A Phase II Randomized Controlled Trial of Genomically Directed Therapy After Preoperative Chemotherapy in Patients With Triple Negative Breast Cancer: Hoosier Oncology Group BRE12-158
Phase: PHASE2
Conditions: Malignant Neoplasm of Breast, Breast Cancer
Sponsor: Bryan Schneider, MD

Clinical Study Protocol 
 
Confidential 
Page 1 of 56 
 
 
Protocol Title 
A Phase II Randomized Controlled Trial of Genomically Directed Therapy 
After Preoperative Chemotherapy in Patients with Triple Negative Breast Cancer 
HCRN BRE12-158 
 
Sponsor Investigator 
Bryan P. Schneider, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Co-Investigators 
Kathy D. Miller, MD 
Milan Radovich, PhD 
Sunil Badve, MD 
Gail Vance, MD 
Bert O’Neil, MD 
Paul Helft, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Statistician 
Lang Li, PhD 
Indiana University School of Medicine 
 
Pharmacist: 
Patrick Kiel, PharmD 
Chris Fausel, PharmD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Trial Support and Funding Provided By 
Vera Bradley Foundation for Breast Cancer 
Walther Cancer Foundation, Inc. 
Strategic Research Initiative grant through IUSCC 
 
Initial Protocol Version:  31DEC2013 
Amended Protocol Version Dates: 
14JUL2014 
02APR2015 
27OCT2015  
25JAN2016  
05MAY2016 
27JUN2016 
22DEC2016 
27MAR2017 
29SEP2017 
27APR2018 
 
 

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PROTOCOL SIGNATURE PAGE 
 
A Phase II Randomized Controlled Trial of Genomically Directed Therapy 
After Preoperative Chemotherapy in Patients with Triple Negative Breast Cancer 
 
VERSION DATE: 27APR2018 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual.  
I will accept the monitor’s overseeing of the study.  I will promptly submit the protocol to 
applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
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COMPLETE AND EMAIL COPY TO HOOSIER CANCER RESEARCH NETWORK  
 
 
 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to HCRN and keep a copy for your files. 
 

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SYNOPSIS 
TITLE 
A Phase II Randomized Controlled Trial of Genomically Directed 
Therapy After Preoperative Chemotherapy in Patients with Triple 
Negative Breast Cancer 
STUDY PHASE  
Phase II 
OBJECTIVES 
Primary Objective:  
To compare 2-year disease-free survival (DFS) in participants with 
confirmed triple negative breast cancer (TNBC) treated with a 
genomically directed therapy or standard of care following preoperative 
chemotherapy 
 
Secondary Objectives:  
• To compare overall DFS and 1-year DFS 
• To determine 5-year overall survival (OS) 
• To collect archived tumor specimens and genomic DNA to 
explore potential correlates of recurrence and toxicity.  
• To describe the toxicities associated with genomically directed 
therapies in this population 
 
Exploratory Objectives: 
• To describe the evolution of genomically directed therapies 
during the course of the study 
• To evaluate the drug specific effect on both efficacy outcomes 
(DFS and OS) and toxicity. 
 
STUDY DESIGN 
Sequencing:  
DNA from archived tumor samples collected at the time of surgery 
(residual disease post neoadjuvant chemotherapy) will be extracted and 
sequenced. The resulting sequencing data will be interrogated for known 
genomic drivers of sensitivity or resistance to existing FDA approved 
agents. 
 
Cancer Genomics Tumor Board (CGTB): 
Realizing that optimal treatment recommendations cannot be made based 
on sequencing data alone, the CGTB will be responsible for the final 
treatment recommendation. The CGTB will consider the genomic data 
along with the participant’s prior treatment history, ongoing toxicities, 
and comorbidities. Preference will be given to the treatment identified by 
the sequencing data unless a significant clinical or safety contraindication 
exists for that therapy. All participants and treating investigators will be 
blinded to sequencing results and CGTB deliberations until the time of 
relapse. 
 

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STUDY DESIGN 
Participants with a CGTB treatment recommendation: 
Participants with a CGTB recommendation will be randomized to 
Experimental Arm A (genomically directed monotherapy) or Control 
Arm B (standard therapy). 
 
Experimental Arm A (genomically directed monotherapy) 
Participants randomized to Experimental Arm A will receive an FDA 
approved drug at standard dose for four cycles (12-16 weeks total 
duration, depending on cycle length).  Clinical and laboratory monitoring 
and dose-reductions will follow the FDA package insert guidelines. 
Detailed information about the drugs expected to be recommended most 
commonly can be found in Appendix A. 
 
Control Arm B (standard therapy) 
Recently, a randomized phase III trial of over 900 HER2-negative 
participants demonstrated an improvement in DFS and OS for the 
addition of 8 cycles of capecitabine in the post-neoadjuvant setting. The 
hazard ratios were also significant in the triple negative subgroup. Thus, 
capecitabine can be considered a standard option in this setting. As this 
represents only a single trial (with prior data not demonstrating benefit 
for the addition of capecitabine in the neoadjuvant nor adjuvant settings 
in unselected participants), observation can be considered an option as 
directed by the treating physician. While not recommended, other 
therapies can be used as deemed appropriate by the treating physician.  
 
Participants with no CGTB recommendation: 
Participants may have no CGTB recommendation either because 1) 
sequencing did not identify a matched drug or 2) the matched drug was 
contraindicated. These participants will be assigned to Control Arm B 
and treated as described above for Control Arm B. As the outcome of 
participants without an ‘actionable’ genomically directed therapy may 
differ, the primary analysis will include only participants randomized to 
Control Arm B.  
NUMBER OF 
PARTICIPANTS 
Total number REQUIRED to be randomized and evaluable for efficacy = 
136 
 
Estimated number with technical failure in sequencing = 5 
 
Estimated number of participants expected to have no CGTB  
recommendation = 30  
 
Estimated total number of participants to be enrolled = 192 
 
Maximum number of participants to be enrolled = 200 

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ELIGIBILITY 
1. Written informed consent and HIPAA authorization for release of 
personal health information. 
NOTE:  HIPAA authorization may be included in the informed 
consent or may be obtained separately. 
NOTE: Central pathology review may be conducted any time after 
definitive surgery. Consenting participants may be pre-registered to 
the study and proceed with central pathology review before full 
eligibility has been confirmed. However, ALL of the eligibility 
criteria must be met and formal study registration completed prior to 
submission of the sample for sequencing.  
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status 0 or 1 within 14 days prior to study 
registration. 
4. Women and men of childbearing potential must be willing to use an 
effective method of contraception (e.g. hormonal or barrier method 
of birth control; abstinence) from the time consent is signed until 4 
weeks after protocol therapy discontinuation. 
5. Women of childbearing potential must have a negative pregnancy 
test within 30 days prior to study registration.  Women should be 
counseled regarding acceptable birth control methods to utilize from 
the time of screening to start of treatment.  If prior to treatment after 
discussion with the subject it is felt by the treating physician there is 
a possibility the subject is pregnant a pregnancy test should be 
repeated. 
NOTE:  Women are considered not of childbearing potential if they 
are surgically sterile (they have undergone a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy), or they are 
postmenopausal for at least 12 consecutive months. 
6. Women must not be breastfeeding. 
7. Must have histologically or cytologically confirmed triple negative 
(ER-/PR-/HER2-) invasive breast cancer, clinical stage I-III at 
diagnosis (AJCC 6th edition) based on initial evaluation by physical 
examination and/or breast imaging prior to study registration.  
NOTE:  ER, PR, and HER2 status will be confirmed by central 
pathology review prior to randomization. ER and PR will be 
considered negative if ≤ 10% of cells stain weakly positive. HER2 
will be considered negative if scored 0 or 1+ by 
immunohistochemistry (IHC) or 2+ by IHC associated with a 
fluorescence in situ hybridization (FISH) ratio of < 2.0 or < 6 copies 
per cell. 
8. Must have completed preoperative (neoadjuvant) chemotherapy. 
NOTE: Acceptable preoperative regimens include an anthracycline 
or a taxane, or both. Participants who received preoperative therapy 
as part of a clinical trial may enroll. Participants may not have 
received adjuvant chemotherapy after surgery prior to 
randomization. Bisphosphonate use is allowed. 

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9. Must have completed definitive resection of primary tumor. For those 
that do not require radiotherapy, the most recent surgery for breast 
cancer must have been completed at least 14 days prior, but no more 
than 84 days prior, to study registration. 
NOTE: Negative margins for both invasive and ductal carcinoma in 
situ (DCIS) are desirable, however participants with positive margins 
may enroll if the treatment team believes no further surgery is 
possible and participant has received radiotherapy. Participants with 
margins positive for lobular carcinoma in situ (LCIS) are eligible. 
Either mastectomy or breast conserving surgery (including 
lumpectomy or partial mastectomy) is acceptable. 
10. Must have significant residual invasive disease at the time of 
definitive surgery following preoperative chemotherapy.  Significant 
residual disease is defined as at least one of the following: 
• Residual Cancer Burden (RCB) classification II or III6 
• Residual invasive disease in the breast measuring at least 2 cm. 
The presence of DCIS without invasion does not qualify as 
residual disease in the breast. 
• Residual invasive disease in the breast measuring at least 1 cm 
with any lymph node involvement (does not include metastases 
in lymph node which are only detected by 
immunohistochemistry). 
• Any lymph node involvement that results in 20% cellularity or 
greater regardless of primary tumor site involvement (includes 
no residual disease in the breast). 
11. Must have an FFPE tumor block with tumor cellularity of 20% or 
greater. 
NOTE: Prior to registration, the tumor cellularity will be confirmed 
by central pathology review. Percent values will be double-checked at 
Paradigm (a Next Generation Sequencing Company). 
12. BREAST RADIOTHERAPY 
• Whole breast radiotherapy is required for participants who 
underwent breast-conserving therapy, including lumpectomy or 
partial mastectomy. Participants must have completed 
radiotherapy at least 14 days prior (but no more than 84 days 
prior) to study registration. 
• Participants with a primary tumor > 5 cm or involvement of ≥4 
lymph nodes who require a mastectomy must also have 
radiotherapy pre- or post-operatively at the discretion of the 
treating physician.   For participants with primary tumors ≤ 5 
cm or with < 4 involved lymph nodes, provision of post-
mastectomy radiotherapy is at the discretion of the treating 
physician.  Registration must occur within 84 days of the 
completion of the last local therapy. 
• For radiation required prior to surgery, the participant must 
register within 84 days of surgery.  Also, participants in this 

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situation would not be required to have additional post-
mastectomy radiation therapy. 
• For those participants who do not require radiation, registration 
must be within 84 days of surgery.    
13. No stage IV (metastatic) disease, however no specific staging studies 
are required in the absence of symptoms or physical exam findings 
that would suggest distant disease. 
14. No treatment with any investigational agent within 30 days prior to 
study registration. 
15. No history of chronic hepatitis B or untreated hepatitis C. 
16. Adequate laboratory values must be obtained within 14 days prior to 
study registration. 
• Hemoglobin (Hgb) ≥ 9.0 g/dL 
• Platelets ≥ 100 K/mm3 
• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
• Calculated creatinine clearance of ≥ 50 cc/min using the 
Cockcroft-Gault formula 
• Bilirubin ≤ 1.5   ULN (except in participants with 
documented Gilbert’s disease, who must have a total bilirubin 
≤ 3.0 mg/dL) 
• Aspartate aminotransferase (AST, SGOT) ≤ 2.5  ULN 
• Alanine aminotransferase (ALT, SGPT) ≤ 2.5  ULN 
17. Left ventricular ejection fraction within normal limits obtained within 
30 days prior to study registration. 
NOTE: Participants with an unstable angina or myocardial infarction 
within 12 months of study registration are excluded. 
18. No clinically significant infections as judged by the treating 
physician. 
19. Must consent to allow submission of adequate archived tumor tissue 
sample from definitive surgery for genomic assessment of tumor. 
20. Must consent to collection of whole blood samples for genomic 
analysis. 
21. No clinically significant arrhythmia or baseline ECG abnormalities in 
the opinion of the treating physician. 
22. No active second malignancy (except non-melanomatous skin cancer 
or incidental prostate cancer found on cystectomy): Active second 
malignancy is defined as a current need for cancer therapy or a high 
possibility (> 30%) of recurrence during the study. Previous 
contralateral breast cancer is allowable unless it meets “active” 
criteria as stated above. 
 
 

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STATISTICAL 
CONSIDERATIONS 
 
Sample Size Justification 
The primary endpoint for this trial is 2-year DFS. In order to detect an 
improvement in the fraction of participants free from disease at 2-year 
from 40% in the Control Arm B to 63.2% in the genomically directed 
Experimental Arm A (corresponding to an HR=0.5), 136 participants will 
have 80% power to detect a difference in DFS using a two-side log-rank 
test with 0.05 level of significance (calculation done using nQuery 
Advisor 7.0) and assuming exponential survival. 
 
