatening): Anorectal 
stenosis (suppository), atrial fibrillation (toxicity), cardiac conduction disturbance (toxicity), 
cerebral infarction (ischemic), cholestatic jaundice, colitis, colonic ulceration, coronary artery 
vasospasm, delirium, esophageal obstruction, esophagitis (with esophageal ulcer), macular 
degeneration (age-related), periorbital edema, rhinosinusitis. 
• 
Nursing Guidelines 
• 
1. 
Patients may experience GI upset and or reflux. Treat symptomatically and 
monitor for effectiveness. 
• 
2. 
Aspirin can cause GI bleeding. Instruct patients to report any black tarry stools 
and/or hematemesis to the study team immediately. 
• 
3. 
Patients may experience increased bruising and/or bleeding. Instruct patients to 
report this to the study team. 
• 
4. 
Patients should be instructed not to take NSAID’s in conjunction with aspirin. 
Concomitant use can lead to increased risk of bleeding and/or renal dysfunction. 
10.2 
Shipment of Study Drug Supply Directly to the Study Participant 
Sites may ship a study participant’s drug supply directly to the participant’s place of residence 
if a site so chooses. The costs associated with the shipping of the participant’s drug supply to 
their place of residence are the sole responsibility of the site. The Alliance will not reimburse a 
site for this cost. 
McKesson will ship a maximum of 2-year supply per shipment per patient. Sites may distribute 
all or a portion of this supply to the participant. If a site were to elect to ship directly to the 
participant’s place of residence, the Alliance recommends shipping the first of 6 months’ supply. 
Subsequent 6 month supplies can be distributed directly to the participant during “scheduled 
“patient visits (see Study Calendar, Section 5.0). 
Participants should be informed about storage requirements per protocol, Section 10.2, namely: 
“Store Aspirin/Placebo at 15 to 30C (59to 86F) in a dry place and keep the container tightly 
closed.” 
11.0 
MEASUREMENT OF EFFECT 
11.1 
Evaluation of Breast Cancer Outcomes 
Disease will be monitored according to ASCO guidelines [22]. The diagnosis of a first breast 
cancer recurrence or second primary can be made only when both the clinical and laboratory 
findings confirm the presence of disease. Suspicious findings do not constitute criteria for breast 
cancer recurrence. PET scans may be performed at the discretion of the investigator. However 
PET scans, in the absence of objective findings on CT, MRI, or other imaging studies do not 
meet the criteria of an acceptable method of determining breast cancer recurrence for this study. 
Any recurrence of malignant disease should be proven by biopsy whenever possible. Treatment 
of a breast cancer recurrence or second primary cancer will be at the discretion of the treating 
physician. 
For all confirmed breast cancer recurrence or second primary cancers, the time to event will be 
based on the earliest date of diagnostic evidence. Initial diagnosis of the event should not be a 
first occurrence of symptoms, but must be based on a clinical assessment with objective 
findings, whether by physical exam or radiological determination that is subsequently confirmed 
(if applicable) as defined below. 


 
 
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11.1.1 Invasive ipsilateral breast cancer recurrence 
Defined as evidence of invasive cancer in the ipsilateral breast or chest wall. Patients who 
develop clinical evidence of tumor recurrence in the remainder of the ipsilateral breast or 
chest wall must have a biopsy of the suspicious lesion to confirm the diagnosis. 
11.1.2 Invasive local/regional recurrence 
Defined as the development of invasive tumor in the ipsilateral internal mammary, 
ipsilateral supraclavicular, ipsilateral infraclavicular, and/or ipsilateral axillary nodes, as 
well as the soft tissue of the ipsilateral axilla. This can be confirmed with positive cytology 
or histologic biopsy. 
11.1.3 Distant recurrence 
Defined as evidence of invasive tumor in any areas of the body, with the exception of those 
defined as local or regional recurrence above.  
11.1.4 Invasive contralateral breast cancer 
Defined as evidence of invasive breast cancer in the contralateral breast or chest wall. This 
must be confirmed histologically. 
11.1.5 Second primary invasive cancer (non-breast) 
Defined as evidence of any non-breast second primary invasive cancer, excluding 
squamous or basal cell carcinoma of the skin and in situ carcinomas of any site. This must 
be confirmed histologically whenever possible. 
11.2 
Definitions of Analysis Variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section of the protocol. 
11.3 
Evaluation of Cardiovascular Outcomes  
11.3.1. Myocardial infarction  
Both non-fatal and fatal myocardial infarctions are to be reported. Standard CTCAE 
adverse event definitions will be used. 
11.3.2. Cerebrovascular event 
Both fatal and non-fatal cerebrovascular events are to be reported. The definition of a 
cerebrovascular event will be based upon radiographic evidence of an ischemic or 
hemorrhagic stroke. 
11.2.3 Need for cardiovascular procedures 
All cardiovascular procedures including coronary artery bypass surgery, coronary stent 
placement, and/ angioplasty of coronary vessels are to be reported. 
12.0 
END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment 
12.1.1 Protocol treatment is for 5 years or until the first occurrence of invasive disease, as 
follows: Distant recurrence, locoregional recurrence, ipsilateral or contralateral 
breast cancer, second primary (non-breast) invasive cancer, or death from any 


