Prospective Validation Trial of Taxane Therapy (Docetaxel or Weekly Paclitaxel) and Risk of Chemotherapy-Induced Peripheral Neuropathy in African American Women
Phase: PHASE2
Conditions: Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Invasive Breast Carcinoma, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8
Sponsor: ECOG-ACRIN Cancer Research Group

 
EAZ171 
1 
Prospective validation trial of taxane therapy (docetaxel or 
weekly paclitaxel) and risk of chemotherapy-induced 
peripheral neuropathy in African American women 
STUDY CHAIR: 
Bryan P. Schneider, MD 
STUDY STATISTICIAN: 
Fengmin Zhao, PhD 
STUDY CO-CHAIR: 
Joseph Sparano, MD 
QUALITY OF LIFE CO-CHAIR: 
Sofia F. Garcia, PhD 
TRANSLATIONAL SCIENCE CO-CHAIR: 
COMMUNITY CO-CHAIR: 
Fei Shen, MD 
Shamsuddin Virani, MD 
CANCER CONTROL AND SURVIVORSHIP 
COMMITTEE CHAIR: 
Lynne Wagner, PhD 
HEALTH EQUITY COMMITTEE CO-CHAIRS: 
Edith Mitchell, MD 
Melissa Simon, MD 
BREAST CANCER COMMITTEE CHAIR: 
Antonio Wolff, MD 
Version Date: February 26, 2021 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in 
Oncology 
 
June 27, 2019 
NRG / NRG Oncology 
 
Addendum #1 
SWOG / SWOG 
 
Addendum #2 
 
 
 
 
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Docetaxel 
IND Exempt Study 
NSC 628503 
Commercially Available 
Paclitaxel 
NSC 673089 
Commercially Available 
 
 

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Rationale for Proposed Study ................................................................... 7 
1.2 Significance of the Study ......................................................................... 16 
1.3 Advantages of this Trial Design ............................................................... 16 
1.4 Patient Reported Outcomes ................................................................... 18 
2. Objectives ......................................................................................................... 20 
2.1 Primary Objectives .................................................................................. 20 
2.2 Secondary Objectives .............................................................................. 20 
2.3 Correlative Study Objectives ................................................................... 20 
2.4 Patient Reported Outcome Objectives ................................................... 20 
3. Selection of Patients ......................................................................................... 22 
3.1 Eligibility Criteria ..................................................................................... 22 
4. Registration Procedures.................................................................................... 24 
4.1 Registration Information ......................................................................... 28 
4.2 Eligibility Verification .............................................................................. 28 
4.3 Classification Factors ............................................................................... 28 
4.4 Additional Requirements ........................................................................ 28 
4.5 Instructions for Patients who Do Not Start Assigned Protocol Treatment30 
5. Treatment Plan ................................................................................................. 31 
5.1 Administration Schedule ......................................................................... 31 
5.2 Adverse Event Reporting Requirements ................................................. 32 
5.3 Dose Modifications ................................................................................. 39 
5.4 Supportive Care ....................................................................................... 45 
5.5 Patient-Reported Outcomes (PRO) Administration ................................ 45 
5.6 PRO Assessment Schedule ...................................................................... 45 
5.7 PRO Instructions ...................................................................................... 46 
5.8 Duration of Therapy ................................................................................ 47 
5.9 Duration of Follow-up ............................................................................. 48 
6. Measurement of Effect ..................................................................................... 49 
6.1 Grade 2-4 neuropathy ............................................................................. 49 
6.2 PRO-based neuropathy ........................................................................... 49 
6.3 PROMIS Physical Function v2 Short Form 10 .......................................... 50 
6.4 Health-related quality of life ................................................................... 50 
6.5 Comprehensive Score for Financial Toxicity – Functional Assessment of 
Chronic Illness Therapy (COST-FACIT) ..................................................... 50 
6.6 Alliance Patient Questionnaire Items on Social Determinants of Health50 
6.7 PRO-CTCAE .............................................................................................. 51 
6.8 Disease recurrence .................................................................................. 51 
6.9 Survival .................................................................................................... 51 

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7. Study Parameters .............................................................................................. 52 
7.1 Therapeutic Parameters for Arms A and B ............................................. 52 
8. Drug Formulation and Procurement ................................................................. 55 
8.1 Paclitaxel ................................................................................................. 55 
8.2 Docetaxel ................................................................................................ 57 
9. Statistical Considerations .................................................................................. 59 
9.1 Primary Objective .................................................................................... 60 
9.2 Secondary Objectives .............................................................................. 61 
9.3 PRO Objectives ........................................................................................ 63 
9.4 Safety Monitoring ................................................................................... 64 
9.5 Gender and Ethnicity .............................................................................. 64 
10. Specimen Submissions ...................................................................................... 66 
10.1 Submissions to Indiana University .......................................................... 66 
10.2 Use of Specimens in Research ................................................................ 68 
10.3 ECOG-ACRIN Sample Tracking System .................................................... 68 
10.4 Sample Inventory Submission Guidelines ............................................... 69 
11. Laboratory Research Studies ............................................................................ 70 
11.1 To prospectively validate & discover additional germline predictive 
biomarkers for paclitaxel-induced peripheral neuropathy in EAZ171. ... 70 
11.2 To determine the impact of germline variability on paclitaxel-induced 
phenotypic changes in patient derived iPSC-iSNs and compare and 
contrast the accuracy and sensitivity of these changes with clinical 
outcomes in EAZ171................................................................................ 74 
11.3 To assess the impact of paclitaxel on gene expression, DNA methylation, 
and chromatin accessibility in patient-derived iPSC-iSNs ....................... 77 
11.4 Lab Data Transfer Guidelines .................................................................. 81 
12. Electronic Data Capture .................................................................................... 82 
13. Patient Consent and Peer Judgment ................................................................ 82 
14. References ........................................................................................................ 82 
Appendix I  ECOG-ACRIN Generic Specimen Submission Form (#2981v3) ............. 88 
Appendix II  Patient Thank You Letter ..................................................................... 90 
Appendix III  ECOG Performance Status .................................................................. 91 
 
 
 

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STUDY CHAIR 
Bryan P. Schneider, MD, 
Indiana University, 
535 Barnhill Dr. RT 473  
Indianapolis, IN 46202, 
Phone: 317-948-3855 
Fax: 371-948-3646 
bpschnei@iu.edu 
 
STUDY CHAIR LIAISON (SCL)-
RECRUITMENT & STUDY KITS/LABS 
Casey Bales, 
Indiana University, 
535 Barnhill Dr. RT 473  
Indianapolis, IN 46202, 
Phone: 317-274-2840 
Fax: 371-948-3646 
calallen@iupui.edu 
 
STUDY CHAIR LIAISON (SCL) -
NURSING 
Jessica Sollars, RN 
Indiana University, 
535 Barnhill Dr. RT 473  
Indianapolis, IN 46202, 
Phone: 317-278-5117 
Fax: 317-948-6796 
jlsherma@iupui.edu 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation can be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
through Medidata Rave. 
Please see the data 
submission section of 
the protocol for further 
instructions. 
Do not submit study data 
or forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. Add2 

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Schema
1. Peripheral blood samples are to be collected and submitted following registration, prior to treatment for the mandatory protocol-defined laboratory 
research studies.
2. PROs are to be administered per Section 5.6. PROs for administration are: Functional Assessment of Cancer Therapy Gynecological Oncology Group 
Neurotoxicity (FACT/GOG-NTX) PROMIS Physical Function v2.0 Short Form 10a, Comprehensive Score for Financial Toxicity (COST-FACIT), five 
items from the Alliance Patient Questionnaire for Clinical Trials In Oncology, PRO CTCAE items, and CIPN20 sensory neuropathy subscale.
3. Treatment arm will be determined at the discretion of the treating investigator.
4. Concurrent therapy is to be administered per Sections 5.1 and 5.4.
5. Every 3 months if patient is < 2 years from their date of registration, every 6 months if patient is 2-5 years from their date of registration. Patients will be 
followed for 5 years from their date of registration.
 L5
O
N
G
-
T
E
R
M 
F
O
L
L
O
W 
-
U   
P
Paclitaxel: 
80mg/m2 Weekly for 
4 cycles
 R3
E
G
I
S
T
R
A
T
I
O
N
Accrual = 240
1 cycle = 21 days
Women self-identified as African- 
American, Black, or of African descent 
and diagnosed with stage I-III breast 
cancer.
• No prior taxane therapy
• No prior or concurrent platinum
• No pre-existing neuropathy
Docetaxel: 
75 mg/m2 Every 3 
weeks for 4-6 cycles 
Arm A1,2,4
Arm B1,2,4
Follow-up
 6 months post-
registration
 
Rev Add1 
Rev Add2 

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1. 
Introduction 
 
Rationale for Proposed Study 
We have compiled compelling evidence in a retrospective fashion to suggest that 
African American patients have substantially higher risk of experiencing taxane-
induced peripheral neuropathy (TIPN) than Caucasian patients when treated with 
adjuvant weekly paclitaxel, a commonly employed regimen in the curative setting 
for breast cancer.1,2 Further, we have demonstrated that this toxicity leads to 
more dose reductions and is associated with higher breast cancer recurrence 
rates in African Americans compared with Caucasians. On the other hand, we 
have also shown that weekly paclitaxel is associated with significantly reduced 
rates of breast cancer recurrence and improved survival compared with other 
taxane regimens, including docetaxel given every 3 weeks, in triple negative 
breast cancer (TNBC),3 a particularly aggressive and potentially lethal breast 
cancer subtype which is more common in African-American women.4 However, 
compared to Caucasian patients, African American patients had a lower rate of 
TIPN from every three-week docetaxel treatment.3,5,6 We have also demonstrated 
the ability to use germline variability to better predict the likelihood of taxane-
associated neuropathy in African American patients, including variants that are 
associated with higher risk (SBF2) or those that are protective (FCAMR).1,7 We 
now set out to evaluate the following in African American patients with breast 
cancer: (1). Prospectively validate the association of germline variants with TIPN 
from commonly used taxane regimens, including weekly paclitaxel (80 mg/m2 
weekly × 12 doses) and every 3-week docetaxel (75 mg/m2 every 3 weeks × 4 
doses) (2). Demonstrate that every three-week docetaxel causes fewer dose 
reductions due to TIPN than weekly paclitaxel (3).Use both physician reported 
(CTCAE) and patient reported outcomes (PRO) to assess and compare both 
acute neuropathy (CTCAE grade 2 or higher occurring during taxane therapy) 
leading to taxane dose reductions and delayed onset (occurring for the first time 
or recurring after resolution or improvement > 6 months based on CTCAE 
criteria) between weekly paclitaxel and three week docetaxel. The objective of 
this study is to prospectively validate the association of germline variants that we 
have previously identified that are either associated with increased risk (SBF2) or 
protective (FCAMR) against TIPN, with the ultimate goal of identifying the 
preferred taxane based on both potential for efficacy and toxicity to be used in 
the curative setting for African Americans with breast cancer. 
Compared to Caucasians, African Americans have a higher risk of being 
diagnosed with advanced stage of breast cancer8 and higher breast cancer 
mortality rate.9,10 African Americans had a 42% higher breast cancer death rate in 
the period of 2008-2012.11 The reason for this imbalance is multifactorial and 
includes higher stage, higher grade, more triple negative breast cancer (TNBC), 
and poorer responsiveness to chemotherapy.12,13 These imbalances in outcome 
have previously been attributed to both socioeconomic factors and a different 
underlying biology of the tumor.10,14,15 Recently, we have demonstrated that 
another significant contributor is the increased need for dose reductions of 
weekly paclitaxel in the curative setting for African Americans due to 
significantly higher rates of TIPN.2 While the taxanes are considered a crucial 
component to improve the cure rate in both the adjuvant and neoadjuvant 
settings, peripheral neuropathy is one of the major adverse effects from taxanes, 
which can be dose-limiting, painful, impact quality of life, and is sometimes 