Here, we have assumed a three-year accrual time period, and each 
participant will subsequently be followed for two years. This three-year 
accrual period will ensure the ability to recruit 192 participants. 
Considering other factors, such as no drug calls and failed sequencing, 
we will ultimately register 136 participants who will be randomized into 
one of two Arms. 
 
Participant Characteristics 
The participant characteristics will be summarized in each treatment 
group for demographics, baseline disease characteristics, and medical 
history.  The two treatment groups will be compared using standard 
methods such as t-tests and chi-square tests. 
 
Analysis of Primary Objective 
The comparison of DFS between the two groups will be made using an 
unstratified Kaplan-Meier analysis with a log-rank test to evaluate for 
differences.  A specific comparison of 2-year DFS will be made using a 
two-sample test based on the complementary log-log transformation as 
suggested in Klein, et al. As a supportive analysis, a stratified log-rank 
test will be done using the stratified randomization factors: 1) 
neoadjuvant anthracycline versus not and 2) lymph node involvement at 
time of definitive surgery versus not. In addition, sensitivity analyses 
using Cox regression may be carried out to identify prognostic factors 
and provide adjusted estimates of the treatment group differences in DFS. 
 
Analysis of Secondary Objectives 
As support for the primary objective, overall DFS and 1-year DFS will be 
compared using the same techniques above.  One-year DFS will be tested 
using the test described above for 2-year DFS. Toxicity variables will be 
tabulated separately for the two groups. Five-year OS will be compared 
between treatment groups using the same methodology as DFS. In 
addition, characteristics of tumor specimens and genomic DNA will be 
correlated with recurrence and toxicity. Continuous measures will be 
correlated with binary variables (e.g. recurrence and toxicity) using 
maximal chi-square tests and continuous variables using Pearson or 
Spearman correlations. Binary variables such as tumor and genomic 
characteristics will be correlated with recurrence and toxicity using chi-
square or Fisher’s Exact test. All of the correlative analyses are 

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exploratory and are designed to complement efforts in other trials using 
this approach. 
 
In the secondary analysis, the participants without an actionable mutation 
in Control Arm B will be compared to the rest of participants in Control 
Arm B. Here our hypothesis is that these participants may have different 
disease biology. We will also compare the entire control Arm B 
(randomized and non-randomized) to Experimental Arm A. This analysis 
assumes that those participants randomized into Control Arm B and those 
participants without actionable mutations have similar disease biology, 
and thus there is no participant selection bias. The secondary analyses 
will look at DFS, OS, and other toxicity outcome. We will also run the 
drug specific analysis using frailty model. 
 
Analysis of Exploratory Objectives 
During the period required for accrual, it is expected that the ability to 
recommend genomically directed therapies will evolve. Changes may 
occur as data from ongoing correlative studies reach the level of evidence 
required to enter the selection algorithm and/or as new therapies are FDA 
approved and thus available for recommendation. To explore the impact 
of this evolution, sequencing data from all participants will be reanalyzed 
and represented along with the initial clinical information to the CGTB 
within 1 month of completion of the enrollment. CGTB 
recommendations for optimal therapy will be compared with the initial 
recommendations and the proportion with a change in recommendation 
will be reported. 
 
Another exploratory analysis will evaluate each specific drug’s effect on 
efficacy parameters (i.e. DFS) and toxicity. Because the number of 
participants receiving a specific drug is expected to be relatively small, 
we will analyze this using a frailty model for DFS. In this model, we 
allow different drug effects to share the same variance estimate in order 
to gain power. This analysis will be implemented in R package, coxph 
function. The drugs’ effect on toxicity will be analyzed with the 
generalized linear mixed effect model, implemented in SAS PROC 
GLIMMIX or GENMOD. 
 
The other exploratory analysis will depend on the results of sequencing. 
Similar to the drug specific analysis, we will use either the frailty model 
or the generalized linear mixed model to analyze clinical outcomes. 
 
 

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SCHEMA: ....................................................................................................................................... 12 
1 
BACKGROUND & RATIONALE ....................................................................................... 13 
1.1 
Primary (neoadjuvant) chemotherapy for breast cancer ................................................... 13 
1.2 
Rationale for genomically directed approach.................................................................... 13 
1.3 
Use of next generation (massively parallel) sequencing to identify therapeutic targets ... 14 
1.4 
Expected actionable mutations/pathways with recommended agents............................... 15 
1.5 
Cancer Genomics Tumor Board (CGTB) ......................................................................... 16 
1.6 
Protocol therapy ................................................................................................................ 17 
2 
OBJECTIVES ........................................................................................................................ 18 
2.1 
Primary Objective: ............................................................................................................ 18 
2.2 
Secondary Objectives: ....................................................................................................... 18 
2.3 
Exploratory Objectives:..................................................................................................... 19 
3 
ELIGIBILITY CRITERIA ................................................................................................... 19 
4 
PARTICIPANT REGISTRATION ...................................................................................... 22 
5 
TREATMENT PLAN ............................................................................................................ 22 
5.1 
Pre-medication .................................................................................................................. 22 
5.2 
Drug Administration ......................................................................................................... 22 
5.3 
Missed doses ..................................................................................................................... 23 
5.4 
Supportive Care ................................................................................................................. 23 
5.5 
Concomitant Medications ................................................................................................. 23 
6 
DOSE MODIFICATIONS .................................................................................................... 23 
7 
SCHEDULE OF EVENTS .................................................................................................... 24 
7.1 
Experimental Arm A ......................................................................................................... 24 
7.2 
Control Arm B ................................................................................................................... 25 
7.3 
Pre-registration (All Participants) ..................................................................................... 26 
7.4 
Screening ........................................................................................................................... 26 
7.5 
On Study Day 1 (CONTROL ARM B ONLY): ............................................................... 26 
7.6 
On Treatment (EXPERIMENTAL ARM A ONLY) ........................................................ 26 
7.7 
Treatment Discontinuation (EXPERIMENTAL ARM A ONLY) ................................... 27 
7.8 
Study Participation Discontinuation (CONTROL ARM B ONLY) ................................. 28 
7.9 
Surveillance (ARMS A & B) ............................................................................................ 28 
8 
CRITERIA FOR DISEASE EVALUATION ...................................................................... 28 
9 
BIOLOGICAL SAMPLES ................................................................................................... 28 
9.1 
Central Pathology Review ................................................................................................. 28 
9.2 
Samples for genomic sequencing ...................................................................................... 29 
9.3 
Samples for future studies ................................................................................................. 30 
10 CLINICAL TRIAL MATERIAL (CTM) INFORMATION ............................................. 30 
11 ADVERSE EVENT MANAGEMENT ................................................................................ 31 

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11.1 
Definitions of Adverse Events ....................................................................................... 31 
11.2 
Adverse Event (AE) Reporting...................................................................................... 31 
12 STATISTICAL CONSIDERATIONS ................................................................................. 33 
12.1 
Sample Size Justification ............................................................................................... 33 
12.2 
Participant Characteristics ............................................................................................. 34 
12.3 
Analysis of Primary Objective ...................................................................................... 34 
12.4 
Analysis of Secondary Objectives ................................................................................. 34 
12.5 
Analysis of Exploratory Objectives ............................................................................... 35 
13 TRIAL MANAGEMENT ...................................................................................................... 35 
13.1 
Quality Controls and Quality Assurance ....................................................................... 35 
13.2 
Data Handling and Record Keeping .............................................................................. 36 
13.3 
Confidentiality ............................................................................................................... 37 
13.4 
Changes to the Protocol ................................................................................................. 37 
13.5 
Ethics ............................................................................................................................. 38 
14 REFERENCES ....................................................................................................................... 39 
15     APPENDIX A……………………………………………………………………………..  40
 
 

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SCHEMA: 
A Phase II Randomized Controlled Trial of Genomically Directed Therapy After Preoperative Chemotherapy in Patients with Triple 
Negative Breast Cancer 
   
 
 
 
 
 
  
 
1: Experimental Arm A 
Genomically directed therapy at FDA approved dose and schedule for 4 cycles (12-16 weeks) 
2: Control Arm B 
Xeloda can be considered a standard option. Observation can also be considered if deemed appropriate by the treating physician. 
Other therapies are not recommended but can be administered at treating physician’s discretion 

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1 BACKGROUND & RATIONALE 
1.1 
Primary (neoadjuvant) chemotherapy for breast cancer 
Neoadjuvant chemotherapy has a well-established role in the management of both early-stage and 
locally advanced breast cancer. Providing treatment prior to definitive surgery not only improves 
the ability to achieve breast conservation, but also allows determination of in vivo sensitivity to 
therapy and offers an ideal platform for clinical research. Although many will experience 
shrinkage in tumor volume with neoadjuvant therapy, at the time of surgery only about 33% of 
patients will experience a pathologic complete response (pCR) with complete lack of invasive 
tumor tissue in the surgical specimen. Long-term follow-up of neoadjuvant studies consistently 
demonstrates significantly improved survival in individuals with pCR, with comparatively inferior 
outcomes in those with residual disease at surgery1-4 The impact of residual disease is more 
striking in patients with triple negative (ER-/PR-/HER2-) disease compared to patients with other 
molecular phenotypes5. Unfortunately, patients with triple negative disease who have substantial 
(Miller-Payne classification6 1 or 2 or residual cancer burden classification II or III7) residual 
disease at the time of surgery have a dismal prognosis with only 35-40% remaining free of 
recurrence at 2 years4,8. In short, the presence of viable invasive tumor after appropriate 
neoadjuvant chemotherapy reflects inherent resistance and portends an exceedingly high risk of 
subsequent recurrence.  
 
Recently, a phase III trial, CREATE-X16, randomized over 900 HER2-negative patients with 
residual disease in the breast or lymph node involvement after completion of standard neoadjuvant 
therapy to 8 cycles of capecitabine at 2500 mg/m2/day (2 out of 3 weeks) vs. no additional 
therapy. Approximately 64% of the population had hormone receptor positive disease and 36% 
had triple negative disease. The trial data was presented at the 2015 San Antonio Breast 
Conference (Toi et al.) after 2 years follow-up from the time of last patient randomized. The DSM 
committee terminated the trial early after the trial results had met a planned interim analysis of 
benefit for the addition of capecitabine. The capecitabine arm demonstrated an improvement in 
DFS from 74% in the control arm to 82% in the capecitabine arm (HR=0.70; p=0.005).  The 
addition of capecitabine also improved OS from 89.2% to 94% (HR=0.60; p<0.01). The hazard 
ratios were highly significant in the triple negative subgroup (HR=0.58; 95% CI=0.39-0.87).  
Thus, capecitabine can be considered a standard option in this setting for triple negative breast 
cancer. As this represents only a single trial (with prior data not demonstrating benefit for the 
addition of capecitabine in the neoadjuvant nor adjuvant settings), observation can also be 
considered an option after discussion of risk to benefit ratio with the patient.  
 
1.2 
Rationale for genomically directed approach 
Currently, many of the therapies delivered in the neo-adjuvant and adjuvant setting for breast 
cancer are non-specific cytotoxic agents that are not selected based on specific characteristics from 
the tumor. Increasingly, molecular aberrancies have opened the door for potential design and use 
of drugs to capitalize on dysregulated pathways. Examples of successful drugs matched to 
aberrancy include various categories of aberrancy: over-expression (e.g. trastuzumab for HER2 
overexpression9), translocation (e.g. imatinib for BCR-ABL translocation10) and point mutation 
(e.g. vemurafenib for BRAF activating mutation; V600E11). In general, the therapeutic index for 
these targeted approaches has been exceptionally high. This proposal will attempt to capitalize on 
this basic philosophy by matching an expansive list of FDA-approved agents with molecular 
aberrancies determined by cutting edge assessment of the tumor using massively parallel 
sequencing. 

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This study will capitalize on an exceptional setting to test a genomic approach and will enrich for 
participants who have already been exposed to standard non-specific chemotherapy in the 
neoadjuvant setting with substantial residual disease. This patient population, by definition, is 
resistant to traditional non-specific cytotoxic chemotherapy. Also, by nature of the high risk of 
relapse, they are clearly in need of additional (and hopefully superior) targeted therapy. Since 
these participants have already received standard therapy, the concern for a “high-risk” patient not 
receiving potentially life-saving therapy will not be an issue. Further, since all drugs used in this 
proposal are FDA-approved and will be used as single agents, there should be no toxicity concerns 
beyond those side effects that are well recognized. From a genomic standpoint, the use of these 
agents in a relatively early point in the tumor’s life (i.e. adjuvant setting) will minimize some 
intrinsic concerns such as genomic drift.12 This proposal, then, sets out to optimally test the 
hypothesis that a genomically directed therapy will improve outcome over standard of care in a 
population that needs a better standard. 
 