 
 
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cause. Treatment after any of these events is at the discretion of the treating 
physician. (See Section 7.0 Treatment Plan). 
12.1.2 Early discontinuation of study agent 
If protocol treatment is discontinued early for reasons other than patient death or the 
invasive disease events listed above, such as, adverse events from A011502 protocol 
therapy, physician discretion, patient withdrawal, early unblinding or extraordinary 
medical circumstances, continue to follow the patient according to Section 12.2. 
12.2 
Patient Follow-up 
Follow all patients enrolled on this study regardless of eligibility status, including those who do 
not receive any protocol therapy, or switch to non-protocol therapy, for a maximum of 10 years.  
• 
Patients who complete five years of study treatment without a disease event will be 
followed annually for 10 years from registration for invasive disease events 
(locoregional and distant recurrence and new primaries in breast and non-breast sites) 
and survival. 
• 
Patients who stop treatment before five years without a disease event will have a follow-
up visit 6 months after end of protocol treatment, and then will be followed annually for 
10 years from registration for invasive disease events (locoregional and distant 
recurrence and new primaries in breast and non-breast sites) and survival. 
• 
Patients who stop treatment before five years due to a disease event will be followed 
annually for 10 years from registration for invasive disease events (locoregional and 
distant recurrence and new primaries in breast and non-breast sites) and survival. 
Reports of all invasive disease events, i.e., first and subsequent, and survival are to be submitted 
yearly for the 10-year follow-up period.  
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This is a randomized double-blind placebo-controlled phase III trial of aspirin (300 mg daily) in 
non-metastatic HER2 negative breast cancer patients. Patients will be randomized 1:1 within 
stratum defined by: Hormone Receptor status (HR positive vs HR negative), body mass index 
(<30 vs ≥ 30 kg/m2) and anatomic stage (Stage I/II vs III). 
The primary objective of this trial is to compare the effect of aspirin versus placebo upon 
invasive disease free survival (iDFS). 
13.2 
Sample Size, Accrual Time and Study Duration 
A stratified log-rank test will be used for the primary comparison of iDFS, with an overall one-
sided Type I error of 0.025. Five year iDFS on placebo is assumed to be 77% based on results 
from the control arm of E5103. This study randomized 4994 patients to doxorubicin, 
cyclophosphamide, and paclitaxel plus or minus bevacizumab, and the patient population was 
similar to current eligibility criteria. An improvement in 5year iDFS to 82.2% would be 
considered clinically meaningful (HR = 0.75) and consistent with published data. Final analysis 
will occur at 381 IDFS events, in order to have 80% power to detect the target improvement.  
A total sample size of 2936 patients will be enrolled in order to reach 381 iDFS events for final 
analysis. This assumes an accrual duration of 30 months including a 6 month ramp-up period to 
a maximum of 108 patients per month, and a constant hazard of loss-to-follow-up rate of 5% at 
48 months in each arm. 


 
 
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An additional follow-up of 24 months is anticipated to reach final analysis, for a total study 
duration of 54 months from activation. 
Because accrual was slower than anticipated, the eligibility criteria have been expanded 
although the sample size and overall analytic plan remain unchanged.  Originally, subjects must 
have histologically confirmed invasive breast cancer and register within 12 months of initial 
diagnosis.  The eligibility criteria have been extended to within 18 months of initial diagnosis 
for hormone receptor negative patients (HR-), and patients with hormone-receptor positive 
disease (HR+) would be eligible to participate within 10 years from initial diagnosis if there is 
no evidence of local/regional recurrence or metastatic disease.  With the proposed change in 
study population, the primary objective will remain to compare the invasive disease free survival 
(iDFS) of patients randomized to receive aspirin (300 mg daily) versus placebo, and is defined 
as the interval from the defined as time from randomization to the first occurrence of any one of 
the following events for invasive disease: Distant recurrence, locoregional recurrence, ipsilateral 
or contralateral breast cancer, second primary (non-breast) invasive cancer or death from any 
cause as per section 13.3, and the primary analysis will be performed in an intention-to-treat 
manner, in which all patients including those who do not begin protocol therapy will be analyzed 
according to their assigned arm (13.3.3). The target effect-size will remain a 25% improvement 
in outcomes with the intervention (HR = 0.75), and under the assumption the risk of recurrence 
in HR+ disease is approximately constant even up to 20 years out from diagnosis (66), the 
number of IDFS events for final analysis would be reached under comparable timelines with the 
target sample size of 2936 patients. With the modification, the HR status stratification factor has 
been modified to be HR-positive patients that are less than or greater than 18 months out from 
initial diagnosis, and HR-negative patients, and a secondary analysis will be done to compare 
the efficacy in the subgroup of patients within 18 months of diagnosis, and explore outcomes 
and relationship to treatment in patients more than 18 months out from initial diagnosis with 
disease-free interval included as a covariate in multivariate regression models. 
13.3 
Primary Endpoint Analysis 
Endpoints for efficacy use only invasive disease. Patients who withdraw consent for clinical or 
survival follow-up or lost patients will be censored at the date of withdrawal/loss according to 
disease and survival status known at that time. 
13.3.1 Primary endpoint 
The primary endpoint of this trial is invasive disease-free survival (iDFS), defined as time 
from randomization to the first occurrence of any one of the following events for invasive 
disease: Distant recurrence, locoregional recurrence, ipsilateral or contralateral breast 
cancer, second primary (non-breast) invasive cancer or death from any cause. Censoring 
will occur on the date the patient was last known to be alive and free from all invasive 
breast cancer and second invasive primaries.  
13.3.2 
Secondary Endpoint 
Secondary endpoints for disease outcome include overall survival (OS) and distant disease 
free survival (DDFS). OS is defined as the time from randomization to death from any 
cause; surviving patients will be censored at the date last known to be alive. DDFS is 
defined as the time from randomization to the first occurrence of any one of the following 
events for invasive disease: Distant recurrence, second primary (non-breast) invasive 
cancer or death from any cause; censoring will occur at the date the patient was last known 
to be alive and free from distant invasive breast cancer and second invasive primaries.  