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irreversible. The American Society of Clinical Oncology deemed TIPN to be one 
of the three most important survivorship issues impacting cancer patients,16 thus 
this toxicity appears to preferentially impact the quality of life of African 
Americans and results in a less cumulative dose of an important drug resulting in 
inferior care. 
TIPN is common for all patients but its frequency and severity are impacted by 
the type and schedule of the taxane. Weekly paclitaxel for 12 weeks has become 
a commonly employed regimen in the curative setting based on the outcomes of 
E1199.3 E1199 compared every three-week paclitaxel with weekly paclitaxel, or 
every three-week docetaxel, or weekly docetaxel. Weekly paclitaxel was the 
most efficacious type and dose of taxane along with every three-week docetaxel 
in the overall population, whereas weekly paclitaxel was associated with 
significantly improved disease free survival (hazard ratio [HR]=0.69, p=0.001) 
and overall survival (HR=0.69, p=0.019) in women with triple negative breast 
cancer (TNBC).6 Weekly paclitaxel had more grade 2-4 and grade 3-4 TIPN than 
every three-week docetaxel but otherwise was associated with much less overall 
acute hematologic and non-hematologic toxicity; thus due to its general 
tolerability profile has been largely considered the favored regimen. There are 
two major flaws with the generalizability of this conclusion. First, it assumes that 
the likelihood of toxicities is uniform across populations. Second, it assumes that 
differential likelihoods of toxicities do not impact efficacy in specific subgroups. 
We evaluated the rates of TIPN in two consecutive trials coordinated by ECOG-
ACRIN, including the E1199 trial that compared 4 different taxane regimens 
(every 3 week paclitaxel 175 mg/m2 × 4, weekly paclitaxel 80 mg/m2 ×12, every 3 
week docetaxel 100 mg/m2 × 4, and weekly docetaxel 35 mg/m2 × 12), and the 
E5103 trial which employed weekly paclitaxel (80 mg/m2 × 12 weeks) in all 
patients; in both trials, the taxane therapy was given sequentially after 
doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (in 
E1199 or E5103) or every 2 weeks (in E5103). At least 8% of patients in both 
trials were of self- reported African American race. The rates of TIPN are 
summarized in Table 1, with a focus on the weekly paclitaxel and every 3-week 
docetaxel arms that were the most efficacious. 
While African American patients are markedly under-represented within clinical 
trials,17 retrospective subgroup analyses from E1199 demonstrated that self-
described African American patients had fewer dose reductions than self-
described Caucasian patients in the every-three week docetaxel arm,5 the only 
arm in E1199 for which this was true. Additional evidence that weekly paclitaxel 
has serious limitations specific to African American patients came from another 
adjuvant phase III trial, E5103.18 In E5103 all patients received a standard 
backbone of weekly paclitaxel with a randomization to bevacizumab or placebo. 
E5103 was a perfect testing ground for these questions as it had a markedly 
greater number of African Americans compared with some of the contemporary 
adjuvant breast cancer trials and collected germline genetic information.1 In this 
trial we demonstrated that African American patients had markedly more grade 
2-4 (HR=2.1, p = 5.6 x 10-16) and grade 3-4 TIPN (HR=2.6, p = 1.1 x 10-11) 
compared with other races (Figure 1).1 

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Figure 1. Comparison of Grade 2-4 (left) and Grade 3-4 (right) TIPN by 
genetically determined race in E5103. The frequency of Grade 2-4 TIPN in 
the genotyped cohort was 39.4% for those of AA vs. 22.9% for all other 
races combined (p =5.6 x10-16). The frequency of G3-4 TIPN in the 
genotyped cohort was 21.5% for those of AA vs. 8.7% for all other races 
combined (p=1.1 x 10-11). 
Table 1. Frequency of TIPN in E1199 and E5103 
Dataset 
Treatment 
TIPN Grade  EA* (%) 
AA**(%) 
E1199 
Every 3 week 
Docetaxel 
Grade 2-4 
17.8 
13.2 
Grade 3-4 
5.2 
4.4 
E1199 
Weekly 
paclitaxel 
Grade 2-4 
22.4 
27.7 
Grade 3-4 
7.3 
10.9 
E5103  
(Genotyped cohort) 
Weekly 
paclitaxel 
Grade 2-4 
22.9 
39.4 
Grade 3-4 
8.7 
21.5 
*Caucasian or patients of European ancestry 
**African American or patients of African ancestry 
We subsequently assessed the intersection of genetic ancestry on both efficacy 
and toxicity in E5103 using ancestry informative markers. Much of the prior work 
has been based on self-reported race, which has limitations. Race, when 
assessed in this fashion, is typically based on skin color and often neglects the 
genetic ancestry and studies suggest there is substantial admixture and 
misclassification of race in the United States when based on self-reported skin 
color.19,20 Thus our findings using genetic ancestry represented the true impact of 
genetic/biological differences at its most accurate level. We compared toxicity 
and efficacy outcomes in E5103 from 386 patients of African ancestry and 2473 
patients of European ancestry (Figure 2).2 

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Figure 2. CONSORT for E5103 
We demonstrated that patients of African ancestry had markedly inferior disease 
free survival (the primary endpoint of E5103) (p=0.02) compared with other races 
(Figure 3).2 As expected, because African Americans had more TIPN, they had 
significantly more dose reductions for the paclitaxel portion of the therapy (p=6.6 
×10-6). Most importantly, however, the dose reductions in paclitaxel for African 
Americans had a significant negative impact on DFS (p=0.03); whereas in 
European Americans, dose reductions did not impact outcome (p=0.35) (Figure 
4). This was a function of severity of dose reductions and less total cumulative 
dosage.2 

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Figure 3. Disease Free Survival (DFS) for African ancestry (AA) compared 
with European ancestry (EA) for all patients (A), DFS for all self-reported 
patients (B), DFS for genetic ancestry with estrogen receptor or 
progesterone receptor positive disease (C), and for genetic ancestry with 
triple negative breast cancer (D). 
 
Figure 4. Disease free survival for European ancestry (left) and African 
ancestry (right) patients who experienced any dose reduction or early 
cessation of paclitaxel compared with those who did not have a dose 
reduction or early cessation. 
The planned pragmatic trial outlined in this proposal will now allow for the unique 
opportunity to uncover the preferred taxane in the curative setting (weekly 

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paclitaxel vs. every-three week docetaxel) for an enriched population of African 
Americans. Our powerful preliminary data allow us to consider clinically 
significant TIPN as a surrogate for inferior outcome in African American patients. 
Further, the focus on TIPN affords the unique opportunity to both improve 
the quality of life and curability within a relatively small number of patients 
in a short period of time. When considering both resources and impact, this 
pragmatic trial design has the potential to move the needle substantially and 
efficiently. 
While African Americans as a group are markedly more likely to experience 
TIPN, there is clearly still heterogeneity from patient to patient. The ability to 
further predict the likelihood of this toxicity at the individual patient level would 
only further refine the ability to make the best therapeutic decision for each and 
every patient. Several prior studies, largely composed of Caucasian patients, 
have shown that germline genetic variability might impact likelihood of 
TIPN.1,2,7,21,22 Our group recently identified both common and rare germline 
variants that predicted differential likelihood of TIPN in African Americans in 
E5103.1,7 Through a genome wide association study in E5103, we identified a 
variant in FCAMR that was strongly associated with a decreased likelihood of 
TIPN (Figure 5).1 We further evaluated the impact of an imbalance in deleterious 
rare variants across the exome using whole exome sequencing.7 In this scan, we 
found a significant increase in the risk of TIPN for those who carried deleterious 
mutations in SBF2. When inheriting two mutations in SBF2, patients are destined 
to have the most common form of hereditary neuropathy, Charcot-Marie Tooth.23 
When carrying one mutation, it appears African American patients are set up for 
a marked increase risk of TIPN (Figure 6).7 

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Figure 5. Manhattan plot for Grade 2-4 TIPN from patients with African 
ancestry in E5103.  The x-axis indicates the chromosomal position of each 
SNP analyzed; Y-axis denotes magnitude of the evidence for association, 
shown as –log10(p-value). 
Figure 6. Manhattan plot for Grade 2-4 TIPN from African ancestry in E5103.  
The x-axis indicates the chromosomal position of each gene analyzed; Y-
axis denotes magnitude of the evidence for association, shown as –
log10(p-value); Each dot represents an evaluable gene.  The dashed line 
indicates the exome-wide significance threshold.

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Thus, by further uncovering the power of genomic variation, we can predict a 
range of grade TIPN in African ancestry from 7%-65% (Figure 7).1,7 Further, our 
group has previously shown that the impact of these markers are deemed 
relevant from a patient’s vantage and these markers could even impact the type 
of therapy they would choose in the curative setting (Figure 8).24 To optimally 
validate these germline predictive markers in a prospective trial, we will plan to 
categorize patients as: “high risk” or “low risk” (Table 2). The trial will be powered 
to confirm that “high risk” patients who receive weekly paclitaxel are more likely 
to experience clinically significant (Grade 2+) TIPN compared with “low risk” 
patients. 
 
Figure 7. Frequency of TIPN Grade 2-4 in African ancestry broken down by 
those with and without a mutated SBF2 gene (rare variant) and those who 
carry one or two variant alleles (rs1856746) in FCAMR (common variant). 
Each bar represents the estimated frequency of TIPN based on the relative 
likelihood of an event. The gray bar represents the frequency of TIPN in the 
entire E5103 sequenced African ancestry cohort. The blue bars represent 
an estimated frequency as determined by the odds ratio for an unmutated 
SBF2 versus carriage of any deleterious mutation. The pink bars represent 
the GG, GA, AA genotypes of rs1856746 in FCMAR, respectively. The 
percentage value above each bar represents the estimated likelihood of a 
patient with that variant or genotype experiencing TIPN. The percentage 
value on the x-axis represents the fraction of the African ancestry with that 
specific genotype. WT= wild type gene with no deleterious mutations. Var = 
variant gene that carries at least one of the 5 deleterious mutations. 

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Figure 8. Patient preference share for any taxane containing regimen (T) 
versus a non-taxane regimen (AC) as the likelihood of TIPN changes. 
Table 2. Genotypes and expected frequencies for high and low risk TIPN 
genotypes 
Clinical  
Category 
Genotypes 
Expected % of 
 trial population 
Expected % of 
Grade 2+ TIPN 
High risk TIPN 
FCAMR GG 
orSBF2 mutated 
76% 
37% 
Low risk TIPN 
FCAMR AA or GA 
AND 
SBF2 wild-type 
24% 
10% 
The assessment of germline predictive markers for TIPN in this planned 
pragmatic trial design will allow for a unique opportunity to validate a clinically 
significant and impactful biomarker in the prospective setting and for an 
enriched population of African Americans. This level of evidence will be 
unprecedented in depth and scope and adds additional utility to the impact 
of the planned trial. In addition to the validation of our markers using the 
conventional reporting methodology (CTCAE), we will also assess the 
reproducibility using PROs as an alternative phenotype. Recent data have 
suggested superior sensitivity with PROs when compared to physician reported 
TIPN25-28 and thus we hypothesize this may further improve the strength of the 
genotype-phenotype relationship. 
Finally, while this protocol boldly sets out to delineate the preferred adjuvant 
taxane use in the African American population and to prospectively validate well-
curated biomarkers, mechanistic insights and additional biomarker enrichment 
(using whole genome sequencing) can also be gained through this pragmatic trial 
design. Although intensively studied, the mechanism of TIPN has not been 
entirely elucidated.29 Unraveling the mechanism will serve as the most definitive 
way to identify drug targets that might lead to therapeutics designed to treat or 

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altogether prevent TIPN. This, in turn, has the potential to improve quality of life, 
drug adherence, and improve therapeutic index of drugs intended to improve 
cancer-specific survival. While assessment of the peripheral nerve in taxane-
treated patients before and after exposure would represent a gold-standard 
approach for mechanistic studies, peripheral nerve biopsies in patients can 
cause severe and irreversible pain and are typically not considered acceptable. 
Recently developed induced pluripotent stem cell (iPSC) technology has 
established a new human platform for the study of TIPN.30 iPSC allows for the 
generation of cells derived from the patient’s blood, which retain the genetic 
diversity and landscape of the donor and have morphologically assessable 
changes in the face of neurotoxins that mimic clinical onset of TIPN.31,32 This 
proposal allows for an unprecedented opportunity to directly compare the fidelity 
and sensitivity of onset of clinically relevant TIPN with ex vivo morphological 
taxane induced neurite damage from the same patient in the context of a clinical 
trial; EAZ171. In addition, this ex vivo model will allow for comprehensive multi-
omic evaluation (transcriptomic and epigenomic changes) of pre- and post-
treatment sensory neurons (iPSC-iSNs) while retaining the patient’s germline 
genomic identity. 
 