1.3 
Use of next generation (massively parallel) sequencing to identify therapeutic targets 
Paradigm is a non-profit joint venture between the University of Michigan and the International 
Genomics Consortium (IGC). Paradigm’s cancer diagnostic test, PCDx (which will be the 
platform implemented in this protocol) is a sophisticated and comprehensive CLIA next-
generation sequencing cancer diagnostic test available for cancer analysis on formalin fixed 
paraffin sections. PCDx uses a custom analysis on the PGM Ion Torrent platform to provide 
patients and physicians with a blueprint of the underlying mechanisms of a patient’s disease 
through next-generation sequencing for mutations, copy number variants (CNV), mRNA and 
chromosomal changes including allelic burden, potential treatment approaches, assessment of 
level of evidence, and comprehensive inventory of relevant clinical trials. This clinical decision 
support tool and analysis is run in a CLIA compliant lab and reports both paper and electronic 
results in approximately 4-5 working days. 
 
The PCDx test identifies all actionable classes of genomic alterations in hundreds of cancer-
related genes having a 1 or 2 level of evidence including: 
• DNA Copy Number Variants (e.g. MYC) 
• Base Substitutions 
• Insertions 
• Deletions (e.g. EGFR) 
• Chromosomal Rearrangements (e.g. EML4-ALK) 
• mRNA Expression 
• Splice Variants 
• Isoforms (e.g. ERCC1, KIT) 

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The Paradigm panel queries greater than 500 genetic regions of interest. This includes evaluation 
of tens of thousands of genomic abnormalities, driver mutations, and changes associated with 
clinical trials. This panel has a near-perfect ability to detect DNA mutations due to a high depth of 
coverage; typically over 3000. This platform also includes a proprietary library creation 
technique that almost completely eliminates the risk of DNA damaged during the FFPE process 
from generating false mutation calls. This was validated in The Cancer Genome Atlas project 
(TCGA) and is the only capture enrichment technology allowed into TCGA. Copy number assays 
are also sequenced with high coverage, allowing excellent sensitivity; typically able to detect a 
change of a single chromosome copy. 
 
The PCDx results report with recommended agent will be sent to Hoosier Cancer Research 
Network, Inc. (HCRN) for disbursement to the CGTB. 
 
1.4 
Expected actionable mutations/pathways with recommended agents 
We have performed an in silico study to predict the most commonly identified and the relative 
diversity of compounds likely to be identified using this approach. To do this, we used 72 cases of 
triple-negative breast cancer from The Cancer Genome Atlas (TCGA), a publically available 
resource of cancer genomics data. For each of these 72 cases we collated the data regarding 
somatic mutations, copy number variation, and differential gene expression (compared to a panel 
of 20 normal breast tissues) and submitted this data through the Paradigm PCDx informatics 
pipeline. For each case, a comprehensive report was generated associating genomic aberrancies 
with potential therapeutics. The report may list any of the following: 1) FDA-approved, 
compendia recommended drug; 2) FDA-approved drug off compendia for breast cancer; 3) Drug 
that is FDA-approved, but with clinical evidence of the biomarker only sufficient to reach the level 
for consideration of a clinical trial; 4) Biomarker that has a high level of evidence connected with 
a drug that is not yet FDA approved. 
 
Approximately 82% of the reports generated from these 72 in silico cases were able to either select 
an FDA-approved drug, or highlight a pathway for which an FDA-drug could be selected. Table 1 
provides the 14 drugs that were identified from these cases with an actionable mutation or 
pathway. Appendix A summarizes the detailed information for these 14 drugs. To maximize 
consistency, we have established recommended agents for the commonly identified biomarkers 
(Table 1). Specifically, there is the potential for multiple drugs to be linked to a specific genetic 
aberration. For example, if COX2 is upregulated, there are multiple potential NSAIDs that could 

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be recommended. To maximize homogeneity, we will select a preferred agent in these cases (e.g. 
COX2 overexpression should result in use of celecoxib if this genetic aberration is considered to 
be highest priority). 
 
Table 1. Top genomic actionable biomarkers/pathways  
 
Biomarker 
 
 
 
 
Drug recommendation  
1.  PIK3CA, PTEN 
 
Everolimus 
2.  TOP2A 
 
Doxorubicin 
3.  PARP1, BRCA1 
 
Cisplatin or Olaparib 
4.  VEGFA 
 
Bevacizumab 
5. TYMP 
 
Capecitabine 
6. SSTR2 
 
Octreotide 
7. MGMT 
 
Temozolomide  
8. MYC 
 
Paclitaxel 
9.  EGFR 
 
Cetuximab 
10. COX2 
 
Celecoxib 
11. hENT 
 
Gemcitabine 
12. MET 
 
Crizotinib 
13. CCND1,2,3 amplifications; 
 
Palbociclib 
 
CDKN2A loss, CDK4/6 amplifications 
14. PDL1 TILS or TUMOR IHC+ 
 
Pembrolizumab 
15. KIT and VEGFR2 
 
Sunitinib 
16. PIK3CA 
 
Copanlisib 
 
The drugs listed in Table 1 will be dosed according to the FDA-approved package inserts (See 
Appendix A). While the drugs listed here will likely comprise a large number of our expected 
drug recommendations, the nature of this trial makes it impossible to anticipate the optimal 
genomic target for all participants. Thus, if the genomic data identifies a less common actionable 
mutation/pathway not included in Appendix A, the Sponsor investigator must obtain approval of a 
protocol exception from the local IRB per local institutional policy. If the same genomic changes 
(and drug) are recommended for a second patient, we will conclude that this represents a recurrent 
aberrancy rather than a sporadic event. With this knowledge, the protocol will be amended to add 
the mutation/pathway and resulting drug. 
 
1.5 
Cancer Genomics Tumor Board (CGTB) 
Realizing that optimal treatment recommendations cannot be made based on sequencing data 
alone, the CGTB will be responsible for the final treatment recommendation. 
The CGTB includes a diverse group of members with specific areas of expertise including: 
 
• Sponsor Investigator (Schneider) 
• Genomics/informatics expert (Radovich)  
• Breast medical oncologist with clinical trial expertise (Miller)  
• Director of the Indiana University Melvin and Bren Simon Cancer Center (IUSCC) Phase I 
Program (O’Neil) 
• Ethics and supportive care (Helft) 
 

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If it becomes necessary to replace a CGTB member, a new member with similar experience and 
expertise will be recruited. At least three members of the CGTB will meet to review the 
sequencing report and relevant clinical data for each participant.  If only two permanent members 
of the CGTB are available to meet, an ad hoc member (other medical oncologist with clinical trial 
expertise) may fill in as the third required member. Assuming there are available cases, the review 
will take place during a standing weekly meeting. Optimal therapy recommendations will be made 
by consensus. Although the participants will be de-identified during the CGTB deliberations, their 
underlying comorbidities and medical history may reveal the identity to the treating physician. To 
avoid the potential that knowledge of the sequencing data might influence the treating 
investigator’s approach (especially if randomized to Control Arm B), any CGTB member who is 
also the treating physician will be recused and excluded from those discussions. 
 
Hoosier Cancer Research Network will provide the CGTB with the Paradigm PCDx sequencing 
results report, recommended agent, and summary of the participant’s relevant clinical data.  The 
CGTB will consider the genomic data along with the participant’s prior treatment history, ongoing 
toxicities, and comorbidities. Preference will be given to the treatment identified by the 
sequencing data unless a significant clinical or safety contraindication exists for that therapy. For 
example, if TOP2A is identified for a participant who previously received anthracycline-based 
neoadjuvant therapy, the CGTB would not recommend additional doxorubicin due to excess 
potential for toxicity and lack of enthusiasm for re-treatment with the same drug. Similarly, if a 
participant has persistent neuropathies, a drug known to cause substantial neuropathy would not be 
recommended. 
 
If more than one actionable mutation/pathways drug is identified (this occurred in 30% of cases in 
our preliminary data set), the CGTB will make the final recommendation for a single drug based 
on the following criteria: 1) Strength of the data that demonstrates an association between the 
genomic aberration and the selected drug; 2) Participant’s prior exposure to therapies; and 3) Co-
morbidities or persistent toxicities. 
 
All participants and treating investigators will be blinded to sequencing results and CGTB 
deliberations until the time of relapse. Reports will automatically be made available to the treating 
investigator at that time. 
 
1.6 
Protocol therapy 
All participants for whom the CGTB recommended an optimal therapy will be randomized to 
Experimental Arm A or Control Arm B. If there is a technical failure in sequencing, no actionable 
mutations/pathways are identified, or the CGTB cannot make a treatment recommendation, 
participants will be assigned to Control Arm B. Based on our preliminary data; we suspect this 
will happen for 18% of our population. Participants who are assigned to Control Arm B will not 
be included in the primary analyses. 
 
Participants in Experimental Arm A will begin protocol therapy within 10 working days of 
randomization. 
 
 
 

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Experimental Arm A (genomically directed monotherapy) 
For participants randomized to Experimental Arm A, HCRN will send the CGTB treatment 
recommendation to the treating investigator in a secure email message. Drug specific details for 
the top 14 most commonly expected drugs can be found in Appendix A. After discussion of the 
drug specific information and expected toxicities, participants will be asked to provide additional 
consent to proceed with protocol therapy. 
 
Consenting participants will receive the CGTB recommended therapy in accordance with the FDA 
label for 4 cycles (12-16 weeks depending on cycle length). For oral drugs administered 
continuously, 3 weeks will be considered one cycle. Dose reductions, modifications, or 
discontinuation will be in accordance with the FDA label and standard clinical practice. 
 
Control Arm B (standard therapy) 
Those randomized to Control Arm B (and those with no drug call who are assigned to Control 
Arm B) will follow the direction of their treating physician. Recently, a phase III trial, CREATE-
X16, randomized over 900 HER2-negative patients with residual disease in the breast or lymph 
node involvement after completion of standard neoadjuvant therapy to 8 cycles of capecitabine at 
2500 mg/m2/day (2 out of 3 weeks) vs. no additional therapy. Approximately 64% of the 
population had hormone receptor positive disease and 36% had triple negative disease. The trial 
data was presented at the 2015 San Antonio Breast Conference (Toi et al.) after 2 years follow-up 
from the time of last patient randomized. The DSM committee terminated the trial early after the 
trial results had met a planned interim analysis of benefit for the addition of capecitabine. The 
capecitabine arm demonstrated an improvement in DFS from 74% in the control arm to 82% in 
the capecitabine arm (HR=0.70; p=0.005).  The addition of capecitabine also improved OS from 
89.2% to 94% (HR=0.60; p<0.01). The hazard ratios were highly significant in the triple negative 
subgroup (HR=0.58; 95% CI=0.39-0.87).  Thus, capecitabine can be considered a standard option 
in this setting for triple negative breast cancer. As this represents only a single trial (with prior data 
not demonstrating benefit for the addition of capecitabine in the neoadjuvant nor adjuvant 
settings), observation can also be considered an option after discussion of risk to benefit ratio with 
the patient. While not recommended, other therapies can be used as deemed appropriate by the 
treating physician.  
 
2 OBJECTIVES 
 
2.1 
Primary Objective: 
To compare 2-year disease-free survival (DFS) in participants with confirmed triple negative 
breast cancer (TNBC) treated with a genomically directed therapy or standard of care following 
preoperative chemotherapy 
 
2.2 
Secondary Objectives: 
• To compare overall DFS and 1-year DFS 
• To determine 5-year overall survival (OS) 
• To collect archived tumor specimens and genomic DNA to explore potential correlates of 
recurrence and toxicity.  
• To describe the toxicities associated genomically directed therapy in this population 
 

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2.3 
Exploratory Objectives: 
• To describe the evolution of genomically directed therapies during the course of the study 
• To evaluate the drug specific effect on both efficacy outcomes (DFS and OS) and toxicity. 
 
3  
ELIGIBILITY CRITERIA 
1. Written informed consent and HIPAA authorization for release of personal health 
information. 
NOTE:  HIPAA authorization may be included in the informed consent or may be 
obtained separately. 
NOTE: Central pathology review may be conducted any time after definitive surgery. 
Consenting participants may be pre-registered to the study and proceed with central 
pathology review before full eligibility has been confirmed. However, ALL of the 
eligibility criteria must be met and formal study registration completed prior to submission 
of the sample for sequencing. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status 0 or 1 within 14 days prior to study registration. 
 
4. Women and men of childbearing potential must be willing to use an effective method of 
contraception (e.g. hormonal or barrier method of birth control; abstinence) from the time 
consent is signed until 4 weeks after protocol therapy discontinuation. 
 
5. Women of childbearing potential must have a negative pregnancy test within 30 days prior 
to study registration.  Women should be counseled regarding acceptable birth control 
methods to utilize from the time of screening to start of treatment.  If prior to treatment 
after discussion with the subject it is felt by the treating physician there is a possibility the 
subject is pregnant a pregnancy test should be repeated. 
NOTE:  Women are considered not of childbearing potential if they are surgically sterile 
(they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), 
or they are postmenopausal for at least 12 consecutive months. 
 