 
 
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Additional secondary endpoints include development of cardiovascular disease (including 
cerebrovascular events, myocardial infarction, or coronary artery disease requiring stent 
placement, angioplasty, or bypass surgery). 
13.3.3 Analysis plans for primary and secondary endpoints 
The primary analyses of iDFS will be performed in an intention-to-treat manner, in which 
all patients including those who do not begin protocol therapy will be analyzed according 
to their assigned arm. The primary determination of efficacy will be a time-to-event 
analysis using the Kaplan-Meier method for estimation, and the stratified log-rank test of 
iDFS to compare the aspirin arm versus the placebo arm (with stratum defined by hormone 
receptor status, BMI and stage), using the nominal alpha defined by the group sequential 
design, as given in Section 13.4.2. A secondary analysis to estimate efficacy will use a 
multivariate Cox proportional hazard model to evaluate differences between arms after 
adjusting for stratification factors and the additional covariates of known importance to 
breast cancer including age, tumor size, and number of involved nodes. Identical models 
will be used to evaluate differences between arms in DDFS and OS.  
Planned subgroup analyses will evaluate the hazard ratio of aspirin to placebo in subgroups 
defined by the study stratifiers of hormone-receptor status and enrollment time (HR 
positive and enrolled < 18 months from time from diagnosis vs HR positive and enrolled 
> 18 months from diagnosis vs HR negative) and body-mass index (less than 30 kg/m2 vs 
at least 30 kg/m2). In addition to the WHO thresholds for underweight (<18.5 kg/m2), 
normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (BMI ≥30kg/m2), 
we will explore a linear association in the multivariate Cox model, based on the findings 
of Ligibel et al. that the prognostic relationship to disease-free survival with adjuvant 
chemotherapy was linear across the entire range of BMI observed at baseline. Further, an 
exploratory analysis will evaluate whether baseline factors are predictive of difference in 
clinical benefit of aspirin over placebo using multiplicative interactions in the Cox model. 
All tests of secondary objectives will use a two-sided Type I alpha of 0.05, and point 
estimates will be reported with 95% confidence intervals taken from Cox models. 
Analyses of toxicity will be conducted on patients who receive at least one dose of aspirin 
or placebo. Toxicity will be reported by type and maximum grade using CTCAE v4.03 and 
contrasts of aspirin to placebo will use Fisher exact tests. 
All study monitoring, data management and statistical analysis will be performed under the 
Alliance Statistics and Data Center. 
13.4 
Study Monitoring and Interim Analysis 
13.4.1 Study monitoring 
Interim monitoring will be conducted by the Alliance Data and Safety Monitoring Board 
(DSMB) and will be scheduled to coincide with the semi-annual calendar of the board’s 
meetings. Under standard monitoring procedures, the DSMB will consider evidence 
regarding safety (adverse events, adherence) and the feasibility of completing the trial 
(accrual rate).  
Adherence will be reported to the DSMB using descriptive statistics to summarize by arm 
compliance to study treatment and non-protocol use of aspirin and NSAIDs. For 
compliance, the proportion that completed 80% of the total number of study tablets over 
the past period (6 months) and a 95% confidence interval will be reported for the number 
of patients on treatment at each study visit. P-values from a two-sided Fisher exact test will 


 
 