Significance of the Study 
The overall goal for this study is to reduce the increased risk of chemotherapy 
induced toxicity for African American patients with breast cancer. 
Despite our compelling retrospective data from unplanned subgroups, we 
recognize that a phase III clinical trial with a primary endpoint of efficacy outcome 
confined to African American patients would require a substantial number of 
patients, many years to complete, and unlikely to happen. Thus, this non-
randomized, pragmatic trial design will uniquely allow for rapid enrollment and 
provide the essential prospective data to optimize the preferred use of taxane in 
the curative setting for African American patients with breast cancer. This 
pragmatic clinical trial will simultaneously address the impact of taxanes on the 
quality of life and curability while prospectively building a testing infrastructure to 
validate previously discovered germline predictive biomarkers for neuropathy and 
creating a discovery platform using cutting edge technology. 
 
Advantages of this Trial Design 
 
Prospective validation of germline predictors of peripheral 
neuropathy: This pragmatic clinical trial is the perfect setting to 
further validate our germline markers for neuropathy. The evaluation 
is non-obtrusive; including only a single venipuncture. This will allow 
direct validation of the markers for the paclitaxel arm. It will also allow 
for an assessment of another taxane, docetaxel, determining whether 
the markers are specific to paclitaxel or more likely to be 
generalizable to the entire class of taxanes. It will also provide an 
opportunity to see if improving the phenotype [patient reported 
outcomes (PROs) as opposed to physician reported outcomes] might 
further strengthen the associations. In addition, the implementation of 
whole genome sequencing will allow for further broad discovery with 
no additional invasive interventions. 
 
Enrichment of African American patients: Clinical trials across the 
United States have been plagued by a lack of accrual for African 

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Americans. Thus, much of the generalized conclusions about best 
treatment options have been made from the risk/benefit ratio 
observed in patients of European descent. We recognize there are 
inherent imbalances in outcomes, toxicity, and biology and thus these 
conclusions may be false for specific populations. Further, much of 
the data regarding disparate outcomes is derived from retrospective, 
unplanned subgroup analyses. This trial will prospectively enroll and 
follow African American patients to determine accurate risk and 
benefits. 
For this study, we will rely on self-reporting of race as an eligibility 
criteria, which is a reasonable surrogate for genetic ancestry.2In 
addition, the primary analysis will be performed using genetic 
assessment of ancestry to further validate links between African 
ancestry and neuropathy outcomes. We recognize that self-identified 
race and ethnicity is a complex and evolving field33 and we have 
adjusted our sample size for the trial to allow for adequate power for 
the expected differences. Our goal is to determine genetic links 
between ancestry and neuropathy to improve standard of care for 
African American women. 
 
Non-randomized trial design: This approach will allow for a direct 
comparison of dose reductions due to TIPN for every three-week 
docetaxel vs. weekly paclitaxel using homogenous phenotype 
definitions. The assigned, non-randomized approach will allow for 
treatment to be delivered in a fashion that is commonly used in clinical 
practice based on disease setting. Because the primary endpoint will 
be centered on toxicity and dose reductions, stratification for important 
disease co-variables can be obviated, which will further facilitate rapid 
enrollment. The design and value of having both arms, however, 
allows for a prospective comparator using identical criteria for toxicity 
and normalizing the conclusions. 
 
Use of clinician reported outcomes AND patient reported 
outcomes: The use of the Common Toxicity Criteria for Adverse 
Events (CTCAE) to be reported by the physician will allow for a 
prospective assessment that can be compared directly to historical 
clinical trials. Thus, marked differences here might be attributed to 
different patient populations or temporal trends in reporting. The 
patient reported outcomes (PROs) can provide a more sensitive and 
superior methodology for reporting. The PROs will likely provide the 
most accurate assessment of the impact on quality of life. 
Comparisons between the methodologies, however, will also allow for 
a direct comparison of the utility of the toxicity marker as a predictor of 
dose reduction and appropriately infer its intersection with efficacy. 
 
Assessment of global gene expression (transcriptome) in 
sensory neurons derived from iPSC of patients: The evaluation of 
global gene expression in patient iPSC derived neurons may identify 
the molecular function and biological process-related genes 
associated with TIPN. This, in turn, will help to understand the 
underlying mechanisms of TIPN and allow for the development of 
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Patient Reported Outcomes 
Patient-reported outcomes (PROs) capture unique data on treatment toxicities 
and disease symptoms in ways that complement clinician-rated toxicities. It is 
important to understand from the patient perspective how the different taxane 
therapies may impact health-related quality of life (HRQoL) and influence 
treatment decision making (e.g., discontinuation in the case of severe 
symptoms). Research has indicated that there can be substantial discrepancy in 
severity grading among clinicians as well as underestimation of symptom severity 
by clinicians (compared to patient report).34 Collecting PROs to document 
treatment toxicities from the patient’s perspective will also provide invaluable 
data to inform patient-centered education regarding the risks and benefits of 
taxane therapies.26  
In addition to using physician reports of adverse events (CTCAE), we will assess 
concurrent patient reported neuropathy with items from the National Cancer 
Institute’s (NCI’s) Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE). The PRO-CTCAE data 
collected will be used to provide descriptive and parallel information about using 
this measurement system to gather information directly from patients about the 
symptomatic adverse effects of their treatment. This trial offers the opportunity to 
validate PRO-CTCAE items to measure two neuropathic symptoms: numbness / 
tingling and pain. If well-validated, in the future, those items could provide 
information to intervene earlier to manage symptoms that may interfere with 
treatment adherence. 
This study will also assess a secondary phenotype of neurotoxicity using the 
FACT/GOG- NTX, which is a well-validated measure for evaluating HRQoL (via 
the FACT-G portion) and neurotoxicity (via the neurotoxicity subscale) in patients 
receiving taxanes.36,72 The FACT/GOG-NTX is an easy-to-interpret PRO 
measure for comparing the neurotoxicity and HRQoL between the two groups in 
this study. Specifically, we will compare the change in the FACT/GOG-NTX 
scores between low- and high-risk genotype groups of the paclitaxel arm, and 
between the paclitaxel arm and the docetaxel arm. In order to harmonize data 
collection with a concurrent SWOG trial developing a predictive model of taxane-
induced peripheral neuropathy, we are adding an additional measures assessing 
neuropathy. The European Organization for Research and Treatment of Cancer 
(EORTC) chemotherapy-induced peripheral neuropathy (CIPN-20)70 includes a 
9-item sensory neuropathy subscale, which has been validated and extensively 
used in prior clinical trials evaluating interventions for treatment of chemotherapy 
induced peripheral neuropathy.71 
Further, given that neuropathy can significantly impact physical function, 40,41 we 
will also compare participant scores on the PROMIS Physical Function v.2 Short 
Form 10a between the two treatment arms. Additionally, we are interested in 
examining the financial toxicity experienced by participants in the two treatment 
arms as reported on the Comprehensive Score for Financial Toxicity (COST-
FACIT). Lastly, in addition to race/ethnicity (discussed earlier), other 
demographic characteristics are important determinants of cancer-related 
outcomes. Research has demonstrated that residents of poorer US counties tend 
to have higher death rates from cancer compared to those in more affluent 
counties.42 Across numerous studies, along with race/ethnicity, poverty is 
associated with poorer survival and worse cancer-related outcomes.42,8,43 Along 
those lines, we will assess various sociodemographic variables (zip code, marital 

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status, education, income and insurance status) in order to better examine the 
role these well-known social determinants of health may play on participant 
outcomes (treatment discontinuations, toxicities and HRQoL). 
 

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2. 
Objectives 
 
Primary Objectives 
 
Prospectively validate a prior germline predictor of paclitaxel-induced 
peripheral neuropathy (TIPN) using the CTCAE. Specifically, this 
study will demonstrate that patients with a high-risk TIPN genotype 
have significantly more Grade 2-4 TIPN than patients with a low risk 
genotype. 
 
Secondary Objectives 
 
Validate a prior germline predictor of TIPN using the FACT/GOG-NTX 
neurotoxicity subscale in Arm A. 
 
Compare grade 2-4 TIPN based on CTCAE between weekly 
paclitaxel (Arm A) vs. every three-week docetaxel (Arm B). 
 
Prospectively confirm dose reductions due to TIPN are lower for every 
three-week docetaxel compared with weekly paclitaxel in a 
prospective cohort of patients of African ancestry. 
 
Prospectively confirm dose reductions due to any cause are lower for 
every three-week docetaxel compared with weekly paclitaxel in a 
prospective cohort of patients of African ancestry. 
 
Assess the ability of the high-risk genotype to predict TIPN risk for 
docetaxel. 
 
Correlative Study Objectives 
 
Identify novel markers of TIPN and elucidate the mechanism. 
 
Whole genome sequencing of germline blood to evaluate for 
additional predictors of TIPN. 
 
Create iPSC derived neurons from patient samples. 
2.3.3.1 
Evaluate whether clinical findings can be mimicked in vitro. 
2.3.3.2 
Evaluate gene expression (RNA seq) and the epigenome 
at baseline versus after exposure in those prone to TIPN 
versus those not. 
 
Create a biorepository of patient derived samples for future 
translational research. 
 
Patient Reported Outcome Objectives 
 
Compare Grade 2-4 TIPN (moderate to life threatening) based on 
PRO-CTCAE items between weekly paclitaxel (Arm A) vs. every 
three-week docetaxel (Arm B). 
 
Prospectively compare FACT/GOG-NTX HRQOL scores (from the 
FACT-G portion and PROMIS Physical Function v.2 SF 10a, scores 
between every three-week docetaxel and weekly paclitaxel and 
between high risk and low risk genotypes (Arm A) in a cohort of 
African ancestry. 

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Compare CIPN-20 sensory neuropathy score between weekly 
paclitaxel (Arm A) vs. every three-week docetaxel (Arm B). 
 
Compare the impact on financial toxicity (COST-FACIT scores) for 
every three-week docetaxel compared with weekly paclitaxel. 
 
Examine associations between social determinants of health (zip 
code, marital status, education, income & insurance status) and dose 
reductions and treatment discontinuation. 
 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
 
Eligibility Criteria 
 
Patients must be women with a known stage I-III invasive breast 
cancer diagnosis. 
 
Patients must be age ≥ 18 years. 
 
Patients must be capable and willing to provide informed consent. 
 
Patients must have plans to receive either neoadjuvant or adjuvant: 
3.1.4.1 
Every 3-week docetaxel x 4-6 cycles 
OR 
3.1.4.2 
Weekly paclitaxel x 4 cycles 
NOTE: Recommended therapies for various therapy regimens are 
outlined in Section 5.1 based on ER/PR/HER2 and nodal 
status. Where there are options, the treating physician will 
choose a regimen best fitted for that patient. If the physician 
does not feel any of the regimens are the best fit for the 
patient, the patient should not be enrolled. Physicians will 
also document why a regimen was felt to be inappropriate 
when an option. Patients who have already started the 
anthracycline portion of their therapy are eligible assuming 

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they have not yet begun the taxane portion and assuming 
they will be receiving one of the regimens deemed 
appropriate for her disease setting as outlined in Section 5.1. 
 
Patients must self-identify their race as black, African American, or of 
African descent. Patients may be of any ethnicity. 
 
Patients must not have received prior taxane or prior/concurrent 
platinum therapy. 
 
Patients must not have received neoadjuvant anti-HER2 therapy. 
 
Patients with a history of other cancers are eligible if they have not 
received prior taxane or platinum or vinca alkaloid therapy. 
 
Patients must not have pre-existing peripheral neuropathy. 
 
Patient must have an ECOG Performance status 0-1. 
 