6. Women must not be breastfeeding. 
 
7. Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) 
invasive breast cancer, clinical stage I-III at diagnosis (AJCC 6th edition) based on initial 
evaluation by physical examination and/or breast imaging prior to study registration. 
NOTE:  ER, PR, and HER2 status will be confirmed by central pathology review prior to 
randomization. ER and PR will be considered negative if ≤ 10% of cells stain weakly 
positive. HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry 
(IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of < 
2.0 or < 6 copies per cell. 
 
 
 

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8. Must have completed preoperative (neoadjuvant) chemotherapy. 
NOTE: Acceptable preoperative regimens include an anthracycline or a taxane, or both. 
Participants who received preoperative therapy as part of a clinical trial may enroll. 
Participants may not have received adjuvant chemotherapy after surgery prior to 
randomization. Bisphosphonate use is allowed. 
 
9. Must have completed definitive resection of primary tumor. For those that do not require 
radiotherapy, the most recent surgery for breast cancer must have been completed at least 
14 days prior, but no more than 84 days prior, to study registration. 
NOTE: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are 
desirable, however participants with positive margins may enroll if the study site treatment 
team believes no further surgery is possible and participant has received radiotherapy. 
Participants with margins positive for lobular carcinoma in situ (LCIS) are eligible. Either 
mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is 
acceptable. 
 
10. Must have significant residual invasive disease at the time of definitive surgery following 
preoperative chemotherapy.  Significant residual disease is defined as at least one of the 
following: 
• Residual Cancer Burden (RCB) classification II or III6 
• Residual invasive disease in the breast measuring at least 2 cm. The presence of DCIS 
without invasion does not qualify as residual disease in the breast. 
• Residual invasive disease in the breast measuring at least 1 cm with any lymph node 
involvement (does not include metastases in lymph node which are only detected by 
immunohistochemistry). 
• Any lymph node involvement that results in 20% cellularity or greater regardless of 
primary tumor site involvement (includes no residual disease in the breast). 
 
11. Must have an FFPE tumor block with tumor cellularity of 20% or greater.  
NOTE: Prior to registration, the tumor cellularity will be confirmed by central pathology 
review. Percent values will be double-checked at Paradigm (a Next Generation Sequencing 
Company). 
 
12. BREAST RADIOTHERAPY 
• Whole breast radiotherapy is required for participants who underwent breast-
conserving therapy, including lumpectomy or partial mastectomy. Participants must 
have completed radiotherapy at least 14 days prior (but no more than 84 days prior) to 
study registration. 
• Participants with a primary tumor > 5 cm or involvement of ≥4 lymph nodes who 
require a mastectomy must also have radiotherapy pre- or post-operatively at the 
discretion of the treating physician.   For participants with primary tumors ≤ 5 cm or 
with < 4 involved lymph nodes, provision of post-mastectomy radiotherapy is at the 
discretion of the treating physician.  Registration must occur within 84 days of the 
completion of the last local therapy. 
• For radiation required prior to surgery, the participant must register within 84 days of 
surgery.  Also, participants in this situation would not be required to have additional 
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• For those participants who do not require radiation, registration must be within 84 
days of surgery.    
 
13. No stage IV (metastatic) disease, however no specific staging studies are required in the 
absence of symptoms or physical exam findings that would suggest distant disease. 
 
14. No treatment with any investigational agent within 30 days prior to study registration. 
 
15. No history of chronic hepatitis B or untreated hepatitis C. 
 
16. Adequate laboratory values must be obtained within 14 days prior to study registration. 
• Hemoglobin (Hgb) ≥ 9.0 g/dL 
• Platelets ≥ 100 K/mm3 
• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
• Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula: 
Males:  (140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
Females:  Estimated creatinine clearance for males × 0.85 
• Bilirubin ≤ 1.5  ULN (except in participants with documented Gilbert’s disease, 
who must have a total bilirubin ≤ 3.0 mg/dL) 
• Aspartate aminotransferase (AST, SGOT) ≤ 2.5  ULN 
• Alanine aminotransferase (ALT, SGPT)  ≤ 2.5  ULN 
 
17. Left ventricular ejection fraction within normal limits obtained within 30 days prior to 
study registration. 
NOTE: Participants with an unstable angina or myocardial infarction within 12 months of 
study registration are excluded. 
 
18. No clinically significant infections as judged by the treating physician. 
 
19. Must consent to allow submission of adequate archived tumor tissue sample from 
definitive surgery for genomic assessment of tumor. 
 
20. Must consent to collection of whole blood samples for genomic analysis.  
 
21. No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the 
treating physician. 
 
22. No active second malignancy (except non-melanomatous skin cancer or incidental prostate 
cancer found on cystectomy): Active second malignancy is defined as a current need for 
cancer therapy or a high possibility (> 30%) of recurrence during the study.  Previous 
contralateral breast cancer is allowable unless it meets “active” criteria as stated above. 
 
 
 

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4 PARTICIPANT REGISTRATION  
All participants must be registered through HCRN’s electronic data capture (EDC) system. A 
subject is considered registered when an “On Study” date is entered into the EDC system 
 
Subjects must be registered prior to starting protocol therapy and begin therapy within 10 days of 
randomization.  
 
NOTE: Central pathology review may be conducted any time after definitive surgery. Consenting 
participants may be pre-registered to the study and proceed with central pathology review before 
full eligibility has been confirmed. However, ALL of the eligibility criteria must be met and 
formal study registration completed prior to submission of the sample for sequencing. 
Blinding:  The protocol therapy is not blinded to the participant or the treating investigator. 
However, all participants and treating investigators will be blinded to sequencing results and 
CGTB deliberations until the time of relapse. 
 
5 TREATMENT PLAN 
If a subject randomizes to Arm B (control group), medications are not covered by the study and 
would be handled similarly to standard of care medication administration. 
 
5.1 
Pre-medication  
It is strongly recommended that all participants receive adequate anti-emetics, hydration, and 
supportive care as directed by the FDA package insert. 
 
5.2 
Drug Administration 
All drugs will be administered in accordance with the FDA-label including dose, route, and 
frequency. Dose modifications will be based on the FDA-label and standard clinical practice. 
Participants will receive four cycles of therapy. As cycle length may vary, the total duration of 
therapy may range from 12-16 weeks. The following conventions will be followed when 
considering cycle length: 
 
Treatment administered 
Cycle length 
every 4 weeks 
4 weeks 
every 3 weeks 
3 weeks 
Weekly 
3 weeks 
continuous oral 
3 weeks 
 
See Appendix A for detailed information on the most commonly expected drugs. 
 
All therapy in Experimental Arm A will be based on the participant’s actual weight unless the 
FDA package insert recommends a fixed dose. The actual weight at screening should be used for 
calculating body surface area (BSA). The BSA may be recalculated based on the actual weight at 
the start of each treatment cycle but recalculation and dose adjustment is only required if a 
participant’s weight changes by ≥ 10%. 
 
 
 

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5.3 
Missed doses 
In general, participants should be encouraged to comply with the FDA-recommended treatment 
schedule. However, if IV treatment is missed for reasons other than toxicity (e.g. participant 
vacation, family emergency, etc.), participants able to resume treatment within 2 weeks should 
receive the full planned number of cycles. If a delay of more than 2 weeks is required, the missed 
IV treatment should be omitted (i.e. not made up) and participants should proceed with the next 
cycle as originally scheduled. For those participants receiving oral agents, missed doses should not 
be made up and should continue for the duration planned at the outset of therapy. 
 
5.4 
Supportive Care 
The use of supportive care including antibiotics, blood transfusions, etc. will be permitted as 
clinically indicated and according to institutional guidelines. 
 
5.5 
Concomitant Medications 
Medications known to interact with the recommended drug will be considered by the CGTB at 
time of drug selection. If a participant is taking a drug with a significant interaction risk, and that 
drug is deemed important for the participant’s ongoing health, the selected therapy will be 
considered contraindicated by the CGTB. Bisphosphonate use is allowed. 
 
6 DOSE MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used to 
grade adverse events. 
 
Participants enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in section 7. 
Schedule of Events. 
 
Participants will be evaluated for adverse events different in type and/or severity from what would 
be expected from the approved drug labeling, serious adverse events, and adverse events requiring 
protocol therapy interruption or discontinuation at each study visit for the duration of their 
participation in the study. As the agents used in this study are FDA approved with well-defined 
safety profiles, only serious adverse events, and adverse events resulting in dose modification 
and/or treatment discontinuation will be entered to the database and analyzed. 
 
For participants in Experimental Arm A, all doses should be modified as outlined in the FDA-
approved package insert (See Appendix A). 
 
Participants in Experimental Arm A discontinued from the treatment phase of the study for any 
reason will be evaluated at least 30 days (± 7) after the last dose of protocol therapy. 

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7 SCHEDULE OF EVENTS 
7.1 
Experimental Arm A 
 
Pre-registration 
(All participants) 
Screening         
(All participants) 
Cycles 1-41 
 (Arm A only) 
Treatment2 
Discontinuation 
 (Arm A Only) 
Surveillance3 
(All participants) 
 
Post-surgery 
-30 days 
D1 of each cycle 
(±3 days) 
30 days  
(±7) after last dose 
±1 month 
REQUIRED ASSESSMENTS 
 
 
 
 
 
Informed consent 
X 
 
X4 
 
 
Complete medical history and height 
 
X 
 
 
 
Complete physical examination 
 
X 
X 
X 
X 
Weight, BP 
 
X 
X 
X 
X 
ECOG performance status 
 
X 
X 
X 
X 
CMP5 
 
X 
Repeat as needed 
based on FDA label 
and standard practice 
X 
 
Calculated creatinine clearance 
 
X 
X 
 
CBC with differential 
 
X 
X 
 
Breast imaging (remaining native breast tissue only) 
 
 
 
 
Yearly  
Electrocardiogram 
 
X 
Follow FDA label and 
standard practice 
 
 
MUGA or Echocardiogram 
 
X 
 
 
Urine pregnancy or serum HCG6 
 
X 
 
 
 
Adverse event & con med assessment 
 
X 
X 
X 
 
TREATMENT EXPOSURE 
 
 
 
 
 
Genomically directed therapy 
 
 
X 
 
 
CORRELATIVE SAMPLES 
 
 
 
 
 
Tumor from initial diagnosis – Optional7 
 
 
X 
 
 
Tumor from definitive surgery – Mandatory7 
X7 
 
 
 
 
Whole blood for genomic DNA – Mandatory8 
 
 
X8 
 
 
Whole blood for Plasma – Optional9 
 
 
X9 
X9 
 
Whole blood for CTC – Mandatory10 
 
 
X10 
X10 
 
1: Cycle 1 Day 1 testing need not be repeated if obtained within 14 days of starting protocol therapy. 
2: Participants in Experimental Arm A discontinued from the treatment phase of the study for any reason will be evaluated 30 days (±7) after the last dose of protocol therapy. 
3: Monitor for the development of either local (chest wall, axillary, or supraclavicular nodes) or distant recurrent disease, complete physical exam including weight, BP and ECOG performance status 
completed at least once every 3 months for the first two years, then at least every 6 months during years 3-5 after Treatment Discontinuation.  At disease progression, participant should be followed 
for survival only. 
4: Following CTGB Review, participants randomized to Experimental Arm A provide drug specific informed consent prior to initiating protocol therapy on Cycle 1 Day 1. 
5: Serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and 
alanine transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium). 
6: Complete only in women of childbearing potential.  Screening test to be done 30 days prior registration.  Women should be counseled regarding acceptable birth control methods to utilize from the 
time of screening to start of treatment.  If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a pregnancy test should be 
repeated. 
7: Optional collection of tumor tissue from initial diagnosis.  Subjects will be asked to consent to this collection.  Mandatory complete central pathology review of tumor tissue from definitive surgery. 
8: Mandatory 8.5 mL whole blood for genomic DNA will be collected at Cycle 1 Day 1 for Experimental Arm A (see Section 9.3 Samples for Future Studies). 
9: Optional 10 mL whole blood for plasma will be collected at Cycle 1 Day 1 and Treatment Discontinuation for Experimental Arm A (See Section 9.3 Samples for Future Studies). 
10: Mandatory 10 mL whole blood for CTC will be collected at Cycle 1 Day 1 and Treatment Discontinuation for Experimental Arm A (See Section 9.3 Samples for Future Studies). 