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be provided to the DSMB to help with interpretation of the data, but they are not considered 
as formal hypothesis tests and will not trigger any decision rule on study status. 
In addition, formal interim analyses are to be conducted to consider early stopping for 
futility. These interim analyses are timed to be occur after 50% of the total number of iDFS 
events are observed in order to sensitive to the known heterogeneity of recurrence rates 
over time for the two subpopulations of triple negative versus HmR-positive breast cancer, 
in which the former disease tends to recur earlier than the latter disease. Therefore, there 
will be no early stopping for superiority of aspirin over placebo in order to be able to fully 
address the question of treatment effect by breast cancer subtype. 
13.4.2 Interim analysis for primary endpoint (IDFS) 
Early stopping for futility is defined under a one-sided hypothesis of clinical benefit of 
aspirin and will be conducted using standard group sequential designs for phase III studies 
of time-to-event outcomes. Specifically, the Z-statistics from stratified log-rank tests will 
be calculated at each interim analysis. Futility boundaries will be defined using a Hang, 
Shih and DeCani Gamma beta-spending function (parameter = -5) whereby the futility 
boundary at the first interim analysis is close to observing no treatment effect with aspirin 
(HR = 1) [23]. Interim monitoring for futility will begin at the first DSMB meeting to occur 
when 50% of expected events are observed and continue to coincide with the semi-annual 
calendar of the board. 
In addition to the boundary and observed Z-statistics, the DSMB will be provided Kaplan-
Meier product limit estimators to the survival functions for each arm, and the 
corresponding hazard ratio (corr. HR) and 95% CIs from a stratified Cox proportional 
hazard model for iDFS. 
The following table provides boundaries under the assumed rates of accrual and target 
hazard rates of iDFS that results three interim analyses for futility starting at exactly 50% 
information. 
 
 
First 
Interim 
Second 
Interim 
Third 
Interim 
Final 
Analysis 
iDFS Events:N (%) 
191 (50%) 
247 (65%) 
305 (80%) 
381 (100%) 
Months from activation 
34 
40 
46 
54 
Futility Bound critical Z 
(corr. HR) 
-0.192 
(1.03) 
0.385 
(0.96) 
0.988 
(0.89) 
 
- 
Superiority Bound: critical Z 
(corr.HR) 
- 
- 
 
1.96  
(0.82) 
Nominal Alpha (Superiority) 
- 
- 
 
0.025 
Accumulated Alpha 
- 
- 
 
0.025 
Accumulated Beta 
0.015 
0.033 
0.071 
0.194 
 
 


 
 
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13.5 
Statistical Section for Lifestyle Measures of Inflammation 
Studies to evaluate epidemiologic measures of lifestyle that are potential pro-inflammatory 
states and modifying factors will be performed after the primary analysis to compare iDFS in 
patients randomized to receive aspirin versus placebo is completed. Studies to evaluate 
inflammatory markers from banked tumor and germline DNA, plasma and urine will be 
performed retrospectively once the primary analysis is completed and laboratory assays have 
been identified. The following statistical methods will be used in the analysis plans for 
secondary objectives relating to lifestyle measures and inflammatory markers derived from 
banked specimens.  
Descriptive statistics (mean, standard deviation, median, interquartile range and range) will be 
used to summarize all quantitative measures obtained at baseline and at 2 years. Absolute change 
from baseline to the 2 year assessment will be summarized accordingly for patient reported 
instruments. For inflammatory markers, difference scores will be summarized and evaluated 
using either absolute or fold-change depending on background information for each assay 
output. 
The following thresholds will be used to summarize lifestyle measures at baseline and at 2 years, 
and to define patient subgroups for evaluating differential treatment effects: Body mass index 
(BMI) categories will be defined according to the World Health Organization as underweight 
(<18.5 kg/m2) or normal weight (18.5-24.9 kg/m2) versus overweight (25-29.9 kg/m2) or obese 
(BMI ≥30kg/m2). The anticipated prevalence of overweight (30%) and obese (36.5%) patients 
are taken from Centers for Disease Control and Prevention report for US Women age 20 years 
or older [24]. Physical activity categories by a modified Paffenbarger questionnaire will be 
defined as sedentary (< 3 METs, 32% prevalence) versus CDC recommended (3-8.9 METs, 
29% prevalence) or active (≥ 9 METs, 39% prevalence) [25]. Sleep will be assessed with the 
Pittsburgh Sleep Quality Index (PSQI) with scores ranging from 0 to 21 and poor quality sleep 
defined as great than 5 [26]. The mean PSQI was 5.5 and 6.7 in cohorts of middle age white and 
black women, respectively [27]. A median PSQI of 9 was reported in early stage breast cancer 
patients with aromatase inhibitor induced musculoskeletal symptoms [28]. Depression will be 
assessed by the Center for Epidemiologic Studies-Depression scale-Revised (CESD-R) with 
scores ranging from 0 to 6 and possible depression defined as ≥16 [29, 30]. Median CESD-R as 
10.5 in early stage breast cancer patients with aromatase inhibitor induced musculoskeletal 
symptoms [28].The Perceived Stress Scale (PSS) will be assessed using the 10 item scale (PSS-
10) with scores less than 16 defining “normal” for breast cancer patients [31] with a prevalence 
of 61% in early stage breast cancer patients 12 months after initiation of chemotherapy [32]. 
Secondary and exploratory analysis will evaluate the lifestyle measures listed above as 
continuous factors and will evaluate individual items from the Brief Pain Inventory (BPI) 
dichotomized at ≥4 on the 0-10 Likert scales [33] Pain had a reported prevalence of 21% in early 
stage breast cancer patients taking aromatase inhibitors [34].  
The hypothesis is that subgroups of participants, defined by lifestyle factors that are potential 
pro-inflammatory states, would receive greater treatment benefit from aspirin. The potential for 
any baseline state to modify the effect of treatment upon iDFS and OS will be evaluated using 
multivariate Cox proportional hazards models that include study stratification factors main 
effects and pairwise interaction between each dichotomous baseline factor and treatment arm. 
Simultaneous testing of the lifestyle factors will be performed, using a single likelihood ratio 
test (LRT) of a "full" model with all terms versus a "reduced" model with only main effects for 
treatment assignment, study stratification factors, and lifestyle factors. The LRT for the 
multivariable Cox regression model will use an alpha = 0.05. If the "full" model is found to be 
superior under the LRT, a stepwise backward-selection process will be used to identify the set 
of individual factors with the strongest interaction with treatment assignment, using a nominal 