Patients must not have a total bilirubin > ULN or AST and/or ALT 
above 1.5 times the ULN concomitant with alkaline phosphatase 
above 2.5 times the ULN. These labs must be obtained within 3 
weeks prior to registration. 
Total bilirubin:__________          ULN:____________ 
AST:__________ALT:________ ULN:____________ 
Alkaline phsosphatase:________ULN:_________ 
 
Patients must not be pregnant or lactating. 
All patients of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. 
A patient of childbearing potential is anyone, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has achieved menarche at some point, 2) has 
not undergone a hysterectomy or bilateral oophorectomy, or 3) has 
not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive 
months). 
Patient of child-bearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
 
Patients of childbearing potential must be strongly advised to use an 
accepted and effective method of contraception or to abstain from 
sexual intercourse for the duration of their participation in the study.  
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 

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4. 
Registration Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE or acting as a primary site 
contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment must be rostered at the enrolling site with a participating organization (i.e., 

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Alliance). Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. 
For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov  
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 

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participate, the institution and its associated investigators and staff must be associated 
with the LPO or a PO on the protocol. 
• 
Log on to the CTSU members’ website https://www.ctsu.org using your CTEP-IAM 
username and password 
• 
Click on the Protocols in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EAZ171 
• 
Click on Documents, select the Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CSTU website. 
To access the Regulatory Submission Portal log on to the CSTU members’ website → 
Regulatory → Regulatory Submission 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 

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• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory at the top of the screen; 
• 
Click on the Site Registration;  
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not have started taxane (paclitaxel or docetaxel) treatment prior to 
registration. 
Treatment should start within fifteen working days after registration. This 
requirement can be fulfilled by starting the anthracycline portion of therapy when 
appropriate. 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 

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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
Registration Information 
 
Protocol Number  
 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
 
Classification Factors 
Treatment arm per discretion of the treating investigator: 
• 
Arm A: Paclitaxel 80 mg/m2 every 7 days for 4 cycles 
• 
Arm B: Docetaxel 75 mg/m2 every 3 weeks for 4-6 cycles 
 
Additional Requirements 
 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
 
Peripheral blood specimens must be submitted for defined laboratory 
research studies as outlined in Section 10. 
 
Plasma specimens are to be submitted for future undefined laboratory 
research studies per patient consent as outlined in Section 10. 

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4.4.4 
Medidata Rave is a clinical data management system being used for 
data collection for this trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments. To 
access Rave via iMedidata: 
• 
Site staff will need to be registered with CTEP and have a valid 
and active CTEP-IAM account; and  
• 
Assigned one of the following Rave roles on the relevant Lead 
Protocol Organization (LPO) or Participating Organization roster at 
the enrolling site: Rave CRA, Rave Read Only, Rave CRA 
(LabAdmin), Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
• 
To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must 
hold a minimum of an AP registration type; 
• 
To hold Rave Investigator role, the individual must be registered 
as an NPIVR or IVR; and 
• 
To hold Rave Read Only role, site staff must hold an Associates 
(A) registration type. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study name in 
iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study 
in Rave will be granted, and a Rave EDC link will display under the 
study name. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
 
The Data Quality Portal (DQP) provides a central location for site staff 
to manage unanswered queries and form delinquencies, monitor data 
quality and timeliness, generate reports, and review metrics. 

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The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, 
delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and 
have access to the CTSU website. Staff that have Rave study access 
can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon 
displayed on the Rave Home, DQP Queries, and DQP Delinquent 
Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form details 
or reports specified on the DQP. A protocol must have the 
Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details 
and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the EAZ171 Forms Completion Guidelines. 
PRO completion and specimen submissions are not required. 

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5. 
Treatment Plan 
 
Administration Schedule 
NOTE: 
Recommended therapies for various therapy regimens are outlined 
below based on ER/PR/HER2 and nodal status. Where there are 
options, the treating physician will choose a regimen best fitted for 
that patient. If the physician does not feel any of the regimens are the 
best fit for the patient, the patient should not be enrolled. Physicians 
will also document why a regimen was felt to be inappropriate when 
an option. 
 
Treatment Arm A 
Paclitaxel 80 mg/m2 every 7 days (weekly) for 4 cycles (1 cycle = 21 
days).  
• 
ER+/HER2-/ LN+ (anthracycline appropriate) = AC→weekly 
paclitaxel x 4 cycles (or refer to Section 5.1.2 for docetaxel 
treatment regimen options) 
• 
TNBC regardless of LN status (anthracycline appropriate) = 
AC→weekly paclitaxel x 4 cycles (or refer to Section 5.1.2 for 
docetaxel treatment regimen options) 
• 
HER2+, <3cm, LN- =weekly paclitaxel x 4 cycles + trastuzumab 
• 
HER2+ (anthracycline preferred) = AC→weekly paclitaxel x 4 
cycles + trastuzumab +/- pertuzumab (or refer to Section 5.1.2 for 
docetaxel treatment regimen option) 
*anthracycline inappropriate: to be determined by treating physician 
based on: 1. risk of tumor recurrence, 2. co-morbidities or medical 
factors, 3. both, or, 4. other. The decision to use or not use an 
anthracycline will be in accordance with that physician’s standard 
practice and with proper discussion with the patient. Physicians will 
document the reason why the individual patient is anthracycline 
inappropriate. If response 4 (i.e. other) is chosen, the specific reason 
needs to be stated. 
NOTE: 
Trastuzumab and pertuzumab are to be administered in 
the adjuvant setting per institution routine care per the 
treating physician’s discretion. 
 
Treatment Arm B 
Docetaxel 75 mg/m2 every 3 weeks (1 cycle = 21 days). 
• 
ER+/HER2-/ LN- = docetaxel/cyclophosphamide x 4-6 cycles 
• 
ER+/HER2-/ LN+ (anthracycline inappropriate*) = 
docetaxel/cyclophosphamide x 4-6 cycles 
• 
ER+/HER2-/ LN+ (anthracycline appropriate) = AC→every 3 
week docetaxel x 4 cycles -OR- 
docetaxel/doxorubicin/cyclophosphamide (TAC) every 3 weeks x 
6 cycles (or refer to Section 5.1.1 for paclitaxel treatment regimen 
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Rev Add1 
• 
TNBC regardless of LN status (anthracycline appropriate) = 
AC→every 3 week docetaxel x 4 cycles -OR- 
docetaxel/doxorubicin/cyclophosphamide (TAC) every 3 weeks x 
6 cycles (or refer to Section 5.1.1 for paclitaxel treatment regimen 
option) 
• 
TNBC regardless of LN status (anthracycline inappropriate*) 
= docetaxel/cyclophosphamide x 4-6 cycles 
• 
HER2+ (anthracycline preferred) = AC→every 3 week docetaxel 
x 4 cycles + trastuzumab +/- pertuzumab (or refer to Section 5.1.1 
for paclitaxel treatment regimen option) 
*anthracycline inappropriate: to be determined by treating physician 
based on: 1. risk of tumor recurrence, 2. co-morbidities or medical 
factors, 3. both, or, 4. other. The decision to use or not use an 
anthracycline will be in accordance with that physician’s standard 
practice and with proper discussion with the patient. Physicians will 
document the reason why the individual patient is anthracycline 
inappropriate. If response 4 (i.e. other) is chosen, the specific reason 
needs to be stated. 
NOTE: 
Cyclophosphamide is to be administered per institution 
routine care per the treating physician’s discretion. 
NOTE: 
Trastuzumab and pertuzumab are to be administered in 
the adjuvant setting per institution routine care per the 
treating physician’s discretion. 
 
Adverse Event Reporting Requirements 
All toxicity grades described in this protocol and all reportable adverse 
events on this protocol will be graded using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. Adverse events will only 
be reported during the taxane portion of therapy. Since the anthracyclines 
portion of therapy will be used in the context of standard of care and are 
not the interest of this study, events will not be collected unless the taxane 
is being used concurrently with the anthracycline. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
Clinician graded CTCAE is the AE (adverse event) safety standard. PRO-CTCAE 
items are to complement CTCAE reporting. Patients will respond to PRO-CTCAE 
items but no protocol directed action will be taken. PRO-CTCAE is not intended 
for expedited reporting, real time review or safety reporting. 
 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents.  

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Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited 
reporting purposes, when either the type of event or the severity of 
the event is NOT listed in the protocol or drug package insert. 
• 
Hospitalization (or prolongation of hospitalization): For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event: Any AE that places the subject 
at immediate risk of death from the AE as it occurred.   
 
Mechanism for Adverse Event Reporting 
Routine reporting: Adverse events are reported in a routine manner 
at scheduled times during a trial using the Medidata Rave clinical data 
management system. Please refer to Section 4 of the protocol for 
more information on how to access the Medidata Rave system and 
the EAZ171 forms packet for instructions on where and when adverse 
events are to be reported routinely. 
Symptomatic Adverse Events reported by patients through PRO-
CTCAE are not safety reporting and may be presented with other 
routine AE data. 
Expedited reporting: In addition to routine reporting, certain adverse 
events must be reported in an expedited manner for timelier 
monitoring of patient safety and care. The remainder of this section 
provides information and instructions regarding expedited adverse 
event reporting. 

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Expedited Adverse Event Reporting Procedure 
Adverse events requiring expedited reporting will use CTEP’s Adverse 
Event Reporting System (CTEP-AERS). CTEP’s guidelines for CTEP-
AERS can be found at http://ctep.cancer.gov.   
For this study, a CTEP-AERS report must be submitted electronically 
via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov, so that ECOG-ACRIN and all appropriate 
regulatory agencies will be notified of the event in an expeditious 
manner. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2900) 
• 
the FDA (1-800-FDA-1088)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of certain agent vs. ≥ 30 days after the last 
administration of certain agent)  
• 
the relationship to the study treatment (attribution) 
• 
the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EAZ171 and outline the 

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specific expedited adverse event reporting requirements for study 
EAZ171. 
 
Steps to determine if an event is to be reported in an expedited 
manner  
 
Expedited Reporting Requirements for protocol EAZ171 
Commercial Agents: Paclitaxel and Docetaxel 
Identify the type and grade of the event 
using the CTCAE 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.2.7 to determine if event is 
reportable via CTEP-AERS. 
Refer to footnote b in 
Section 5.2.7 to 
determine if the event 
meets the protocol 
specific reporting 
requirements for this 
study. If so, report the 
event via CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.2.7 to determine if the event meets 
the criteria as an exception to reporting on this protocol. 
If it does not, report the event via CTEP-AERS.
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 

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Expedited reporting requirements for adverse events experienced by patients on arm(s) with 
commercial agents only 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN 
and Protocol-
Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of 
learning of the event. 
a A death occurring while on study or within 30 days of the last dose of treatment requires both routine 
and expedited reporting, regardless of causality. Attribution to treatment or other cause must be 
provided. 
NOTE: A death due to progressive disease should be reported as a Grade 5 “Disease 
progression” under the System Organ Class (SOC) “General disorder and 
administration site conditions”. Evidence that the death was a manifestation of 
underlying disease (e.g. radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted. 
NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed 
possibly, probably, or definitely to the treatment must be reported within 7 calendar 
days of learning of the event.   
b Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via 
CTEP-AERS within 7 calendar days of learning of the event. For instructions on 
how to specifically report these events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will need to be discussed 
on a case-by-case basis. 
 
Other recipients of adverse event reports and supplemental data 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 

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1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis on the Adverse Event Form or Late 
Adverse Event Form in the appropriate Treatment Cycle or 
Post Registration folder in Medidata Rave 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
NOTE: 
When reporting attribution on the AE Form, 
assess the relationship between the secondary 
malignancy and the current protocol treatment 
ONLY (and NOT relationship to any anti-cancer 
treatment received either before or after 
protocol treatment). 
3. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
4. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
5. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 

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be submitted via CTEP-AERS or by the ECOG-ACRIN 
Second Primary Form. 

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Dose Modifications 
PRO-CTCAE data should not be used for determining dose delays, dose 
modifications, or any other protocol directed action. 
 