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7.2 
Control Arm B 
 
Pre-registration 
(All participants) 
Screening          
(All participants) 
On Study1 
(Arm B only) 
Surveillance2 
(All participants) 
 
Post-surgery 
-30 days 
D1 
±1 month 
REQUIRED ASSESSMENTS 
 
 
 
 
Informed consent 
X 
 
 
 
Complete medical history and height 
 
X 
 
 
Complete physical examination 
 
X 
 
X 
weight, BP 
 
X 
 
X 
ECOG performance status 
 
X 
 
X 
CMP 
 
X 
 
 
Calculated creatinine clearance 
 
X 
 
 
CBC with differential 
 
X 
 
 
Breast imaging (remaining native breast tissue only) 
 
 
 
Yearly  
Electrocardiogram 
 
X 
 
 
MUGA or Echocardiogram 
 
X 
 
 
Urine pregnancy or serum HCG3 
 
X 
 
 
Adverse event & concomitant medication assessment 
 
X 
 
 
TREATMENT EXPOSURE 
 
 
 
 
Capecitabine, other chemotherapy or observation8 
 
X 
 
 
CORRELATIVE SAMPLES 
 
 
 
 
Tumor from initial diagnosis – Optional4 
 
 
X 
 
Tumor from definitive surgery Mandatory4 
X4 
 
 
 
Whole blood for genomic DNA Mandatory5 
 
 
X 
 
Whole blood for Plasma – Optional6 
 
 
X 
 
Whole blood for CTC – Mandatory7 
 
 
X 
X 
1: On Study Day 1 is defined as the next available routine care visit after Randomization. 
2: Monitor for the development of either local (chest wall, axillary, or supraclavicular nodes) or distant recurrent disease, complete physical exam including weight, BP and ECOG 
performance status completed at least once every 3 months for the first two years, then at least every 6 months during years 3-5 after Treatment Discontinuation.  At disease 
progression, participant should be followed for survival only. 
3: Complete only in women of childbearing potential.  Screening test to be done 30 days prior registration.  Women should be counseled regarding acceptable birth control 
methods to utilize from the time of screening to start of treatment.  If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the 
subject is pregnant a pregnancy test should be repeated. 
4: Optional collection of tumor tissue from initial diagnosis.  Subjects will be asked to consent to this collection.  Mandatory complete central pathology review of tumor tissue 
from definitive surgery. 
5: Mandatory 8.5 mL whole blood for genomic DNA will be collected at next available routine appointment (Day 1) (see Section 9.3 Samples for Future Studies). 
6: Optional 10 mL whole blood for plasma will be collected at next available routine appointment (Day 1) (See Section 9.3 Samples for Future Studies). 
7: Mandatory 10 mL whole blood for CTC will be collected at next available routine appointment (Day 1) and the 3 or 6 month visit (See Section 9.3 Samples for Future Studies). 
8For participants where capecitabine or other chemotherapy is planned, monitoring and adjustment for toxicity should be in accordance with standard practice and the experience of 
the treating physician. 

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7.3 
Pre-registration (All Participants) 
• Consenting participants may be pre-registered to the study and proceed with central 
pathology review of tumor tissue from definitive surgery before full eligibility has been 
confirmed. However, ALL of the eligibility criteria must be met and formal study 
registration completed prior to submission of the sample for sequencing. 
• Mandatory - tumor tissue from definitive surgery (See Correlatives Laboratory Manual 
(CLM) for collection, labeling and shipping instructions) 
 
7.4 
Screening 
 
Within 30 days of study registration (ARMS A & B): 
• Complete medical history  
• Complete physical examination including: height, weight, BP, and ECOG performance 
status 
• Complete metabolic profile (CMP) including: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, 
alkaline phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) 
and electrolytes (total calcium, chloride, potassium, sodium) 
• Calculated creatinine clearance 
• Complete Blood Count (CBC) with differential 
• Urine pregnancy test or serum HCG (only in women of child bearing potential.  Women 
should be counseled regarding acceptable birth control methods to utilize from the time of 
screening to start of treatment. If prior to treatment after discussion with the subject it is 
felt by the treating physician there is a possibility the subject is pregnant a pregnancy test 
should be repeated. 
• Electrocardiogram (ECG) 
• Multigated acquisition (MUGA) scan or Echocardiogram (Echo) 
• Adverse event and concomitant medication assessment 
 
7.5 
On Study Day 1 (CONTROL ARM B ONLY): 
On Study Day 1 is defined as the next available routine care visit after Randomization. 
• Genomic and Correlative studies (See CLM for collection, labeling and shipping 
instructions) 
o Optional - tumor tissue from initial diagnosis 
o Mandatory - collect 8.5 mL whole blood for genomic DNA  
o Optional - collect 10 mL whole blood for plasma  
o Mandatory – collect 10 mL whole blood for Circulating Tumor Cells (CTC) 
 
7.6 
On Treatment (EXPERIMENTAL ARM A ONLY) 
Following CTGB Review, participants randomized to Experimental Arm A provide drug specific 
informed consent prior to initiating protocol therapy on Cycle 1 Day 1. 
 
 

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7.6.1 Day 1 of each cycle (± 3 days) (EXPERIMENTAL ARM A ONLY): 
Note: Cycle 1 Day 1 testing need not be repeated if completed within 14 days of starting 
protocol therapy. 
• Complete physical examination including: weight, BP  
• ECOG performance status 
• Complete metabolic profile (CMP): Repeat as needed based on FDA label and standard 
practice  
• Calculated creatinine clearance: Repeat as needed based on FDA label and standard 
practice  
• CBC with differential: Repeat as needed based on FDA label and standard practice 
• ECG: Repeat as needed based on FDA label and standard practice 
• MUGA or Echo: Repeat as needed based on FDA label and standard practice 
• Adverse event and concomitant medication assessment 
• Genomic and Correlative Studies (Cycle 1 Day 1 Only) (See CLM for collection, labeling 
and shipping instructions) 
o Optional - tumor tissue from initial diagnosis 
o Mandatory - collect 8.5 mL whole blood for genomic DNA  
o Optional - collect 10 mL whole blood for plasma  
o Mandatory– collect 10 mL whole blood for CTC 
 
7.7 
Treatment Discontinuation (EXPERIMENTAL ARM A ONLY) 
A participant will be discontinued from the protocol therapy under the following circumstances: 
• If there is evidence of progressive disease.  
• If the treating physician thinks a change of therapy would be in the best interest of the 
participant. 
• If the participant withdraws consent to protocol treatment. 
• If the drug exhibits unacceptable adverse event. (Participants will be followed until the 
resolution of these adverse events.) 
• If a participant becomes pregnant. 
 
NOTE: Participants can stop participating at any time. However, if they decide to stop 
participating in the study, they will continue to be followed for progression and survival unless the 
participant has also withdrawn consent for further follow-up. 
 
7.7.1 Within 30 days (±7) after the last dose of protocol therapy (EXPERIMENTAL 
ARM A ONLY): 
• Complete physical examination including: weight, BP  
• ECOG performance status 
• Adverse event and concomitant medication assessment 
• Correlative Studies  
o Optional - collect 10 mL whole blood for plasma  
o Mandatory – collect 10 mL whole blood for CTC 
 
 

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7.8 
Study Participation Discontinuation (CONTROL ARM B ONLY) 
A participant will be discontinued from study participation under the following circumstances: 
• If the participant requests discontinuation. 
 
NOTE: Participants can stop participating at any time. However, if they decide to stop 
participating in the study, they will continue to be followed for progression and survival 
unless the participant has also withdrawn consent for further follow-up. 
 
7.9 
Surveillance (ARMS A & B) 
• Complete physical examination including: weight, BP  
• ECOG performance status 
• Participants will be monitored by their treating physicians for the development of either 
local (chest wall, axillary, or supraclavicular nodes) or distant recurrent disease at least 
once every 3 months for the first two years, then at least every 6 months during years 3-
5 after Treatment Discontinuation for Experimental Arm A and for those where 
chemotherapy is planned in Arm B. For those on Arm B who have observation only, 
follow-up will begin after randomization. At progression, participants will be followed 
for survival only. 
• Suggested guidelines for surveillance of breast cancer survivors are available through the 
National Comprehensive Cancer Network (www.nccn.org). 
• Routine blood work or radiology in the absence of symptoms suggestive of recurrent 
disease is not recommended. 
• Remaining breast tissue (contralateral breast and ipsilateral breast in participants treated 
with breast conserving surgery) should be imaged annually according to standard screening 
guidelines. 
• Correlative Studies for Arm B only  
o Mandatory – collect 10 mL whole blood for CTC at 3 or 6 month visit 
 
8 CRITERIA FOR DISEASE EVALUATION 
DFS is defined as the duration of time from randomization to time of a DFS event, defined as local 
failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-
invasive), or death from any cause. The diagnosis of local or distant recurrence should ideally be 
pathologically confirmed, however if biopsy if not possible, radiology confirmation by CT, MRI, 
or PET scan is acceptable. 
 
9 BIOLOGICAL SAMPLES 
HCRN will provide sample collection kits and shipping supplies for tissue sample submissions 
and for blood samples collected for genomic and correlative studies. All sample labels will only 
include the HCRN participant study ID#, date/time of collection and sample type. No personal 
identifiers will be included. Refer to the CLM associated with this protocol for collection, 
processing, labeling, and shipping instructions. 
 
9.1 
Central Pathology Review 
Analysis by an American Society of Clinical Oncology (ASCO) and College of American 
Pathology (CAP) expert panel suggests that approximately 20% of ER, PR, and HER2 tests 
performed in community laboratories are inaccurate with a fairly equal distribution of false 
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reliability. As such, ER, PR, and HER2 status will be confirmed by central pathology review prior 
to randomization. 
• ER and PR will be considered negative if ≤ 1% of cells stain weakly positive. 
• HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry (IHC) or 2+ 
by IHC associated with a fluorescence in situ hybridization (FISH) ratio of < 2.0 or < 6 
copies per cell. 
 
Additionally central pathology review will confirm the cellularity of the residual disease sample (> 
20% required for eligibility). If the sample fails to meet the percent value required, a new sample 
(if available) will be requested from the participating site. 
 
Formalin-fixed paraffin-embedded (FFPE) tissue from the residual disease removed at the time of 
definitive surgery (mandatory) is required to be submitted for central pathology review. The 
estimated timeframe to complete the central pathology review and provide a results report is 5-7 
working days. Once the central pathology review is complete and participant eligibility is 
confirmed, formalin-fixed paraffin-embedded (FFPE) tissue will need to be sent to Paradigm. 
Paradigm will double-check the cellularity percent values and complete the genomic sequencing. 
Refer to the CLM for collection, labeling and shipping instructions. 
 
NOTE: Central pathology review may be conducted any time after definitive surgery. Consenting 
participants may be pre-registered to the study and proceed with central pathology review before 
full eligibility has been confirmed. However, ALL of the eligibility criteria must be met and 
formal study registration completed prior to submission of the sample for sequencing. 
 
9.2 
Samples for genomic sequencing 
Prior to registration, the tumor cellularity will be confirmed by central pathology review. Percent 
values will be double-checked at Paradigm (a Next Generation Sequencing Company). A 
minimum of 20% tumor cellularity is needed to initiate the next generation sequencing analysis. 
Paradigm will use a proprietary tumor enrichment technology called Laser Capture Enrichment 
(LCE) that allows the macroscopic and microscopic isolation of populations of cells such as 
cancer cells to be separated from the non-malignant populations. The LCE technology has been 
validated in The Cancer Genome Atlas project (TCGA) and is the only capture enrichment 
technology allowed into TCGA. Paradigm can provide the mutational next generation sequencing 
analysis when the cellularity is equal to or above 20% tumor nuclei. LCE will be used to enrich 
above the 20% tumor cellularity cut point. Above 50% tumor nuclei, the full Paradigm analysis of 
mutation, copy number abnormality, chromosomal aberrations, and mRNA can be performed in 
totality on formalin fixed paraffin sections.  When the tumor cellularity is between 20% and 50% 
tumor nuclei than some subset of the Paradigm analysis can be performed and thus all samples 
above 20% will be sent. 
 
 

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9.3 
Samples for future studies 
Participant consent will be obtained for additional samples for future studies.  These samples and 
any leftover required samples will be banked. NOTE: Participants will be asked to consent to 
allow banking of their DNA and RNA for future studies. 
 
This includes: 
• Tumor from initial diagnosis (sample collected prior to neoadjuvant chemotherapy): 
Optional for both Arms 
o Formalin-fixed paraffin embedded tissue that contains > 60% tumor cellularity will 
be obtained after the participant is formally registered to the trial.  
• Tumor from definitive surgery:  
Mandatory for both Arms 
o Formalin-fixed paraffin embedded tissue that contains > 20% tumor cellularity will 
be obtained after the participant is formally registered to the trial.  
• Whole blood for genomic DNA:  
Mandatory for both Arms 
o 8.5 mL whole blood will be collected on Cycle 1 Day 1 for Experimental Arm A 
and after Randomization at their next routine care visit (Day 1) for Control Arm B 
participants.  
• Whole blood for Plasma:  
Optional for both Arms 
o 10 mL whole blood for plasma will be collected on Cycle 1 Day 1 and at Treatment 
Discontinuation for Experimental Arm A and after Randomization at their next 
routine care visit (Day 1) for Control Arm B. 
• DNA and RNA extracted from Circulating Tumor Cells (CTC):  
Mandatory for both Arms 
o 10 mL whole blood for CTC enumeration and DNA and RNA extraction will be 
collected on:  
▪ Cycle 1 Day 1 and at Treatment Discontinuation for Experimental Arm A.  
▪ After Randomization at their next routine care visit (Day 1) and at the 3 or 6 
month visit for Control Arm B. 
 