 
 
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p < 0.05 for inclusion in the final model. The following table proves the effect sizes there will 
be 80% power to detect using the method of [35] for a marginal bivariable test with time-to-
event data. Effect sizes are calculated for varying prevalences of pro-inflammatory states, 
assuming a quantitative interaction and final analysis occurs when 381 IDFS events (216 events 
in the placebo arm and 165 events in the aspirin arm). 
Prevalence 
Ratio of HRs 
50% 
0.56 
40% 
0.55 
30% 
0.53 
20% 
0.48 
Association of measures of inflammatory states, factors or markers at 2-years with clinical 
outcome will be explored using landmark analyses of IDFS and OS in the subset of patients that 
are evaluable and event-free. All adjusted HRs and ratios of HRs from the final multivariable 
models will be reported with 95% confidence intervals. Hypothesis tests of inflammatory 
markers from banked biospecimen will be exploratory and hypothesis-generating using a 
nominal two-sided alpha = 0.05 for each analyte, and estimates of the false discovery rate (FDR) 
for multiple inflammatory markers that are potentially correlated will be obtained using the 
resampling-based Yekutieli-Benjamini method [36]. 
The pairwise correlations of baseline immune markers, states and factors, and changes from 
baseline, will be estimated within and across treatment arms using Spearman coefficients with 
empirical 95% confidence intervals drawn from the BCA bootstrap method. Unsupervised 
learning methods (e.g. agglomerative hierarchical clustering with Spearman correlation as the 
measure of distance) will be used to look for patterns of correlation among any multi-analyte 
markers of inflammation. 
13.6 
CDUS Reporting 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are 
due January 31, April 30, July 31, and October 31. Instructions for submitting data using the 
CDUS can be found on the CTEP Web site 
 
 
 


 
 
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13.7 
Inclusion of Women and Minorities  
Participating institutions will not exclude potential subjects from participating in this study 
solely on the basis of ethnic origin, gender or socioeconomic status. Every attempt will be made 
to enter all eligible patients into this protocol and therefore address the study objectives in a 
patient population representative of the entire breast cancer population treated by participating 
institutions. The following enrollment is estimated from previous clinical trials conducted by 
this Group in a similar patient population. 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
20 
0 
5 
0 
25 
Asian 
50 
0 
11 
0 
61 
Native Hawaiian or 
Other Pacific 
Islander 
10 
0 
5 
0 
15 
Black or African 
American 
285 
5 
49 
1 
340 
White 
2240 
26 
201 
3 
2470 
More Than One 
Race 
15 
0 
10 
0 
25 
Total 
2620 
31 
281 
4 
2936 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


 
 