Paclitaxel Dose Modifications:  AC dose modification or delay will not 
impact paclitaxel therapy.  
NOTE: 
Day 1 of paclitaxel may be delayed. However, held doses 
on Day 8 (week 2) and Day 15 (week 3) are considered 
missed doses and will not be made up.  
NOTE: 
If paclitaxel is not administered for > 3 weeks due to 
toxicity, stop paclitaxel.  
Event 
Paclitaxel Dose Modification 
Neutrophil Count Decrease/Neutropenia 
Grade 0-2 
≥ 1000/mm3 
No change 
≥ Grade 3 
< 1000/mm3 
Hold until ANC >1000, resume based on timing of recovery: 
≤ 1 week – no change 
>1 but ≤ 3 weeks - reduce dose 20% for subsequent cycles 
> 3 weeks – stop paclitaxel. 
Febrile Neutropenia 
≥ Grade 3 
ANC < 1000/mm3 
with a single temperature of  
> 38.3o C  
or 
a sustained temperature of 
≥38o C for more than one 
hour 
Interrupt until resolved (ANC >1000/mm3, fever < 38.3o C), 
resume according to number of episodes: 
1st = no change 
2nd = 20% dose reduction 
3rd = stop paclitaxel. 

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Event 
Paclitaxel Dose Modification 
Platelet Count Decrease/Thrombocytopenia 
≥ 100,000/mm3 
No change 
Grade 1 
< LLN - 75,000/mm3 
Hold until ≥ 100,000, resume based on timing of recovery: 
If ≤ 1 week – no change. 
If >1 but ≤ 3 weeks - reduce dose 20% for subsequent cycles. 
If > 3 weeks delay is required, stop paclitaxel. 
Grade 2 
< 75,000 
Hold until ≥ 100,000, Resume with 20% dose reduction for 
subsequent cycles.  
If > 3 weeks delay is required, stop paclitaxel. 
Anemia 
All grades 
No change. 
Hepatobiliary Disorders 
Grade 0 or 1 
No change 
≥ Grade 2 
Interrupt until ≤ Grade 1, then resume previous dose.  
If > 3 weeks delay is required, stop paclitaxel. 
Nausea or Vomiting 
Grade 0 – 2 
No change 
≥ Grade 3 
Hold until resolved to ≤ Grade 1, reduce dose 20% in subsequent 
cycles. 
Mucositis (any) 
Grade 0 – 2  
No change  
≥ Grade 3  
Hold until resolved to ≤ Grade 1, reduce dose 20% in subsequent 
cycles.  
Nervous system-Neurotoxicity  
Grade 0 - 1  
No change  
Grade 2  
If Grade 2 toxicity has resolved to ≤ Grade 1 on the day of treatment, 
proceed with treatment at the previous dose.  
If Grade 2 toxicity is present on the day of treatment, reduce dose 
20% for all subsequent cycles. 
Grade 3  
Hold until resolved to ≤ Grade 1, reduce dose 20% in all subsequent 
cycles.  
If > 3 weeks delay is required, stop paclitaxel. 
Grade 4  
Discontinue paclitaxel.  

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Event 
Paclitaxel Dose Modification 
Hypersensitivity or Anaphylaxis 
Mild Symptoms: mild flushing, rash, pruritis 
No treatment needed. Supervise at bedside and 
complete paclitaxel infusion.  
Moderate Symptoms: moderate flushing, 
rash, mild dyspnea, chest discomfort 
Stop paclitaxel.  
Administer diphenhydramine 25 mg and 
dexamethasone 10 mg IV.  
After recovery, resume infusion at half the previous rate 
for 15 minutes. If no further symptoms occur, complete 
the infusion at the full dose rate.  
If symptoms recur, stop paclitaxel.  
Severe Symptoms: hypotension requiring 
pressors, angioedema, respiratory distress 
requiring bronchodilators 
Stop paclitaxel.  
Administer diphenhydramine 25 mg and 
dexamethasone 10 mg IV.  
Add epinephrine or bronchodilators as needed.  
Do not restart paclitaxel.  
Life threatening symptoms: Anaphylaxis, 
urgent intervention indicated  
Stop Paclitaxel. 
Do not restart. NO FURTHER STUDY THERAPY 
Other clinically significant toxicity excluding fatigue, alopecia and white blood cell 
decrease/leukopenia 
Grade 0 or 1  
No change  
Grade 2  
Hold until resolved to ≤ Grade 1, resume at previous 
dose.  
Increase supportive care measures if possible.  
≥ Grade 3  
Hold until resolved to ≤ Grade 1, resume with 20% dose 
reduction for subsequent cycles.  
If Grade 3 or greater toxicity recurs, stop paclitaxel. 
 

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Docetaxel Dose Modifications: No more than two dose 
modifications should be allowed for any patient. If a patient requires a 
third reduction of docetaxel, they will be followed every 12 weeks and 
treated at their physician’s discretion.  
NOTE: 
Dose adjustments are to be made according to the system 
showing the greatest degree of toxicity.  
NOTE: 
Dose adjustments for toxicity should be made according to 
the guidelines that follow. If a dose is reduced due to 
toxicity the dose will not be re-escalated back to starting 
level. Treatment may be delayed no more than three 
weeks to allow recovery from toxicity. 
Dose Level 
Docetaxel (mg/m2) 
Level 0 
75 mg/m2 
Level 1 
65 mg/m2 
Level 2 
55 mg/m2 
 

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Event 
Docetaxel Dose Modification 
Platelet Count Decrease/Thrombocytopenia 
≥ 100,000/mm3 
No change 
Grade 1 
< LLN - 75,000/mm3 
Hold until ≥ 100,000, resume based on timing of recovery: 
If ≤ 1 week – no change. 
If >1 but ≤ 3 weeks - reduce dose by one dose level for subsequent 
cycles. 
If > 3 weeks delay is required, stop docetaxel. 
≥ Grade 2 
< 75,000/mm3 
Hold until ≥ 100,000, Resume with one dose level reduction for 
subsequent cycles.  
If > 3 weeks delay is required, stop docetaxel. 
White Blood Cell Decrease/Leukopenia 
Grade 0 or 1  
No change  
Grade 2  
Hold until resolved to ≤ Grade 1, resume at previous dose. Increase 
supportive care measures if possible.  
≥ Grade 3  
Hold until resolved to ≤ Grade 1, resume dose by one dose level 
reduction for subsequent cycles.  
If Grade 3 or greater toxicity recurs, stop docetaxel. 
Febrile Neutropenia 
≥ Grade 3 
ANC < 1000/mm3 
with a single temperature of 
>38.3o C  
or  
a sustained temperature of 
≥38o C for more than one 
hour 
Interrupt until resolved (ANC >1000mm3, fever < 38.3o C), resume 
according to number of episodes: 
1st = no change 
2nd = dose reduction by one dose level 
3rd = stop docetaxel. 
Hepatic Dysfunction (Blood Bilirubin or Alanine aminotransferase increase) 
Grade 0 or 1 
Treat without delay but reduce docetaxel dose by one dose level.  
If Grade 1 bilirubin, docetaxel should be held until resolved to Grade 0. 
≥ Grade 2 
Interrupt until ≤ Grade 1, then resume reduced docetaxel dose by one 
dose level.  
If > 3 weeks delay is required, stop docetaxel. 
Diarrhea* 
Grade 0 or 1 
No change 
≥ Grade 2 
Treat prophylactically in subsequent cycles with loperamide or 
diphenoxylate. 
If patient experiences > grade 2 despite prophylaxis, docetaxel should be 
dose reduced by one dose level. 
If diarrhea continues despite prophylaxis AND dose reduction, stop 
docetaxel. 
*If patients experience > grade 2 diarrhea and concurrent grade 3 or 4 neutropenia, hold Docetaxel until 
ANC ≥ 1000/mm3 and diarrhea ≤ grade 2. 

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Event 
Docetaxel Dose Modification 
Peripheral (Motor or Sensory) Neuropathy 
Grade 0-1 
No change 
≥ Grade 2 
Hold until resolved to ≤ Grade 1, reduce dose by one dose level in 
subsequent cycles. 
If > 3 weeks delay is required, stop docetaxel. 
Mucositis (any) 
Grade 0 - 2  
No change  
≥ Grade 3  
Hold until resolved to ≤ Grade 1, reduce dose by one dose level in 
subsequent cycles.  
Hypersensitivity or Anaphylaxis 
Mild symptoms: mild 
flushing, rash, pruritis  
• 
Consider decreasing the rate of infusion until recovery from 
symptoms, stay at bedside or monitor patient 
• 
Then, complete docetaxel infusion at initial planned rate.  
Moderate symptoms: 
moderate flushing, rash, mild 
dyspnea, chest discomfort 
• 
Stop docetaxel.  
• 
Administer diphenhydramine 50 mg and dexamethasone 10 mg IV.  
• 
After recovery, resume infusion at half the previous rate for 15 
minutes. If no further symptoms occur, complete the infusion at the 
full dose rate.  
• 
Depending on the intensity of the reaction observed, additional oral or 
IV premedication with an antihistamine should be given for the next 
cycle of treatment, and the rate of infusion should be decreased 
initially ante increased back to initial planned rate. 
Severe symptoms: 
hypotension requiring 
pressors, angioedema, 
respiratory distress requiring 
bronchodilators 
• 
Stop docetaxel.  
• 
Administer diphenhydramine 50 mg and dexamethasone 10 mg IV. 
Add epinephrine or bronchodilators as needed.  
• 
Do not restart.  
Life threatening symptoms: 
Anaphylaxis, urgent 
intervention indicated 
Stop Docetaxel. 
Do not restart. NO FURTHER STUDY THERAPY 

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Rev Add1 
Rev Add1 
Rev Add2 
Rev Add2 
 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. Hematologic growth factors are not required but may be 
used in accordance with the ASCO guidelines. 
 
Patient-Reported Outcomes (PRO) Administration 
A detailed description of the PRO measures to be administered has been 
included in Section 6. 
 
PRO Instruments to be administered 
1. Functional Assessment of Cancer Therapy Gynecological 
Oncology Group Neurotoxicity (FACT/GOG-NTX) 
2. PROMIS Physical Function v2.0 Short Form 10a 
3. EORTC QLQ-CIPN 20 Sensory Neuropathy subscale 
4. Comprehensive Score for Financial Toxicity – Functional 
Assessment of Chronic Illness Therapy (COST-FACIT) 
5. Five social determinants of health items from the Alliance Patient 
Questionnaire for Clinical Trials In Oncology 
6. PRO-CTCAE items to be administered: # 39 & 48 - Numbness 
and Tingling a-b and General Pain a-c. 
 
PRO Assessment Schedule 
The FACT-G portion (HRQoL) portion of the FACT/GOG-NTX and the PROMIS 
Physical Function Short Form 10a will be used to assess patient-reported 
HRQoL and physical function using the following schedule: 
1. Baseline (Prior to first taxane treatment: must be within 14 days prior to or on 
the day of taxane therapy but prior to delivery of treatment) 
2. Day 1 Cycle 3. 
3. At end of protocol treatment, including treatment discontinuation for any 
reason (i.e. toxicity, progression, completion of protocol therapy) 
4. Follow-up at 6 months, 1, 2 and 3 years after initiation of taxane treatment 
The FACT/GOG-NTX 11-item neurotoxicity scale, CIPN-20 9-item sensory 
neuropathy subscale and PRO-CTCAE items assessing neuropathy (#39a-b) 
and general pain (#48a-c) will be administered using the following schedule to be 
consistent with the Symptom/Toxicity Assessments: 
1. Baseline (Prior to first taxane treatment: must be within 14 days prior to or on 
the day of taxane therapy but prior to delivery of treatment) 
2. Day one of every cycle except cycle 1 (baseline evaluation will take the place 
of cycle 1), following the same schedule as trial symptom/toxicity 
assessments 
3. At end of protocol treatment, including treatment discontinuation for any 
reason (i.e. toxicity, progression, completion of protocol therapy) 
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NOTE: 
The PRO-CTCAE items should be completed each time a 
Symptom/Toxicity Assessments is completed. 
The COST-FACIT to assess financial toxicity will be administered using the 
following schedule:  
1. Baseline (Prior to first taxane treatment: must be within 14 days prior to or on 
the day of taxane therapy but prior to delivery of treatment) 
2. At end of protocol treatment, including treatment discontinuation for any 
reason (i.e. toxicity, progression, completion of protocol therapy) 
3. At 6 months after initiation of taxane treatment  
The Alliance Patient Questionnaire for Clinical Trials In Oncology (items 
from education, marital status, health insurance status income) and current zip 
code to capture important social determinants of health. These variables will be 
assessed at the following time points: 
1. Baseline (Prior to first taxane treatment: must be within 14 days prior to or on 
the day of taxane therapy but prior to delivery of treatment) 
2. At end of protocol treatment, including treatment discontinuation for any 
reason (i.e. toxicity, progression, completion of protocol therapy) 
The total length of PRO assessment is dependent on the assessment time point. 
One of the lengthiest assessments will occur at Baseline (PRO-CTCAE items, 
FACT/GOG-NTX, PROMIS Physical Function Short Form 10a, CIPN-20 sensory 
neuropathy items, COST-FACIT, & social determinants of health items) is 78 
multiple-choice items. The anticipated time to complete all items is approximately 
16 minutes (roughly, an average of five items completed per minute). We have 
scheduled PRO assessments with standard clinic office visits to minimize 
participant and site burden, thus minimizing the risk of missing PRO data. 
PRO assessments at treatment discontinuation and follow-up time points post-
treatment discontinuation for all participants, regardless of the reason for 
treatment discontinuation (toxicity, progression), will provide valuable information 
on HRQoL and symptom burden. Patient HRQoL can appear to improve overall 
as the trial progresses due to participant selection bias.44 Participants with poorer 
performance status, more aggressive disease, and greater treatment toxicities 
come off treatment earlier. To obtain more unbiased assessment of HRQoL and 
treatment toxicities, PRO assessments at the end of treatment and follow-up for 
all participants is needed. Otherwise, PRO assessments only capture data on 
participants who remain on treatment and are likely to be healthier, therefore, 
presenting a biased source of data that will likely indicate that HRQoL improves 
over time. 
 