Refer to the CLM associated with this protocol for collection, processing, labeling, and shipping 
instructions. 
 
10 CLINICAL TRIAL MATERIAL (CTM) INFORMATION  
See Appendix A for drug information. If treatment recommendation is an injectable drug, this will 
be supplied from the participating site’s own pharmacy. All drugs should be stored in a securely 
locked area with limited access. If treatment recommendation is an oral agent other than Olaparib, 
the site is to obtain the drug from US Bioservices. If treatment recommendation is Olaparib, the 
site will obtain the drug from Biologics. Specific instructions for ordering drug are contained in 
the CLM. Consult the package insert for the common and serious adverse events in addition to 
proper storage, preparation, administration, and handling instructions. CTM is to be dispensed 
only by authorized personnel under the supervision of a licensed physician at 
the investigative site. 
 

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All drugs assigned to participants randomized to Experimental Arm A will be paid for by this 
study. 
 
11 ADVERSE EVENT MANAGEMENT 
Adverse events will be collected and reported as described below for the Experimental Group 
(Arm A) only.  Arm B subjects are undergoing treatment that is considered standard of care, 
recording and reporting of adverse events will not be done. 
 
11.1 
Definitions of Adverse Events 
 
11.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a participant or clinical trial subject administered an 
investigational product and which does not necessarily have a causal relationship with the 
treatment.  An adverse event (AE) can, therefore, be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational product. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce 
clinical signs or symptoms or require treatment or further diagnostic testing. 
 
11.1.2 Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
• Results in death 
• Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the participant or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above).  Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Unexpected Adverse Event 
An adverse event not mentioned in the package insert or the specificity or severity of which is not 
consistent with the package insert. 
 
11.2 
Adverse Event (AE) Reporting 
Adverse events will be recorded from the time of consent and for at least 30 days after final 
protocol treatment. As the agents used in this study are FDA-approved and have a well-defined 
safety profile, only serious adverse events, and adverse events resulting in dose modification 
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will be followed until resolution, return to baseline, or deemed clinically insignificant, even if this 
occurs post-trial. 
 
11.3 
Serious Adverse Event (SAE) Reporting 
 
11.3.1 
Study Center (Site) Requirements for Reporting SAEs 
Treating investigators and other site personnel must report any SAEs occurring during the course 
of the study within 24 hours of discovery of the event.  This includes events both related and 
unrelated to the product. 
 
The definition of “related” being that there is a reasonable possibility the drug caused the adverse 
experience. 
 
Table 15: Relationship of adverse event to the investigational agent 
Unrelated 
The Adverse Event is clearly not related to the agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the agent(s) 
Possible 
The Adverse Event may be related to the agent(s) 
Probable 
The Adverse Event is likely related to the agent(s) 
Definite 
The Adverse Event is clearly related to the agent(s) 
 
The completed SAE Reporting Form (see Study Procedure Manual) must be emailed to 
safety@hoosiercancer.org at HCRN within 24 hours of discovery of the event. The treating 
investigator is responsible for informing the IRB and/or the Regulatory Authority of the SAE as 
per local requirements. 
 
The original copy of the SAE Reporting Form along with the email cover sheet and/or fax 
confirmation sheet must be kept within the study binder at the study site. 
 
Follow-up information should be emailed to safety@hoosiercancer.org at HCRN, using a new 
SAE Reporting Form stating that this is a follow-up to the previously reported SAE and giving the 
date of the original report. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how it was treated, 
and whether the participant continued or withdrew from study participation. 
 
11.3.2 
Death and Immediately Life-Threatening Events  
Any death and immediately life-threatening event from any cause while a participant is receiving 
protocol therapy or up to 30 days after the last dose of protocol therapy, or any death and 
immediately life-threatening event occurring more than 30 days after protocol therapy has ended 
but which is felt to be treatment related must be reported within 24 hours of discovery of event.  
All deaths must be reported primarily for the purposes of SAE reporting; however, deaths due 
unequivocally to progression are not SAEs. 
 
Your local IRB should be notified and their reporting procedure followed.  The completed SAE 
Reporting Form should be emailed to safety@hoosiercancer.org at HCRN within 24 hours of 
discovery of the event. 
 

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11.3.3 
HCRN Requirements for Reporting SAEs 
HCRN will voluntarily report to the FDA, regardless of the study site of occurrence, any SAE that 
is reasonably related (i.e. possible, probable, definite) to the protocol therapy and different in type 
and/or severity from what would be expected from the approved drug labeling (unexpected). 
Unexpected fatal or life-threatening experiences associated with the protocol therapy will be 
voluntarily reported to the FDA as soon as possible but in no event later than 7 calendar days after 
initial receipt of the information by HCRN. All other serious unexpected experiences associated 
with the use of the protocol therapy will be voluntarily reported to the FDA no later than 15 
calendar days after initial receipt of the information by HCRN. 
 
For Guidelines and MedWatch Form FDA 3500, refer to the FDA Voluntary Reporting for 
Consumers and Healthcare Professionals Guidelines webpage: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
 
12 
STATISTICAL CONSIDERATIONS 
 
Table 16: Data Sets for Protocol Endpoints 
Data Set/Endpoint 
Criteria 
Disposition 
All participants registered into the study 
General safety 
All participants in Experimental Arm A receiving at least one dose of any 
protocol therapy 
Efficacy 
All participants (Experimental Arm A receiving at least one dose of any protocol 
therapy and Control Arm B) with at least one post-Randomization disease 
evaluation  
Participants will be included in the analysis for the treatment to which they were randomized. 
 
12.1 
Sample Size Justification 
The primary endpoint for this trial is 2 year DFS. In order to detect an improvement in the fraction 
of participants free from disease at 2-year from 40% in the Control Arm B to 63.2% in the 
genomically directed Experimental Arm A (corresponding to an HR=0.5), 136 participants will 
have 80% power to detect a difference in DFS using a two-side log-rank test with 0.05 level of 
significance. The power calculation was calculated and validated by SAS, R, and nQuery and 
based on SAS (Table 17).  
 
Table 17. 
2 Year Survival 
HR 
Arm A/B* 
Power R 
Power SAS 
Power 
nQuery 
Arm 
A 
Arm B* 
Log rank 
Cox 
Log rank 
Log rank 
0.682 
0.40 
2.40 
0.93 
0.92 
0.92 
0.92 
0.632 
0.40 
2.00 
0.80 
0.80 
0.80 
0.80 
0.582 
0.40 
1.70 
0.58 
0.58 
0.58 
0.57 
*Randomized participants (excludes participants assigned to Control Arm B) 

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Here, we have assumed a three-year accrual time, and each participant will subsequently be 
followed for two years. This three-year accrual period will ensure the ability to recruit 192 
participants. Considering other factors, such as no drug calls and failed sequencing, we will enroll 
136 eligible participants who will be randomized into one of two Arms. 
 
12.2 
Participant Characteristics 
Participant characteristics will be summarized by treatment group for demographics, baseline 
disease characteristics, and medical history.  The two treatment groups will be compared using 
standard methods such as t-tests and chi-square tests. 
 
12.3 
Analysis of Primary Objective 
The comparison of DFS between the two groups will be made using an unstratified Kaplan-Meier 
analysis with a log-rank test to evaluate for differences.  A specific comparison of 2-year DFS will 
be made using a two-sample test based on the complementary log-log transformation as suggested 
in Klein, et al15. As a supportive analysis, a stratified log-rank test will be done using the stratified 
randomization factors: 1) neoadjuvant anthracycline versus not and 2) lymph node involvement at 
time of definitive surgery versus not. In addition, sensitivity analyses using Cox regression may be 
carried out to identify prognostic factors and provide adjusted estimates of the treatment group 
differences in DFS. 
 
Participants who are assigned to Control Arm B will not be included in the primary analyses. 
 
12.4 
Analysis of Secondary Objectives 
As support for the primary objective, overall DFS and 1-year DFS will be compared using the 
same techniques above.  One-year DFS will be tested using the test described above for 2-year 
DFS. Toxicity variables will be tabulated separately for the two groups. Five-year OS will be 
compared between treatment groups using the same methodology as DFS. In addition, clinical and 
demographic characteristics of tumor specimens and genomic DNA will be correlated with 
recurrence and toxicity. Continuous measures will be correlated with binary variables (e.g. 
recurrence and toxicity) using maximal chi-square tests and continuous variables using Pearson or 
Spearman correlations. Binary variables such as tumor and genomic characteristics will be 
correlated with recurrence and toxicity using chi-square or Fisher’s exact test. All of the 
correlative analyses are exploratory and are designed to complement efforts in other trials using 
this approach. 
 
In the secondary analysis, the participants without an actionable mutation in Control Arm B will 
be compared to the rest of participants in Control Arm B. Here our hypothesis is that these 
participants may have different disease biology. We will also compare the entire control Arm B 
(randomized and non-randomized) to Experimental Arm A. This analysis assumes that those 
participants randomized into Control Arm B and those participants without actionable mutations 
have similar disease biology, and thus there is no participant selection bias. The secondary 
analyses will look at DFS, OS, and other toxicity outcome. We will also run the drug specific 
analysis using frailty model. 
 
 

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12.5 
Analysis of Exploratory Objectives 
During the period required for accrual, it is expected that the ability to recommend genomically 
directed therapies will evolve. Changes may occur as data from ongoing correlative studies reach 
the level of evidence required to enter the selection algorithm and/or as new therapies are FDA 
approved and thus available for recommendation. To explore the impact of this evolution, 
sequencing data from all participants will be reanalyzed and represented along with the initial 
clinical information to the CGTB within 1 month of completion of the study enrollment. CGTB 
recommendations for optimal therapy will be compared with the initial recommendations and the 
proportion with a change in recommendation will be reported. 
 
Another exploratory analysis will evaluate each specific drug’s effect on the participant efficacy 
outcome (i.e. DFS) and toxicity. Because the number of participants receiving a specific drug 
treatment is expected to be relatively small, we will analyze using a frailty model for DFS. In this 
model, we allow different drug effects to share the same variance estimate, in order to gain power. 
This analysis will be implemented in R package, coxph function. The drug effects on the toxicity 
will be analyzed with the generalized linear mixed effect model, implemented in SAS PROC 
GLMMIX or GENMOD. 
 
The other exploratory analysis will depend on the results of sequencing. Similar to the drug 
specific analysis, we will use either the frailty model or the generalized linear mixed model to 
analyze clinical outcomes. 
 
13 
TRIAL MANAGEMENT 
 
13.1 
Quality Controls and Quality Assurance 
 
13.1.1 Data and Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB) that will review and monitor 
study progress, toxicity, safety and other data from this trial. The DSMB is separate from the 
IUSCC Data and Safety Monitoring Committee (DSMC) referred to below. The board is chaired 
by an independent medical oncologist external to this trial. Questions about participant safety or 
protocol performance will be addressed with the Sponsor investigator, statistician, and study team 
members. Should any major concerns arise; the DSMB will offer recommendations regarding 
whether or not to suspend the trial. 
 
The DSMB will meet twice a year to review accrual, toxicity, response, and reporting information. 
The DSMB will meet annually after the last participant is off treatment and has completed the end 
of treatment evaluation. Information to be provided to the DSMB may include: participant accrual, 
treatment regimen information, adverse events, and serious adverse events reported by category, 
summary of any deaths on study, audit, and/or monitoring results. 
 
The DSMB will provide a recommendation to the team after all information is reviewed. This 
information should also be provided to the IRB at the time of continuing review for the trial. 
 
13.1.2 Data Safety Monitoring Committee  
HCRN will provide the DSMC with data summary reports as requested.  The DSMC will also 
review DSMB reports regarding this study.  

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13.1.3 HCRN Oversight Activities 
This trial is subject to auditing and/or monitoring. The HCRN data management team provides 
safety oversight for all HCRN trials. Specific data and safety monitoring tasks conducted by 
HCRN include: 
• Review all adverse events requiring expedited reporting as defined in the protocol 
• Notify participating sites of adverse events requiring expedited reporting  
• Provide trial accrual progress and safety information to the sponsor-investigator  
• Provide data summary reports to the sponsor-investigator  
• Submit data summary reports to the Data Safety Monitoring Board per their Charter. 
 
13.1.4 Study Monitoring 
For-cause monitoring visits to the trial sites may be made periodically during the trial.  Source 
documents will be reviewed for verification of agreement with data as submitted via the data 
collection system.  The treating investigator/institution guarantee access to source documents by 
HCRN or its designee and appropriate regulatory agencies. 
 