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14.0 
COMPANION STUDY  
14.1 
Life Style Measures of Inflammation 
The patient questionnaires for this study are only being made available in English. Study 
participants who do not speak, read or write English should not complete the questionnaires. Ad 
hoc translation of patient-completed measures is not permitted.  
14.1.1 Background 
There are several possible mechanisms for aspirin decreasing the risk of cancer recurrence 
with inflammation being one of them. We hypothesize that the effect of aspirin may be 
strongest in those participants who have lifestyle factors associated with inflammation. The 
lifestyle factors we have chosen to assess are body mass index, physical activity, sleep 
quality, depression, perceived stress, and pain for the reasons detailed below. 
Many obese individuals develop a chronic low-grade inflammatory state that can possibly 
be assessed histologically and biochemically. Their enlarged adipocytes show higher 
expression of pro-inflammatory proteins such as TNFα, IL-6 and to recruit macrophages, 
all of which correlate with insulin resistance [37, 38] Simpson and Brown recently 
reviewed the role of inflammation and aromatase in obesity-related breast cancer [39]. The 
adipocytes in the breasts of obese women have been shown sometimes to be surrounded 
by macrophages forming crown-like structures and to have correlated increased aromatase 
activity as a consequence of increased generation of pro-inflammatory mediators [39-41]. 
Mouse models have shown that obesity increases tumor associated macrophage infiltration 
[42]. Physical activity of course ameliorates obesity and is of itself associated with lower 
markers of inflammation [43]. 
Stress-related changes in the hypothalamic-pituitary-adrenal (HPA) and the sympathetic 
nervous system (SNS) have been associated with low-grade inflammation by increasing 
systemic C-reactive protein (CRP) and IL-6 levels. Neuroendocrine stress pathways lead 
to increased secretion of epinephrine and norepinephrine has been shown to suppress 
cellular immunity, particularly NK cells. These stress pathways promote angiogenesis via 
proangiogenic cytokines VEGF and IL-6, and facilitate migration and invasion of tumor 
cells by inducing production of matrix metalloprotienases (MMP). 
One interesting consideration is that these relationships could be bidirectional; an increased 
tumor inflammatory response could lead to increased subjective experience of depression 
and stress [38]. Chronic pain and depression frequently co-occur, and are thought to be 
linked by inflammation as the common mediator [44]. Sleep disturbances are common in 
those with chronic pain and in those with depression; experimental studies in healthy 
humans have shown that both prolonged and moderate sleep loss increase mediators of 
inflammation [45]. 
The available literature shows that these common factors among cancer patients are 
involved with inflammation in complex interactive ways. Measures of body mass index, 
physical activity, perceived stress, depression, pain, and sleep quality will be captured as 
part of the data collection at the same time as the blood collection which is baseline and 2 
years. 
14.1.2 Objective 
To collect measures of lifestyle that are potential pro-inflammatory states and potential 
modifying factors, such as obesity, physical activity, stress, depression, pain and sleep loss. 
Our goal is to determine if there are subgroups of participants characterized by lifestyle 
factors associated with greater inflammation for whom aspirin may provide greater benefit. 


 
 
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14.1.3 Methods 
Lifestyle measures of inflammation 
14.1.3.1 Body mass index assessment 
Body mass index will routinely measured at the time of routine clinical visits.  
14.1.3.2 Recreational physical activity assessment 
Recreational physical activity will be assessed using a modified Paffenbarger 
questionnaire that was originally developed for the Nurses’ Health Study. Participants 
are asked to indicate the average time per week over the last year spent in a list of 
specific activities, selected to represent the most important contributors to total 
activity. Detailed validation study of the physical activity questionnaire has been 
conducted against both 1-week activity recalls and 7-day activity diaries. For total 
physical activity (in MET-hrs per week) the correlation for the overall sample with 
the recalls was 0.79 and with the records diaries was 0.62. Validity has also been 
documented by comparisons with activity diaries and resting pulse [46]. Finally, 
physical activity as measured by this questionnaire has shown important associations 
with multiple disease endpoints, including breast cancer survival, cardiovascular 
disease, and diabetes. 
14.1.3.3 Sleep assessment 
Sleep will be assessed with the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a 
self-administered 19-item questionnaire used to measure the quality and patterns of 
sleep in adults. It differentiates “poor” from “good” sleep by measuring seven areas: 
subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbances, use of sleeping medication, and daytime dysfunction during the last 
month. Scoring is based on a 0 to 3 scale, where a score of 3 reflects the negative 
extreme on the Likert Scale. A global score of five or greater indicates a “poor” 
sleeper [26]. 
14.1.3.4 Depression assessment 
Depression will be assessed by the Center for Epidemiologic Studies-Depression 
scale revised (CESD-R). The CESD-R is a self-administered 20-item questionnaire to 
assess depressive symptoms over the past week that has been tested in healthy 
subjects, as well as patients with a history of breast cancer. A score of 16 or greater 
indicates depression within the preceding week [29, 30]. 
14.1.3.5 Perceived stress assessment 
The Perceived Stress Scale (PSS) is a widely used scale to measure self-perception of 
stress. Designed for use in community samples, the questions are general and 
applicable to multiple populations. Fourteen, 10, and 4-item versions of the scale have 
been validated. It better predicts psychological symptoms, physical symptoms, and 
healthcare utilization than life-event scales [47]. We propose using the 10 item PSS 
(PSS-10) as normative values have been determined from large 2006 and 2009 
probability samples of the U.S. Scores range from 0 (least perceived stress) to 40 
(most perceived stress) with a mean of 16 for women [31]. 
14.1.3.6 Brief Pain Inventory 
The Brief Pain Inventory is a widely used validated scale to measure pain over the 
last week. It has been used in many cancer clinical trials. To avoid participant burden, 
we have chosen two questions which are recommended by the Brief Pain Inventory 


 
 