PRO Instructions 
All PRO questionnaires will be administered as a paper survey at the time points 
listed above. Ideally, participants will complete questionnaires at the time of 
scheduled study visits. If the PRO assessments are not administered in clinic, the 
study questionnaires will be mailed to participants who will be asked to complete 
questionnaires and return by mail to clinic. After 7 days, clinic or research staff 
may contact participants by telephone and ask participants to complete the 
questionnaire on paper and then read their answers over the telephone to the 
staff person. This procedure will minimize mode effect, whereby participants 
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written surveys. This approach will approximate the completion of PROs in clinic 
as closely as possible. This will also compensate for potential responder bias, 
wherein healthier patients are more likely to return to clinic and thus, to complete 
the post-treatment surveys. 
The patient should be instructed to respond to the questionnaires in terms of her 
experience during the timeframe specified on each questionnaire. The patient 
should be asked to read the instructions at the beginning of each questionnaire 
and complete all the items. It is permissible to assist the patient with the 
completion of the questionnaires as long as the staff person does not influence 
the patient’s responses. 
PRO-CTCAE items assessing numbness/tingling (#39a-b) and general pain 
(#48a-c) will be administered on paper along with other study PRO measures 
following procedures for PRO administration as described above. PRO-CTCAE 
items will be administered prior to clinic visits, or prior to participant’s discussion 
of disease status and treatment side effects with health-care professionals. This 
is modeled after NCI PRO-CTCAE study procedures employed in other clinical 
trial validation studies. Clinicians will be instructed to complete clinician-rated 
treatment toxicities (CTCAE) prior to reviewing PRO-CTCAE ratings. This will 
minimize the extent to which PRO-CTCAE responses introduce a bias to clinician 
CTCAE ratings. PRO-CTCAE are currently undergoing validation and exploratory 
in nature. Therefore, at this point, PRO-CTCAE item responses should not be 
used to inform clinician CTCAE ratings. Clinicians will be instructed to review 
PRO-CTCAE items after clinician toxicity ratings have been completed in order to 
identify any patient-reported symptoms and toxicities that warrant clinical 
attention. 
The questionnaires should be reviewed by the protocol nurse or research 
coordinator as soon as the patient completes them to ensure all items were 
marked appropriately. If more than one answer was marked, the patient should 
be asked to choose the answer which best reflects how she is feeling. If a 
question was not answered, the patient should be asked if she would like to 
answer it. The patient should always have the option to refuse. If the patient 
refuses, it should be indicated on the questionnaire that she declined to answer 
the item. If the patient cannot complete a questionnaire, or if the patient refuses 
to complete the questionnaire, the reason should be noted according to the 
instructions in the EAZ171 Forms Completion Guidelines. 
Given the geographic locations of recruitment sites concurrent with a sample of 
Black / African-American women, we do not anticipate a significant number of 
Spanish-speaking participants. However, we are committed to making study 
recruitment as inclusive as possible. Therefore, in accordance with the NCORP 
Part 3 Guidelines, we will make all PRO measures with validated Spanish-
language versions available to any eligible Spanish-language patients interested 
in participating. 
 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Completion of protocol therapy 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
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discontinued. In this event, submit forms according to the instructions in the 
EAZ171 Forms Packet. 
• 
Patient has relapse of disease. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for recurrence and second primary cancer, even if non-
protocol anti-cancer therapy is initiated, and for survival for 5 years from the date 
of registration. All patients must also be followed through completion of all 
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6. 
Measurement of Effect 
NOTE: 
The primary endpoint of the trial is grade 2-4 TIPN based on CTCAE, and a 
secondary phenotype of neurotoxicity will be assessed using patient reported 
outcome via FACT/GOG-NTX questionnaire. This study also will evaluate 
several other PRO endpoints. Although there is no efficacy endpoint in the 
study, it is standard for ECOG-ACRIN to collect disease recurrence and 
survival information on treatment and long-term follow-up forms. 
 
Grade 2-4 neuropathy 
Grade 2-4 TIPN is the primary endpoint of the study, and will be assessed by 
treating physician using the CTCAE. While on taxane treatment, AE assessment 
will be administered on the first day of each cycle (1 cycle=21 days on both arms) 
and at the end of treatment to collect any occurrence of neuropathy during 
treatment. After treatment completion, AE assessment will be administered at 6 
months, 1, 2, and 3 years after initiation of taxane treatment to collect any long-
term TIPN. For the primary endpoint, the observation period will be from initiation 
of taxane treatment until 1 year after that (i.e. total period of 1 year including 
taxane treatment time). Patients will be coded as having the event as long as 
grade 2-4 neuropathy based on the CTCAE occurred at any time during the 
observation period. Patients without neuropathy or with maximum of grade 1 
neuropathy during the whole observation period (including patients without grade 
2-4 TIPN during the whole year and patients without grade 2-4 TIPN before loss 
to follow up within 1 year) will be coded as having no event. Of note, only 
neuropathy with a treatment relationship code of 3-5 (possibly, probably, 
definitely) will be considered as taxane-induced neuropathy, and neuropathy with 
a treatment relationship code of 1-2 (unrelated or unlikely) will not be considered 
in the study design. 
 
PRO-based neuropathy 
The PRO-based neurotoxicity will be assessed using the 11-item neurotoxicity 
subscale of the FACT/GOG-NTX. Each item is scored from 0–4, and the 
neurotoxicity total score is the sum of the scores for the 11 items, and ranges 
from 0 to 4426,36,38. Lower values of the FACT/GOG-NTX neurotoxicity total score 
indicate higher neurotoxicity.  
To harmonize with the SWOG1714 trial, we will also be assessing patient-
reported neuropathy with the CIPN20 9-item sensory neuropathy subscale. Each 
item is measured on a 1-4 scale (1, not at all; 4, very much). The sensory 
subscale raw scores range from 1 to 36. CIPN-20 subscale raw scores are 
linearly converted to a 0-100 scale such that a high score corresponds to a worse 
condition or more symptoms. 
Assessment of PRO-based neurotoxicity will take place at the same schedule as 
CTCAE (i.e., baseline or day 1 of cycle 1, at first day of each following cycle, at 
treatment completion, and at 6 months, 1, 2, and 3 years post initiation of taxane 
treatment). The FACT/GOG-NTX neurotoxicity total score and CIPN-20 sensory 
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PROMIS Physical Function v2 Short Form 10 
The PROMIS Physical Function v2 Short Form 10a measures self-reported 
capability rather than actual performance of physical activities. This includes the 
functioning of one’s upper and lower extremities (dexterity), lower extremities 
(walking or mobility), and central regions (neck, back), as well as instrumental 
activities of daily living. Starting with the PROMIS pool of universal physical 
function items, members of the PROMIS-Cancer team and multidisciplinary 
panels of clinical experts working in oncology selected the items for this short 
form based on information from cancer-specific focus groups, expert reviewers 
and large-scale field-testing. Item selection emphasized, clinical relevance, 
content coverage and ability to identify cases in need of intervention64. As for all 
PROMIS measures, summary scores are calculated as a T-score (with 50 = 
mean & 10 = SD of the reference population) and higher scores reflecting more 
of the concept being measured (physical function). There are multiple options for 
calculating PROMIS T-scores. If an electronic data collection platform cannot be 
used, as in this study, the free web-based HealthMeasures Scoring Service is 
preferred because it provides accuracy.66 Users download an Excel template 
from the site, add the raw responses from a PROMIS measure, and then upload 
the file and receive by email a spreadsheet with calculated T-scores and 
standard errors. The HealthMeasures Scoring Service can handle missing data 
and multiple timepoints. No participant protected health information is requested 
or used by the service. If it is not possible to utilize response pattern scoring, 
PROMIS Scoring Manuals include tables for transforming the sum of all raw 
responses to a T-score. We will compare PROMIS Physical Function v.2 SF 10a 
scores for the two treatment arms (A&B) and for the high risk vs. low risk 
genotypes (in arm A). 
 
Health-related quality of life 
The FACT/GOG-NTX questionnaire referenced above also contains 27 core 
items (the FACT-G) that cover four areas of HRQoL: physical, social, emotional, 
and functional well-being. HRQoL will be measured by the summed total score of 
the 27 core items, which will range from 0 to 108. The FACT-G total score will be 
analyzed as a continuous variable. The primary comparison will be change in 
HRQoL total score between registration and treatment completion between two 
groups. 
 
Comprehensive Score for Financial Toxicity – Functional Assessment of Chronic 
Illness Therapy (COST-FACIT) 
The Comprehensive Score for Financial Toxicity (COST-FACIT) is an 11-item 
patient-reported measure of financial toxicity that uses a 7-day time window and 
a 5-point Likert response scale ranging from 0 (“not at all”) to 5 (“a lot”). Higher 
COST-FACIT scores (range: 0-44) represent better financial well-being.67 We will 
compare the total COST-FACIT scores for the two treatment arms (A and B). 
 
Alliance Patient Questionnaire Items on Social Determinants of Health 
To further examine social determinants of health that may be related to 
participants’ treatment and HRQoL, we will ask participants to complete items 
from the Alliance Patient Questionnaire for Clinical Trials In Oncology (education, 
marital status, health insurance status income) and current zip code to capture 
important social determinants of health. We will examine associations between 

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those social determinants of health and participant’s dose reductions or 
treatment discontinuation, reported toxicities and HRQoL. 
 
PRO-CTCAE 
We will compare scores on the two patient-reported neuropathic-related adverse 
events, as assessed by the two PRO-CTCAE items between the two taxane 
regimens (arm A vs. arm B). PRO-CTCAE responses are scored from 0 to 4, and 
there are as yet no standardized scoring rules for how to combine attributes into 
a single score or how best to analyze PRO-CTCAE data longitudinally. PRO-
CTCAE scores for each attribute (frequency, severity and/or interference) should 
be presented descriptively. PRO-CTCAE scores should be presented in 
conjunction with CTCAE grades for the corresponding time periods. The items 
we have selected (#39a-b – numbness & tingling and #48a-c – general pain) 
include ratings of severity and interference with usual activities; the pain item 
also includes a frequency rating. 
 
Disease recurrence 
Recurrence should be diagnosed by radiological examination and/or 
histopathological confirmation when the lesion is easily accessible for biopsy. 
Abnormal blood studies alone (e.g., elevated transaminases or alkaline 
phosphatase) are not sufficient evidence of relapse. Disease recurrence or new 
cancers should be reported on the clinical database as soon as possible after 
they are discovered. This includes events diagnosed during study visits but also 
any event diagnosed during non-study visits. 
 
Survival 
Date of registration to date of death from any cause. 
 