The trial site may also be subject to quality assurance audit by appropriate regulatory agencies. 
 
It is important for the treating investigators and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
13.2 
Data Handling and Record Keeping 
 
13.2.1 Case Report Forms and Submission 
This study will utilize electronic case report form (eCRF) in the Electronic Database Capture 
(EDC) system.  The EDC system is a comprehensive database used by HCRN and, properly used, 
is compliant with Title 21 CFR Part 11. Access to the data through the EDC system is restricted by 
user accounts and assigned roles. Once logged into the EDC system with a user ID and password, 
EDC defines roles for each user, which limits access to appropriate data. User information and 
passwords can be obtained by contacting HCRN at 317-921-2050. 
 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database. If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source document. 
Select standard of care data will also be captured in the EDC system, according to study-specific 
objectives. Detailed guidelines for eCRF completion can be found in the eCRF Instructions. 
 
The completed dataset is the sole property of HCRN and should not be made available in any form 
to third parties, except for authorized representatives of appropriate Health/Regulatory Authorities, 
without written permission from HCRN. 
 
 

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13.2.2 Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the treating investigator 
agrees to keep records, including the identity of all participants (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all eCRFs, 
and detailed records of drug disposition. To comply with international regulations, the records 
should be retained by the treating investigator in compliance with regulations. 
 
During data entry, range and missing data checks will be performed on-line.  The checks to be 
performed will be documented in the Data Management Plan for the study.  A summary report 
(QC Report) of these checks together with any queries resulting from manual review of the eCRFs 
will be generated for each site and transmitted to the site and the site monitor. Corrections will be 
made by the study site personnel. This will be done on an ongoing basis. 
 
13.3 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
participant will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. 
 
Information collected will be maintained on secure, password protected electronic systems. Paper 
files that contain personal information will be kept in locked and secure locations only accessible 
to the study team. Samples that are collected will be identified by a participant study number 
assigned at the time of registration to the trial. Any material issued to collaborating researchers 
will be anonymized and only identified by the participant study number. 
 
Participants will be informed in writing that some organizations including the treating investigator 
and his/her research associates, HCRN, IRB, or government agencies, like the FDA, may inspect 
their medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
 
If the results of the study are published, the participant’s identity will remain confidential. 
 
13.4 
Changes to the Protocol 
Study procedures will not be changed without the mutual agreement of the sponsor-investigator 
and HCRN. 
 
If it is necessary for the study protocol to be amended, a new version of the study protocol 
(amended protocol) will be generated by HCRN and must be approved by each participating site 
IRB, and if applicable, local regulatory authority.  Local requirements must be followed. 
 
If a protocol amendment requires a change to the Informed Consent Form, then the IRB must be 
notified.  Approval of the revised Written Informed Consent Form by the IRB is required before 
the revised form is used. 
 
The Sponsor investigator is responsible for the distribution of these documents to his or her IRB, 
and to the staff at his or her center.  The distribution of these documents to the regulatory authority 
will be handled according to local practice. 
 

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13.5 
Ethics 
 
13.5.1 Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved by an IRB.  The treating investigator must submit written approval to the HCRN office 
before he or she can enroll any participant into the study. 
 
The treating investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit participants for the study.  The protocol must be re-approved by the IRB annually, as local 
regulations require. 
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided to 
the IRB according to local regulations and guidelines. 
 
These reports will be reviewed by the Sponsor investigator, and those considered unexpected and 
possibly related to protocol therapy, and all deaths within 30 days of discontinuing treatment, will 
be forwarded to participating sites for submission to their Institutional Review Boards per their 
guidelines.  All other events will be held and submitted to the sites for continuing review. 
 
13.5.2 Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration 
of Helsinki, which are consistent with ICH Good Clinical Practice, and applicable regulatory 
requirements. 
 
13.5.3 Informed Consent 
The treating investigator will ensure the participant is given full and adequate oral and written 
information about the nature, purpose, possible risks, and benefits of the study. Participants must 
also be notified they are free to discontinue from the study at any time.  The participant should be 
given the opportunity to ask questions and allowed time to consider the information provided. The 
participant’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. 
 
Following CTGB Review and Randomization, Experimental Arm A participant’s signed and dated 
drug specific informed consent form must be obtained before initiating protocol therapy on 
Cycle 1 Day 1. 
 
The treating investigator must store all original, signed Informed Consent Forms.  A copy of the 
signed Informed Consent Form must be given to the participant. 
 
 

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14 
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4. Von Minckwitz G, Untch M, Blohmer JU, et al: Definition and impact of pathologic complete 
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5. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: primary tumor 
chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329-34, 2007 
6. Ogston KN, Miller ID, Payne S, et al: A new histological grading system to assess response of 
breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12:320-
7, 2003 
7. Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast cancer burden to 
predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414-22, 2007 
8. Esserman LJ, Perou C, Cheang M, et al: Breast cancer molecular profiles and tumor response 
of neoadjuvant doxorubicin and paclitaxel: The I-SPY TRIAL. J Clin Oncol 27:(suppl; abstr 
LBA515), 2009 
9. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody 
against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 
2001;344:783-92. 
10. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose 
cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 
348:994-1004 
11. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma 
with braf v600e mutation. N Engl J Med 2011; 364:2507-2516 
12. Nik-Zainal S, Van Loo P, Wedge DC, et al. The life history of 21 breast cancers. Cell, Volume 
149, Issue 5, 994-1007, 17 May 2012 
13. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: american society of clinical oncology/college of 
american pathologists clinical practice guideline update. Archives of Pathology & Laboratory 
Medicine, Vol. 137 Issue 10, 2013 
14. Hammond ME, Hayes DF, Dowsett M, et al. American society of clinical oncology/college of 
american pathologists guideline recommendations for immunohistochemical testing of 
estrogen and progesterone receptors in breast cancer. J Clin Oncol, 28, 2010 
15. Klein JP and Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated 
Data, New York: Springer-Verlag. 1997 
16. S Ohtani, N Masuda, Y-H Im, S-A Im, B-W Park, S-B Kim, Y Yanagita, S Takao, S Ohno, K 
Aogi, H Iwata, K Yoshidome, R Nishimura, Y Ohashi, S-J Lee, and M Toi.  Adjuvant 
capecitabine in breast cancer patients with pathologic residual disease after neoadjuvant 
chemotherapy: First safety analysis of CREATE-X (JBCRG-04).  Cancer Res 2013;73(24 
Suppl): Abstract nr P3-12-03. 
 
 

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HCRN BRE12-158 Appendix A. 
Chemotherapy dosing, monitoring and dose adjustments. 
 
Bevacizumab  
Recommended dosing for bevacizumab 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Bevacizumab 15 mg/kg 
Every 3 weeks 
Cycle=3 weeks 
IV 
4 cycles  
(12 weeks) 
 
Recommended monitoring for bevacizumab 
1. Urine protein every cycle 
a. -hold if urine protein > 2+ 
2. Blood pressure every cycle  
a. -if BP>150/100 add anti-hypertensive 
b. -If BP>180/110 hold 
3. Sign/Symptoms of bleeding or thrombosis, every cycle 
4. Dose adjustments: 
a. hypertension, severe, not controlled: temporarily suspend bevacizumab; 
discontinue with hypertensive crisis or hypertensive encephalopathy.  
b. proteinuria, moderate to severe: temporarily suspend bevacizumab; discontinue for 
nephrotic syndrome.  
c. surgery: suspend treatment with bevacizumab at least 28 days prior to elective 
surgery; do not restart until the surgical incision has completely healed; do not give 
for at least 28 days following major surgery; discontinue if wound healing 
complications require medical intervention. 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event. 
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel. The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 

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Capecitabine 
Recommended dosing for Capecitabine 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Capecitabine 
1250 mg/m2 
(round for 
tablet) 
Twice daily for 
2 weeks then  
1 week off 
Cycle=3 weeks 
orally 
4 cycles  
(12 weeks) 
 
Recommended monitoring for capecitabine 
1. Complete metabolic panel, prior to each cycle 
2. Complete blood counts, prior to each cycle 
3. Dose adjustments: 
a. renal impairment: CrCl 30 to 50 mL/min, decrease starting dose to 75% of the 
original dose  
b. hepatic impairment: mild to moderate, no initial dosage adjustment necessary  
c. monotherapy, grade 2 adverse event: first appearance, hold capecitabine dose until 
resolved to grade 0 to 1; second appearance, hold capecitabine dose until resolved 
to grade 0 to 1 and give 75% of the original capecitabine dose at the start of the 
next cycle; third appearance, hold capecitabine dose until resolved to grade 0 to 1 
and give 50% of the original capecitabine dose at the start of the next cycle; fourth 
appearance, discontinue treatment  
d. monotherapy, grade 3 adverse event: first appearance, hold capecitabine dose until 
resolved to grade 0 to 1 and give 75% of the original capecitabine dose at the start 
of the next cycle; second appearance, hold capecitabine dose until resolved to grade 
0 to 1 and give 50% of the original capecitabine dose at the start of the next cycle; 
third appearance, discontinue permanently  
e. monotherapy, grade 4 adverse event: first appearance, discontinue permanently or 
continue if the physician considers it to be in the best interest of the participant; 
give 50% of the starting capecitabine dose at the start of the next cycle 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event. 
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel. The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
 

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Celecoxib 
Recommended dosing for Celecoxib 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Celecoxib 
200 mg 
Daily  
Cycle = 3 weeks 
Orally 
4 cycles  
(12 weeks) 
 
Recommended monitoring for celecoxib 
1. Signs/symptoms of skin reaction 
2. Complete blood counts and complete metabolic panel at the discretion of the physician.  
3. Dose adjustments 
a. Discontinue in severe renal (CrCl < 30 ml/min) and hepatic (Child-Pugh Class C) 
impairment 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event. 
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel. The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
  

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Cetuximab 
Recommended dosing for Cetuximab 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administrati
on 
Number of 
cycles 
Cetuximab 
400 mg/m2 week 1 
loading dose, then, 
250 mg/m2 weekly 
thereafter 
Weekly 
Cycle = 3 weeks 
IV 
4 cycles  
(12 weeks) 
 
Recommended monitoring for cetuximab 
1. Signs/symptoms of dermatologic toxicity 
2. Signs/symptoms of infusion reactions 
3. BMP plus magnesium, monthly 
4. Premedicate with a H1 antagonist prior to first dose; premedication should be administered 
for subsequent doses based upon clinical judgement and presence/severity of prior infusion 
reactions. 
5. Dose adjustments: 
a. dermatologic toxicities (severe, grade 3 or 4 acneiform rash): delay for 1 to 2 
weeks; if improved, restart at 250 mg/m(2) after the first occurrence, 200 mg/m(2) 
after the second occurrence, and 150 mg/m(2) after the third occurrence; cetuximab 
should be discontinued if a participant does not improve from a previous episode or 
has a fourth occurrence  
b. infusion-related toxicities: decrease infusion rate by 50% for grade 1 or 2 infusion-
related reactions and non-serious grade 3 infusion reactions; immediately and 
permanently discontinue cetuximab in participants experiencing a serious reaction 
that requires medical intervention and/or hospitalization  
c. pulmonary toxicities: interrupt for acute onset or worsening of pulmonary 
symptoms; permanently discontinue cetuximab in participants if interstitial 
pulmonary lung disease is confirmed. 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 

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Cisplatin 
Recommended dosing for Cisplatin 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Cisplatin 
75 mg/m2 
Every 3 weeks 
Cycle = 3 weeks 
IV 
4 cycles  
(12 weeks) 
 
Recommended monitoring for cisplatin 
1. Complete metabolic panel, prior to each cycle 
2. Complete blood counts, prior to each cycle 
3. Dose adjustments: 
a. renal impairment: repeat courses should not be given until serum creatinine is less 
than 1.5 mg/100 mL and/or BUN is less than 25 mg/100 mL 
b. absolute neutrophil count (ANC) 1.0 K/mm3 to 1.5 K/mm3or platelets 50 to 
100K/mm3): hold therapy until ANC is greater than 1.5 K/mm3 and platelets greater 
than 100 K/mm3; maintain initial dose. 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
 
 

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Copanlisib 
Recommended dosing for Copanlisib 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Copanlisib 
60 mg 
Days 1, 8 and 15 
of a 28 day cycle 
Cycle = 4 weeks 
IV over 60 
minutes 
4 cycles  
(16 weeks) 
 