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scoring manual and consensus guidelines as the ones that have been used most widely 
in clinical trials and best capture the pain experience [33, 48]. 
15.0 
BIOSPECIMEN COLLECTION 
15.1. Rationale 
Although we do not currently have funding to perform biomarker analyses but we do have 
funding for the collection and processing of specimens, so we have decided to pursue a 
pragmatic approach of collecting biospecimens now, which will be at two time points: baseline 
prior to starting the intervention and after two years on study. Two years was chosen as the 
second collection time since that would present a uniform time for all subjects and would be 
within the time frame of the Department of Defense funding. Tumor blocks will also be collected 
at baseline. The plan for testing the banked samples will include a specific background, methods, 
and statistical section and will be submitted to NCI to be reviewed and approved according to 
NCTN procedures before any testing is done. As detailed in section 6, all biospecimens will be 
stored at the Alliance Biorepository at Washington University of St. Louis. 
15.2. Biomarker selection 
There are a large number of potential inflammatory markers that could be considered for 
correlative studies. Some of these are best measured in plasma, whereas others are best 
measured in a spot urine. Rather than committing to specific assays which may become 
outdated, we will submit a proposal at the time of analysis that would utilize assays that 
represent the state of the science and best reflect the best knowledge mechanistic pathways 
at that time. 
Although there is large body of preclinical, epidemiologic, and pooled trial analysis data 
suggesting a possible role for aspirin as adjuvant therapy for cancer, the exact mechanisms 
are unknown and may vary by tumor site. Possible mechanisms include, but are not limited 
to: antiplatelet effect (platelet activation can lead to release of vascular endothelial growth 
factor (VEGF) , epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), 
cytokines such as interleukin-1β (IL-1 β) and IL-8, or proteases such as matrix 
metalloproteinase-2 (MMP2) and MMP9, which could promote angiogenesis, tumor 
growth, and metastases [49-51] and platelets may protect against immune mediated 
clearance by natural killer cells [52] and inhibition of the COX (COX expression has been 
associated with invasiveness and aggressiveness of breast tumors [53-55] and HER2 
overexpression [55-57] and COX-2 inhibitors can enhance TNF-induced apoptosis [58], 
PIK3CA (aspirin use was associated with survival only in PIK3CA mutated colon cancer, 
not wildtype [59, 60], mTOR [61], NF kappa B [62] pathways. Urine specimens are also 
important since some measures of the prostaglandin pathway [63] and oxidative stress [64] 
are currently best measured in urine and proven stable over time [65]. These would not be 
an excessive burden on participants since it is a spot urine that could be done at the clinic 
visit.  It should be noted that both of the large scale aspirin randomized trials (Add-Aspirin 
in the UK and ASCOLT for colorectal cancer in Asia) are also collecting urine samples. 
Given the varied possibilities for mechanistic/correlative studies, with some assays best 
done in tumor, some in plasma, some in DNA/RNA, and some in urine, all of these 
specimens will be collected. 


 
 
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16.0 
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65. 
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years, N Engl J Med, 377 (19): p 1836-1846. 
 


 
 
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APPENDIX I  LIFESTYLES MEASURES OF INFLAMMATION 
Modified Paffenbarger Physical Activity Questionnaire 
During the past year, what was your average time per week spent at each of the following 
recreational activities?   
 
Walking or hiking outdoor (include walking to work): (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
Jogging (slower than 10 minutes/mile): (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
Running (10 minutes/mile or faster): (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
Bicycling (include stationary machine): (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
Calisthenics/aerobics/aerobic dance/rowing machine: (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
Tennis, squash, or racquetball: (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
Lap swimming: (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
Other aerobic recreation (e.g. lawn mowing): (check one) 
 
 Zero 
 5-19 minutes 
 One hour 
 2-3 hours 
 7-10 hours 
      
 1-4 minutes     
 20-59 minutes 
 1-1 ½ hours 
 4-6 hours 
 11+ hours 
 
 


 
 
Alliance A011502 
 
 
Version date 01/26/2021 
56  
 
 
 
Update #06 
On average, how many hours per week do you spend:  
 
Standing or walking around at work: (check one) 
 
 Zero 
 2-5 hours 
 11-20 hours 
 41-60 hours 
 Over 90 hours 
      
 1 hour     
 6-10 hours 
 21-40 hours 
 61-90 hours 
 
 
Standing or walking around at home: (check one) 
 
 Zero 
 2-5 hours 
 11-20 hours 
 41-60 hours 
 Over 90 hours 
 
 1 hour     
 6-10 hours 
 21-40 hours 
 61-90 hours 
 
Sitting at work or while driving: (check one) 
 
 Zero 
 2-5 hours 
 11-20 hours 
 41-60 hours 
 Over 90 hours 
 
 1 hour     
 6-10 hours 
 21-40 hours 
 61-90 hours 
 
Sitting at home: (check one) 
 
 Zero 
 2-5 hours 
 11-20 hours 
 41-60 hours 
 Over 90 hours 
 
 1 hour     
 6-10 hours 
 21-40 hours 
 61-90 hours 
 
 
What is your usual walking pace outdoors? (check one) 
 
 Easy, casual (less than 2 mph) 
 
 Normal, average (2-2.9 mph) 
 
 Brisk pace (3-3.9 mph) 
 
 Very brisk/striding (4 mph or faster) 
 
 Unable to walk 
 
How many flights of stairs (not individual steps) do you climb daily? (check one) 
 
 2 flights or less 
 
 3-4 
 
 5-9 
 
 10-14 
 
 15 or more flights 
 
 


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Alliance A011502 
 
 
Version date 01/26/2021 
59  
 
 
 
Update #06 
Center for Epidemiological Studies - Depression Scale Revised (CESD-R) 
During the past week, how often have you felt this way? 
 