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7. 
Study Parameters 
 
Therapeutic Parameters for Arms A and B 
1. All required baseline assessments must be done ≤ 3 weeks prior to registration, with the exception of pregnancy 
tests for patients of childbearing potential. 
Assessment 
Time-points 
 
Baseline/ 
Registration 
Cycle11,3 
Cycles 
2,4,61,3 
Cycles3,51,3 
End of 
treatment7 
6 months post 
initiation of 
taxane 
Long-term 
follow-up8 
 
- 21 days 
± 7 days 
± 7 days 
± 7 days 
± 14 days 
± 30 days 
Informed Consent 
X 
 
 
 
 
 
 
History and physical (must include 
height, weight, and ECOG 
performance status) 
X 
X 
X 
X 
 
X 
X 
Laboratory Assessments2 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test2 
X 
 
 
 
 
 
 
Symptom/Toxicity Assessment 
X 
X 
X 
X 
X 
X 
X11 
Survival and relapse 
 
X 
X 
X 
 
X 
X 
PRO Instrument Administration4 
PRO-CTCAE Items10 
X12 
 
X 
X 
X 
X 
X11 
FACT/GOG-NTX 11 neurotoxicity 
items 
X12 
 
X 
X 
X 
X 
X11 
CIPN-20 9-item sensory neuropathy 
subscale 
X12 
 
X 
X 
X 
X 
X11 
PROMIS Physical Function v2 Short 
Form 10a 
X12 
 
 
X 
X 
X 
X11 
FACT-G 
X12 
 
 
X 
X 
X 
X11 
COST-FACIT 
X12 
 
 
 
X 
X 
 

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Assessment 
Time-points 
Alliance Patient Questionnaire for 
Clinical Trials In Oncology (social 
determinants of health items) 
X12 
 
 
 
X 
 
 
Biological Sample Submissions5,9 
MANDATORY: Peripheral Blood, one 
(1) 6mL EDTA Purple Top Tube13 
 
X12 
 
 
 
 
 
MANDATORY: Peripheral Blood, one 
(1) 10mL Sodium Heparin Green Top 
Tube13 
 
X12 
 
 
 
 
 
OPTIONAL: Plasma and residual 
cells from one (1) 10mL EDTA Purple 
Top Tube6 
 
X12 
 
 
 
X 
 
1. Cycles are 21 days long. Data will be collected on the 1st day of each treatment cycle. +/- 7 day window for cycles 1-6. 
2. Baseline: History & Physical, CBC, ANC, CMP, and Hemoglobin A1C. Assessments are to be drawn and results obtained ≤ 3 weeks 
prior to registration. Patients of childbearing potential must have a negative serum or urine pregnancy test ≤ 2 weeks prior to 
registration. 
Treatment cycles: CBC and CMP. 
End of treatment: CBC and CMP 
6 months post initiation of taxane treatment: Hemoglobin A1C 
3. Investigators must specify why they did not choose to use an anthracycline in those scenarios where it is considered an option. 
4. PROs for administration are: Functional Assessment of Cancer Therapy Gynecological Oncology Group Neurotoxicity (FACT/GOG-
NTX), PROMIS Physical Function Short Form 10a, Functional Assessment of Cancer Therapy – General (FACT-G), CIPN-20 9-item 
sensory neuropathy subscale, Comprehensive Score for Financial Toxicity (COST-FACIT), five social determinants of health items from 
the Alliance Patient Questionnaire for Clinical Trials In Oncology, and PRO CTCAE items. Please refer to Section 5.6 for complete 
information regarding instruments to be administered and the instrument administration schedule. For the baseline assessments, these 
must occur within 14 days of the beginning of the taxane portion of therapy. This baseline assessment will take the place of the 
assessment for C1. 
5. All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
6. Submit from patients who answer “Yes” to “I agree to provide additional samples for research.” 
7. 30 days post treatment. 
8. After patient has completed treatment, every 3 months if patient is < 2 years from their date of initiation of taxane treatment, every 6 
months if patient is 2-5 years from their date of initiation of taxane treatment. Patients will be followed for 5 years from their initiation of 
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9. Kits are being provided for the collection and shipment of the blood specimens. Allow up to two (2) weeks for kit delivery. See Section 10 
for instructions. 
10. The PRO-CTCAE items should be completed each time a Symptom/Toxicity Assessment is completed. 
11. Long-term follow-up at 1, 2, and 3 years from initiation of treatment. 
12. Baseline specimen collection and PROs are to be done after registration, but prior to taxane treatment on C1D1. 
13. Draw Monday – Thursday only. 

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8. 
Drug Formulation and Procurement 
All agents in this protocol are commercially available; drug will be obtained from 
institutional pharmacy supply. 
 
Paclitaxel 
NOTE: 
Please refer to the commercial package insert for more information. 
 
Other Names  
Taxol, NSC 673089. 
 
Classification  
Anti-microtubule agent. 
 
Mode of Action  
Promotes microtubule assembly and stabilizes tubulin polymers by 
preventing their depolarization, resulting in the formation of extremely 
stable and nonfunctional microtubules, and consequently inhibition of 
many cell functions. 
 
Storage and Stability  
The intact vials are stored under refrigeration. Freezing does not 
adversely affect the product. Solutions diluted to a concentration of 
0.3 to 1.2 mg/mL in normal saline, 5% dextrose, 5% dextrose and 
normal saline, or 5% dextrose in Ringer’s solution are stable for up to 
27 hours when stored at room temperature and normal room light. 
 
Dose Specifics  
80 mg/m2 
 
Preparation  
The concentrated solution must be diluted prior to use in normal 
saline, 5% dextrose, 5% dextrose and normal saline, or 5% dextrose 
in Ringer's solution to a concentration of 0.3 -1.2 mg/mL. Solutions 
exhibit a slight haze, common to all products containing non-ionic 
surfactants. Glass, polypropylene, or polyolefin containers and non-
PVC-containing (nitroglycerin) infusion sets should be used. A small 
number of fibers (within acceptable limits established by the USP) 
have been observed after dilution. Therefore, a hydrophilic 0.22 
micron in-line filter should be used. Analyses of solutions filtered 
through IVEX-2 and IVEX-HP (Abbott) 0.2 micron filters showed no 
appreciable loss of potency. 
Solutions exhibiting excessive particulate formation should not be 
used. 
 
Route of Administration  
Paclitaxel will be administered to patients as an IV infusion over 
approximately three hours, or per institutional standards for care. 

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Incompatibilities  
Avoid the use of PVC bags and infusion sets due to leaching of DEHP 
(plasticizer). Ketoconazole may inhibit paclitaxel metabolism, based 
on in vitro data. 
 
Availability  
Paclitaxel is commercially available, and is to be obtained from 
institutional pharmacy supply. 
 
Side Effects  
Please refer to the package insert. 
 
Nursing/Patient Implications  
1. Monitor CBC and platelet count prior to drug administration. 
2. Symptom management of expected nausea, vomiting, and 
stomatitis. 
3. Monitor for and evaluate abdominal pain occurring after paclitaxel 
administration (especially in severely neutropenic patients and in 
those receiving G-CSF) due to the risk of ischemic and 
neutropenic enterocolitis. 
4. Advise patients of possible hair loss. 
5. Cardiac monitoring for assessment of arrhythmias in patients with 
serious conduction abnormalities. 
6. Monitor liver function tests. 
7. Advise patient of possible arthralgias and myalgias which may 
occur several days after treatment. Monitor for symptoms of 
peripheral neuropathy. 
8. Monitor for signs and symptoms of hypersensitivity reactions. 
Insure that the recommended premedications have been given. 
Premedications (diphenhydramine, steroids, and H2 blocker) 
appear to reduce the incidence and severity of hypersensitivity 
reactions but do not provide complete protection. Emergency 
agents (diphenhydramine and epinephrine) should be available. 
9. Evaluate IV site regularly for signs of infiltration. It is not known if 
paclitaxel is a vesicant; however, the CremophorEL vehicle for this 
drug can cause tissue damage.  
10. In-line filtration with a 0.22 micron filter should be used. 
 
References  
Rowinsky EK, Casenave LA, Donehower RC.  Taxol:  A novel 
investigational microtubule agent.  J Natl Cancer Inst 1990; 82:1247-
1259. 
Gregory RE, DeLisa AF.  Paclitaxel:  A new antineoplastic agent for 
refractory ovarian cancer.  Clin Pharm 1993; 12: 401-415. 
Rowinsky EK, Eisenhauer EA, Chaudry V, et al.  Clinical toxicities 
encountered with paclitaxel.  Semin Oncology 1993; 20:1-15. 

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Walker FE.  Paclitaxel:  Side effects and patient education issues.  
Semin Oncology Nurs 1993; 9(suppl 2):6-10. 
 
Docetaxel 
NOTE: 
Please refer to the commercial package insert for more information. 
8.2.1 
Other Names 
Taxotere, RP 56976, NSC #628503. 
8.2.2 
Classification 
Antimicrotubule agent. 
8.2.3 
Mode of Action 
Docetaxel, a semisynthetic analog of taxol, promotes the assembly of 
tubulin and inhibits microtubule depolymerization. Bundles of 
microtubules accumulate and interfere with cell division. 
 
Storage and Stability 
Store intact vials between 2o and 25oC (36o and 77oF). Retain in the 
original package to protect from bright light. The final dilution (in either 
0.9% sodium chloride or 5% Dextrose solution) is stable for 4 hours if 
stored between 2o and 25oC (36o and 77oF). 
8.2.5 
Dose Specifics 
75 mg/m2 
8.2.6 
Preparation 
Just prior to use, allow the docetaxel vial to reach room temperature 
for 5 minutes. Add the entire contents of the ethanol diluent vial and 
mix by gently rotating the vial for 45 seconds. Allow to stand for 5 
minutes at room temperature, and check that the solution is 
homogeneous and clear (persistent foam is normal). The resulting 
solution contains 10 mg/mL of docetaxel. Please note that the solution 
contains 15% overfill. Dosing amounts should be based in the 
concentration per extractable volume, not the total volume of the vial. 
The desired dose is diluted in D5W or NS. The volume of the infusion 
should be adjusted in order to have a final docetaxel concentration of 
between 0.3 mg/mL and 0.74 mg/mL. Non-PVC-containing 
intravenous infusion bags and administration sets should be used to 
avoid patient exposure to the plasticizer DEHP. 
8.2.7 
Administration 
Docetaxel will be administered to patients as an IV infusion over 
approximately one hour, or per institutional standards for care. 
8.2.8 
Incompatibilities 
Intravenous bags and administration sets containing DEHP (di-[2-
ethylexyl] phthalate). No further information available. 
8.2.9 
Availability 
Docetaxel is commercially available, and is to be obtained from 
institutional pharmacy supply. 

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8.2.10 
Side Effects 
Please refer to the package insert. 
8.2.11 
Nursing Implications 
1. Monitor CBC and platelet count prior to drug administration. 
2. Symptom management of expected nausea, vomiting, and 
mucositis. 
3. Advise patients of possible hair loss. 
4. Monitor for signs and symptoms of hypersensitivity reactions.  
Insure that recommended pre-medications are given. 
5. Monitor liver function tests. 
6. Evaluate site regularly for signs of infiltration. 
7. Monitor for symptoms of peripheral neuropathy. 
8. Monitor for signs of fluid retention and cutaneous reactions. 
8.2.12 
References 
Investigator’s Brochure: Docetaxel. Rhone-Poulenc Rorer, June 14, 
1995. 
Pazdur R, et al. Phase I trial of Taxotere; Five-day schedule.  J Natl 
Cancer Inst 84:1781-8, 1992. 
Pazdur R, et al. Phase I trial of Taxotere (RP56976).  Proc Am Soc 
Clin Oncol 11:111, 1992. 
Burris H, et al. A phase I clinical trial of Taxotere as a 6-hour infusion 
repeated every 21 days in patients with refractory solid tumors.  Proc 
Am Soc Clin Oncol 11:137, 1992. 
Bissett D, et al. Phase I study of Taxotere (RP56976) given as a 24-
hour infusion. Proc Am Assoc Cancer Res 33:526, 1992. 
Bruno R, et al. Clinical pharmacology of Taxotere (RP56976) given as 
a 1-2 hour infusion every 2-3 weeks.  Proc Am Assoc Cancer Res 
33:261, 1992. 
DeValeriola D, et al. Phase I pharmacokinetic study of Taxotere 
(RP56976) administered as a weekly infusion.  Proc Am Assoc 
Cancer Res  33:1563, 1992. 