Recommended monitoring for copanlisib 
1. Complete blood counts with differential, baseline then weekly  
2. Dose adjustments: 
a. Withhold treatment until ANC ≥ 0.5 x 103 cells/mm3 
b. Withhold treatment if platelet count < 25 x 109 and utilize dose reduction 
guidelines per PI. 
b. Withhold treatment in patients until both the systolic blood pressure (BP) is less than 
150 mmHg and the diastolic BP is less than 90 mmHg. Consider reducing dose if anti-
hypertensive treatment is required. Discontinue in patients with BP that is uncontrolled 
or with life-threatening consequences. Monitor for signs and symptoms of congestive 
heart failure and abnormal arrhythmia 
b. Monitor urine protein  
c. Monitor serum glucose 
d. Monitor for severe cutaneous reactions 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  The dose of copanlisib will be held and 
reduced per package insert guidelines for the given medication.  For any toxicity that is grade 3 or 
higher, the treatment will be discontinued and re-evaluated at the resolution of the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
 
 

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Crizotinib 
Recommended dosing for Crizotinib 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Crizotinib 
250 mg 
Twice daily 
Cycle = 3 weeks 
Orally 
4 cycles  
(12 weeks) 
 
Recommended monitoring for crizotinib 
1. Complete blood counts, baseline then monthly 
2. liver function tests, including ALT and total bilirubin; monthly 
3. BMP plus magnesium monthly 
4. Electrocardiograms in participants with congestive heart failure, bradyarrhythmias, 
electrolyte abnormalities, and participants taking concomitant QT-prolonging drugs 
5. Evaluate for CYP3A4 drug interactions. 
6. Dose adjustments: 
a. hepatic impairment, grade 3 or 4 ALT or AST elevation with concurrent grade 1 or 
lower elevation of total bilirubin: withhold crizotinib until recovery to grade 1 or 
lower or to baseline, then resume at 200 mg orally twice a day; if toxicity recurs 
withhold until recovery to grade 1 or lower, then resume at 250 mg orally once a 
day; permanently discontinue in case of grade 3 or 4 recurrence. 
b. renal impairment: no dosage adjustments required in mild (CrCl 60 to 90 mL/min) 
or moderate renal impairment (CrCl 30 to 60 mL/min). 
c. hematologic toxicity, grade 3: except lymphopenia unless associated with clinical 
events (e.g., opportunistic infections), withhold crizotinib until recovery to grade 2 
or lower, and then resume at the same dose schedule. 
d. hematologic toxicity, grade 4: except lymphopenia unless associated with clinical 
events (e.g., opportunistic infections), withhold crizotinib until recovery to grade 2 
or lower, then resume at 200 mg orally twice a day; if grade 4 hematologic toxicity 
recurs withhold until recovery to grade 2 or lower, then resume at 250 mg orally 
once a day; permanently discontinue in case of grade 4 recurrence. 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel. The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
  
 

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Doxorubicin 
Recommended dosing for Doxorubicin  
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of cycles 
Doxorubicin 
60 mg/m2 
Every 3 weeks 
Cycle=3 weeks 
IV 
4 cycles  
(12 weeks) 
 
Recommended monitoring for Doxorubicin 
1. LVEF (via MUGA or ECHO) at baseline then periodically if cardiac risk factors present 
2. Complete blood count, prior to each dose  
3. Complete metabolic panel, prior to each dose 
4. Dose adjustments: 
a.  neutropenic fever/infection (adjuvant treatment of axillary node-positive breast 
cancer) administer 75% of the starting doses of doxorubicin; delay next cycle until 
the absolute neutrophil count is at least 1.0 K/mm3 the platelet count is at least 100 
K/mm3), and non-hematologic toxicities have resolved.  
b. hepatic impairment: 50% dose reduction for serum bilirubin of 1.2 to 3 mg/dL; 
75% dose reduction for serum bilirubin of 3.1 to 5 mg/dL 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 

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Everolimus 
Recommended dosing for Everolimus 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Everolimus 
10 mg 
Daily 
Cycle = 3 weeks 
Orally 
4 cycles  
(12 weeks) 
 
Recommended monitoring for Everolimus 
1. Complete blood counts, baseline then monthly 
2. Complete metabolic panel, baseline then monthly 
3. Fasting serum glucose, baseline then every 3 months 
4. Fasting lipid panel, baseline then every 3 months.  Treatment of dyslipidemia in 
accordance with National institute of health guidelines. 
a. metabolic events (e.g., hyperglycemia, dyslipidemia): if dose reduction below the 
lowest available strength is necessary, consider alternate-day dosing; grade 3, 
temporarily interrupt therapy and consider reinitiating at approximately 50% the 
previous dose; grade 4, discontinue Everolimus. 
5. Non-hematologic toxicities (not metabolic events): if dose reduction below the lowest 
available strength is necessary, consider alternate-day dosing; grade 2 and intolerable 
symptoms, interrupt therapy until recovery to grade 1 or less and reinitiate at the same 
dose, if symptoms recur again at grade 2, interrupt therapy again until symptoms improve 
to grade 1 or less and reinitiate at approximately 50% the previous dose; grade 3, interrupt 
therapy until symptoms improve to grade 1 or less and consider reinitiating at 
approximately 50% the previous dose, consider discontinuation if toxicity recurs at grade 
3; grade 4, discontinue Everolimus. 
6. Evaluate for CYP3A4 drug interactions. 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 

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Gemcitabine 
Recommended dosing for Gemcitabine 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Gemcitabine 
1250 mg/m2 
Days 1, 8  every 
21 days 
Cycle = 3 weeks 
IV 
4 cycles 
(12 weeks) 
 
Recommended monitoring for gemcitabine 
1. Complete blood counts with differential, prior to each dose 
2. Complete metabolic panel, baseline then periodically as needed 
3. Dose adjustments: 
a. non-hematologic toxicity (grade 3 or 4) (except alopecia, nausea, or vomiting): 
hold dose or decrease by 50%. 
b. On Day 1 of gemcitabine; if the absolute neutrophil count (ANC) is 1500 × 106/L 
or greater and the platelets are 100 K/mm3 or greater, give the full dose; if the ANC 
is less than 1.5 K/mm3 or the platelets are less than 100 K/mm3, hold the dose. On 
Day 8 of treatment; if the ANC is 1.0-1.199 K/mm3 or platelets are 50 - 75 K/mm3, 
give 75% of the dose; if the ANC is 0.7 – 0.999 K/mm3 and platelets are > 50 
K/mm3, give 50% of the dose; if the ANC is < 0.7 K/mm3 and platelets are < 50 
K/mm3, hold the dose. 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 

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Octreotide 
Recommended dosing for Octreotide 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
 
Number of 
cycles 
Octreotide 
20 mg 
Every 4 weeks 
Cycle = 4 weeks 
IM, 
intragluteally 
4 cycles  
(16 weeks) 
 
Recommended monitoring for octreotide 
1. Thyroid function, baseline and prior to last dose 
2. BMP prior to each dose 
3. Electrocardiogram baseline 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 

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Olaparib 
Recommended dosing for Olaparib 
  
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Olaparib 
400 mg 
Twice daily 
Cycle = 4 weeks 
PO 
4 cycles  
(16 weeks) 
  
Recommended monitoring for Olaparib  
2. Basic metabolic panel, prior to each cycle 
3. Complete blood counts, prior to each cycle 
4. Dose adjustments:  
a. Renal impairment, mild (CrCl 50 to 80 mL/min): No dose adjustment is required, 
although monitoring is recommended. No data is available for participants on 
dialysis or with moderate to severe impairment (CrCl less than 50mL/min). 
b. Absolute neutrophil count (ANC) 1.0 to 1.5 K/mm3 or platelets 50 to 100 K/mm3): 
hold therapy until ANC is greater than 1.5 K/mm3 and platelets greater than 100 
K/mm3; maintain initial dose. If participant experiences toxicity again, reduce dose 
to 200 mg BID. 
  
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading. For any toxicity that is Grade 2, the dose will 
be held and reduced per package insert guidelines for the given medication. For any toxicity that is 
grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of the 
adverse event.  
  
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel. The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
 
 

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Paclitaxel 
Recommended dosing for Paclitaxel 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of cycles 
Paclitaxel 
80 mg/m2 
Weekly 
Cycle = 3 weeks 
IV 
4 cycles  
(12 weeks) 
 
Recommended monitoring for paclitaxel 
2. Complete blood counts, prior to each dose 
3. Complete metabolic panel, monthly 
4. Sign/symptoms of infusion reaction 
5. Premedication for paclitaxel included diphenhydramine 50 mg and an H2 blocker 
approximately 30 minutes prior to each paclitaxel infusion plus dexamethasone 10 mg 
prior to weekly paclitaxel. 
6. Dose adjustments: 
a. do not initiate therapy if baseline neutrophils are less than 1.5 K/mm3; do not 
administer a subsequent cycle until neutrophils are greater than 1.5 K/mm3  and 
platelets are greater than 100 K/mm3; if neutrophil count drops below 0.5 K/mm3 
for one week or longer, decrease dose by 20% on subsequent cycles. 
b. peripheral neuropathy: decrease dose by 20% on subsequent cycles 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
 
 

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Palbociclib 
Recommended dosing for Palbociclib 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Palbociclib 
125 mg 
Daily for 21 days 
of a 28 day cycle 
Cycle = 4 weeks 
Orally 
4 cycles  
(16 weeks) 
 
Recommended monitoring for palbociclib 
1. Complete blood counts with differential, baseline then on day 14 (14 days after the first 
dose) of 28-day treatment cycle and weekly until recovery if the absolute neutrophil count 
falls below 150 K/mm3  
2. Dose adjustments or dose reductions per package insert guidelines 
  
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For certain Grade 3 toxicities or higher, the 
dose will be held and possibly reduced per package insert guidelines for the given medication.   
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
 
 
 

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Pembrolizumab 
Recommended dosing for pembrolizumab 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Pembrolizumab 
200 mg  
Every 3 weeks 
Cycle = 3 weeks 
IV 
4 cycles  
(12 weeks) 
 
Recommended monitoring for pembrolizumab 
1. Signs/symptoms of immune mediated problems 
• Pneumonitis 
• Colitis 
• Hepatitis 
• Endocrinopathies  
• Rash (Steven Johnson’s Syndrome) 
• Changes in eyesight 
• Muscle pain or weakness 
• Myocarditis 
2. Signs/symptoms of infusion reactions 
5. CBC and CMP before each dose.  Thyroid function at baseline then as clinically needed. 
6. No pre-medications required 
7. Withhold pembrolizumab for any of the following: 
• Grade 2 pneumonitis  
• Grade 2 or 3 colitis  
• Grade 3 or 4 endocrinopathies  
• Grade 2 nephritis  
• Grade 2 hypophysitis 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 
3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 
and up to 3 times ULN 
• Any other severe or Grade 3 treatment-related adverse reaction  
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.   
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required.  The current package insert can be found at 
http://www.accessdata.fda.gov/scripts/cder/daf/ 
 
 
 
 

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Sunitinib 
Recommended dosing for Sunitinib 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Sunitinib 
37.5 mg 
Daily for 21 days 
of a 21 day cycle 
Cycle = 3 weeks 
Orally 
4 cycles  
(12 weeks) 
 
Recommended monitoring for sunitini 
1. Complete blood counts with differential, baseline then on day 1 of each 
cycle  
2. Dose adjustments: 
a. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse 
events and discontinued if there is no resolution. Do not restart SUTENT if patients 
subsequently experience severe changes in liver function tests or have other signs 
and symptoms of liver failure. 
b. Monitor for signs and symptoms of congestive heart failure and abnormal 
arrythmia 
c. Monitor for high blood pressure 
d. Monitor urine protein  
e. Monitor serum glucose 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/ 
 
 

BRE12-158 
Clinical Study Protocol 
Version Date: 27APR2018  
 
 
 
 
 
 
Page 56 of 56 
 
Temozolomide 
Recommended dosing for Temozolomide 
 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Temozolomide 
150 mg/m2 
(round for 
tablet) 
Daily for 5 days of 
a 28 day cycle 
Cycle = 4 weeks 
Orally 
4 cycles  
(16 weeks) 
 
Recommended monitoring for temozolomide 
1. Complete blood counts with differential, baseline then on day 22 (21 days after the first 
dose) of 28-day treatment cycle and weekly until recovery if the absolute neutrophil count 
and platelet count fall below 150 K/mm3 and 100 K/mm3, respectively 
2. Dose adjustments: 
a. absolute neutrophil count (ANC) 1.0 to 1.5 K/mm3 or platelets 50 to 100 K/mm3): 
hold therapy until ANC is greater than 1.5 K/mm3 and platelets greater than 100 
K/mm3; maintain initial dose. 
 
The National Cancer Institute Common Terminology Criteria for Adverse events v4.0 (CTCAE) 
will be used for adverse event reporting and grading.  For any toxicity that is Grade 2, the dose 
will be held and reduced per package insert guidelines for the given medication.  For any toxicity 
that is grade 3 or higher, the treatment will be discontinued and re-evaluated at the resolution of 
the adverse event.  
 
The package insert will be consulted and followed for the recommended manufacturer monitoring 
or dose adjustments required based on complete blood counts and metabolic panel.  The current 
package insert can be found at http://www.accessdata.fda.gov/scripts/cder/daf/