Last Week 
 
 
Nearly 
every day 
for 2 
week 
Below is a list of the way 
you might have felt or 
behaved. Please check the 
boxes to tell me how often 
you have felt in the past 
week or so. 
Not at all or 
Less than 1 
day 
1-2 
days 
3-4 
days 
5-7 
days 
My appetite was poor. 
0 
1 
2 
3 
4 
I could not shake off the 
blues. 
 
 
 
 
 
I had trouble keeping my 
mind on what I was doing. 
 
 
 
 
 
I felt depressed. 
 
 
 
 
 
My sleep was restless. 
 
 
 
 
 
I felt sad. 
 
 
 
 
 
I could not get going. 
 
 
 
 
 
Nothing made me happy. 
 
 
 
 
 
I felt liked a bad person. 
 
 
 
 
 
I lost interest in my usual 
activities. 
 
 
 
 
 
I slept much more than 
usual. 
 
 
 
 
 
I felt like I was moving too 
slowly. 
 
 
 
 
 
I felt fidgety. 
 
 
 
 
 
I wished I were dead. 
 
 
 
 
 
I wanted to hurt myself. 
 
 
 
 
 
I was tired all the time. 
 
 
 
 
 
I did not like myself. 
 
 
 
 
 
I lost a lot of weight 
without trying to. 
 
 
 
 
 
I had a lot of trouble getting 
to sleep. 
 
 
 
 
 
I could not focus on the 
important things. 
 
 
 
 
 
 
 


 
 
Alliance A011502 
 
 
Version date 01/26/2021 
60  
 
 
 
Update #06 
Perceived Stress Scale 
The questions in this scale ask you about your feelings and thoughts during the last month. In each case, 
please indicate with a check how often you felt or thought a certain way. 
1. In the last month, how often have you been upset because of something that happened unexpectedly? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
2. In the last month, how often have you felt that you were unable to control the important things in 
your life? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
3. In the last month, how often have you felt nervous and "stressed"? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
4. In the last month, how often have you felt confident about your ability to handle your personal 
problems? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
5. In the last month, how often have you felt that things were going your way? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
6. In the last month, how often have you found that you could not cope with all the things that you had 
to do? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
7. In the last month, how often have you been able to control irritations in your life? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
8. In the last month, how often have you felt that you were on top of things? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
9. In the last month, how often have you been angered because of things that were outside of your 
control? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 
10. In the last month, how often have you felt difficulties were piling up so high that you could not 
overcome them? 
___0=never 
___1=almost never 
___2=sometimes
 
___3=fairly often 
___4=very often 
 


 
 
Alliance A011502 
 
 
Version date 01/26/2021 
61  
 
 
 
Update #06 
BRIEF PAIN INVENTORY 
Please rate your pain by circling the one number that best describes your pain at its worst in the last week. 
(No pain) 0 1 2 3 4 5 6 7 8 9 10 (Pain as bad as you can imagine) 
 
Please rate your pain by circling the one number that best describes your pain on the average. 
(No pain) 0 1 2 3 4 5 6 7 8 9 10 (Pain as bad as you can imagine) 
 
 
 


 
 
Alliance A011502 
 
 
Version date 01/26/2021 
62  
 
 
 
Update #06 
Registration Fatigue/Uniscale Assessments 
 
These questions have been incorporated into the Baseline Lifestyles Measures of Inflammation 
booklet. This paper copy of the questions is for IRB purposes only. 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 
 
 
 


 
 
Alliance A011502 
 
 
Version date 01/26/2021 
63  
 
 
 
Update #06 
APPENDIX II A011502 STUDY MEDICATION LOG  
 
Aspirin/Placebo Medication Log 
 
Number of tablets Given:____________ Tablets Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of tablets returned:_____________ 
(To be completed by a member of the study team) 
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS 
1. Study tablets should be taken with food or a full glass of water. 
2. Do not crush tablets. 
 
 
 
 


 
 
Alliance A011502 
 
 
Version date 01/26/2021 
64  
 
 
 
Update #06 
Study Month #_______ 
 
DAY 
Medication 
DATE 
TIME 
Number of 
300 mg or 100
mg tablets 
taken 
Comments 
Example 
Aspirin/placebo 
07/01/2016 
9:00 
AM/PM 
1 
/300 mg 
 
1 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
2 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
3 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
4 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
5 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
6 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
7 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
8 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
9 
Aspirin/placebo 
 
 
AM/PM/ 
/ 
 
10 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
11 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
12 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
13 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
14 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
15 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
16 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
17 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
18 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
19 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
20 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
21 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
22 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
23 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
24 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
25 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
26 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
27 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
28 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
29 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
30 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
31 
Aspirin/placebo 
 
 
AM/PM 
/ 
 
 
 
Patient initials: _________________________________________Date:__________ 
 
Comments:_____________________________________________________________ 
 
Patient Alliance Study ID Number_____________________