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9. 
Statistical Considerations 
The study is designed primarily to validate a previously identified germline predictor 
(homozygous wild-type allele in FCAMR and/or mutations in SBF2) for paclitaxel-
induced peripheral neuropathy (TIPN) in African American women diagnosed with early 
stage breast cancer. The over-arching goal of this study, however, is to change the 
standard of care for patients of African descent. This requires both confirmation of the 
higher risk of neuropathy with weekly paclitaxel AND a lower risk of neuropathy with 
docetaxel in the study patients. Thus the study includes two treatment arms based on 
taxane type: weekly paclitaxel and every 3 weeks docetaxel. Self-identified African 
American or black women with histologically confirmed early stage invasive 
adenocarcinoma of the breast will be registered to the trial and assigned to one of two 
neoadjuvant or adjuvant taxane regimens based on their disease characteristics 
(receptor status determined by local site, lymph node, tumor size, and anthracycline 
appropriate or not). Specifically, 
Paclitaxel 80 mg/m2 - weekly for 4 cycles (1 cycle = 21 days); 
• 
ER+/HER2-/ LN+ (anthracycline appropriate) = AC→weekly paclitaxel x 4 cycles 
• 
TNBC regardless of LN status (anthracycline appropriate) = AC→weekly 
paclitaxel x 4 cycles 
• 
HER2+, <3cm, LN- = weekly paclitaxel x 4 cycles + trastuzumab 
• 
HER2+ (anthracycline preferred) = AC→weekly paclitaxel x 4 cycles + 
Trastuzumab +/- Pertuzumab 
-OR- 
Docetaxel 75 mg/m2 - every 3 weeks x 4 cycles (1 cycle = 21 days) 
• 
ER +/HER2 -/ LN- = docetaxel/cyclophosphamide x 4 cycles 
• 
ER+/HER2-/ LN+ (anthracycline inappropriate*) = docetaxel/cyclophosphamide x 
4-6 cycles 
• 
ER+/HER2-/ LN+ (anthracycline appropriate) = AC→every 3 week docetaxel x 4 
cycles -OR- docetaxel/doxorubicin/cyclophosphamide (TAC) every 3 weeks x 6 
cycles 
• 
TNBC regardless of LN status (anthracycline inappropriate*) = 
docetaxel/cyclophosphamide x 4-6 cycles OR 
• 
TNBC regardless of LN status (anthracycline inappropriate*) = 
docetaxel/cyclophosphamide x 4-6 cycles 
• 
HER2+ (anthracycline preferred) = AC→every 3 week docetaxel x 4 cycles + 
trastuzumab +/- pertuzumab 
*anthracycline inappropriate: to be determined by treating physician based on risk of 
tumor recurrence and co-morbidities or medical factors in accordance with that 
physician’s standard practice 
For the evaluation of the germline predictor for TIPN, the two arms will be assessed 
separately. Section 9.1 provides the details for sample size consideration (n=120) for the 
paclitaxel arm (primary endpoint). The same number of patients will be enrolled to the 
docetaxel arm as well to explore whether the germline predictor can predict TIPN in 
patients receiving docetaxel as well, and to compare the two arms regarding the 
incidence of grade 2-4 TIPN (the top secondary endpoint, see Section 9.2.1), dose 
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(QOL). Since patients will be assigned to treatment arm based on their disease 
characteristics (receptor status, lymph node, tumor size, and anthracycline appropriate 
or not), the treatment arm that meets the accrual goal first will be closed while accrual is 
continuing for the other arm. 
The two taxane regimens are both standard of care, and there is no efficacy endpoint, 
no interim analysis is planned for the study. Final analysis will take place at about 1.5 
years after the enrollment of the last patient (1 year of follow up + 6 months of data 
cleaning), i.e., about 2.5 years after study activation assuming accrual will be completed 
within 12 months (see Section 9.1).  
9.1 
Primary Objective 
The primary objective of this validation study is to determine whether 
homozygous wild-type allele in FCAMR and/or mutations in SBF2 (high risk 
genotype) can predict taxane-induced peripheral neuropathy (TIPN) in self-
identified African American or black women diagnosed with early stage breast 
cancer and receiving neoadjuvant or adjuvant weekly paclitaxel treatment (arm 
A). 
Incidence of grade 2-4 TIPN is the primary endpoint of the study, and will be 
assessed by treating physician using CTCAE. While on taxane treatment, AE 
assessment will be administered on the first day of each cycle (1 cycle=3 weeks 
on both arms) and at the end of taxane treatment to collect any occurrence of 
neuropathy during treatment. After treatment completion, AE assessment will be 
administered at 6 months after initiation of taxane treatment, and then every 3 
months within 2 years of initiation of taxane treatment and every 6 months in year 
3-post initiation of taxane treatment to collect any long-term TIPN. For the 
primary endpoint, the observation period will be from initiation of taxane 
treatment until 1 year after that (i.e. total period of 1 year including treatment 
time). Patients will be coded as having the event as long as grade 2-4 
neuropathy based on CTCAE occurred at any time during the observation period. 
Patients without neuropathy or with maximum of grade 1 neuropathy during the 
whole observation period (including patients without grade 2-4 TIPN during the 
whole year and patients without grade 2-4 TIPN before loss to follow up within 1 
year) will be coded as having no event. Sensitivity analysis will be conducted by 
excluding patients without any grade 2-4 TIPN before loss to follow up within 1 
year from the denominator. Of note, only neuropathy with a treatment 
relationship code of 3-5 (possibly, probably, definitely) will be considered as 
taxane-induced neuropathy, and neuropathy with a treatment relationship code of 
1-2 (unrelated or unlikely) will not be considered in the study design.  
The germline predictor of interest in the study is homozygous wild-type allele in 
FCAMR and/or mutations in SBF2. Previously, we identified a common variant in 
FCAMR (rs1856746) that predicted a decreased risk for TIPN1 and rare variants 
in SBF2 associated with an increased risk of TIPN.7 Overall, 76% of patients of 
African descent in E5103 carried homozygous wild-type allele in FCAMR and/or 
mutations in SBF2 (high risk genotypes), which predicted a 37% likelihood of 
TIPN. Conversely, 24% of patients of African descent carried the FCAMR variant 
and had no SBF2 mutations (low risk genotypes), which predicted a 10% 
likelihood of TIPN. We assume the same distribution of the germline predictor in 
the current study (ie, 76% with high risk genotype and 24% with low risk 
genotype in the study patients).  

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With an accrual of 102 analyzable patients of African descent in the paclitaxel 
arm (arm A), there is 81% power to detect a 27% difference (37% vs.10%) in risk 
of TIPN between the previously determined high and low risk genotypes (76% vs. 
24%) using Fisher exact test with one-side alpha of 0.05. Assuming 10% of 
misclassification of race via patient’s self-report and 5% assay failure rate for 
testing the germline predictor, a total of 120 African American or black patients 
based on self-report will be enrolled to the paclitaxel arm.  
This study is open to patients who self-identify as black, African American, and/or 
of African descent. Approximately 15-16 African American patients were enrolled 
per month in E5103 and TAILORx. Given the simplistic design, minimal exclusion 
criteria, and focused attention to accrual specific to African Americans, it is 
expected to complete the accrual of 240 patients (120 patients in each arm) in 
approximately 12 months (average accrual rate of 20 patients per month).  
9.2 
Secondary Objectives 
9.2.1 
Grade 2-4 TIPN based on CTCAE between Arm A vs. Arm B.  
Our top secondary objective is to compare the incidence of grade 2-4 
TIPN based on CTCAE between the two taxane regimens (arm A vs. 
arm B). Incidence of grade 2-4 TIPN is defined the same as that used 
for the primary objective. With an accrual of the same number (n=120) 
of patients and the same misclassification rate (10%) in arm B 
(docetaxel arm) as that in arm A, there is 81% power to detect a lower 
incidence of grade 2-4 TIPN in arm B (13.2%) compared to arm A 
(27.7%) using Fisher exact test with one-side alpha of 0.05.The 
expected incidence of grade 2-4  TIPN (13.2% and 27.7%) was based 
on the estimated TIPN rates caused by every 3-week docetaxel and 
weekly paclitaxel in the E1199 trial (Table 1). As exploratory analysis, 
we will also perform subset analyses to estimate the frequency of 
TIPN across the various docetaxel-containing regimens (i.e. 4 vs. 6 
cycles) if there are 20 or more patients in a subset (95% confidence 
interval for frequency of TIPN will be no wider than 0.46 with 20 
patients), and to estimate frequency of TIPN at the end of each cycle 
in the docetaxel arm. 
9.2.2 
PRO-based neurotoxicity 
The preliminary data for this study was based on physician reported 
neuropathy via CTCAE. Recent data have supported improved 
accuracy and sensitivity for use of patient reported outcomes 
(PROs).25,26,28 Thus, in this trial we will simultaneously assess 
neuropathy, using PRO as a secondary phenotype of the primary 
endpoint. The PRO-based neurotoxicity will be assessed using the 11 
items about neurotoxicity in the FACT/GOG-NTX questionnaire and 
the CIPN-20 9-item sensory neuropathy subscale. 
For the FACT/GOG-NTX, each item is scored from 0–4, and the 
neurotoxicity total score is the sum of the scores for the 11 items, and 
ranges from 0 to 4426,36,38. Lower values of the FACT/GOG-NTX 
neurotoxicity total score indicate higher neurotoxicity. Assessment of 
PRO-based neurotoxicity will take place at the same schedule as 
CTCAE (i.e., at first day of each cycle, at end of treatment, and at 6 
months, 1, 2, and 3 years post initiation of taxane therapy). The 

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FACT/GOG-NTX reference time frame is the past 7 days, but we don’t 
expect the total neurotoxicity score has significant change from week 
to week. 
The FACT/GOG-NTX neurotoxicity total score will be analyzed as a 
continuous variable. The sample size/power calculation for repeated 
measures usually requires some assumptions about the study design. 
Based on Hershman,et al trial68, we assume the variance of the 
FACT/GOG-NTX neurotoxicity total score is 114.5 (i.e., standard 
deviation of 10.7). The following power calculation provides some idea 
about the effect size that the available sample size can detect under 
certain assumption about the correlation between repeated PRO 
measures. Assuming the correlation between repeated PRO 
measures is 0.7, there will be about 80% power to detect the group 
effect of the magnitude of 0.3 (i.e., variance explained by the 
between-subjects effect is 6.7) based on F test for between subjects 
using two-way repeated measure ANOVA analysis at two-sided 
significance level of 0.05, with 77 patients in high risk genotype group 
and 24 patients in low risk genotype group (accrual of 120 patients 
and estimated 10% misclassification rate and 5% missing PRO data). 
A lower correlation between repeated measures and a smaller 
variance for the FACT/GOG-NTX neurotoxicity total score will result in 
a higher power.  
Linear mixed effect models with random intercept (repeated measures 
within single patients with unstructured covariance matrices) will be fit 
to estimate the average difference in FACT/GOG-NTX neurotoxicity 
total score between high vs. low risk genotype groups in the paclitaxel 
arm. Time and patient and disease characteristics will be included as 
covariates in the linear mixed effect model. Likelihood ratio test will be 
used to determine whether time will be coded as a continuous 
variable or dummy variables in the model. Genotype group-by-time 
interaction will be tested to see whether the difference between the 
two genotype groups depends on time. 
For comparison between arm A and arm B, the FACT/GOG-NTX 
neurotoxicity total score change between the baseline and at end of 
treatment will be compared using two sample t test. With 102 
evaluable patients in each arm (accrual of 120 patients and estimated 
10% misclassification rate and 5% missing PRO data), we will have 
80% power to detect an effect size of 0.4 in change of FACT/GOG-
NTX neurotoxicity total score between the two treatment arms at two-
sided significance level of 0.05 using a two-sample t test. In addition, 
multivariable linear mixed effect model will be used to estimate the 
time trend and treatment group difference after adjusting for other 
covariates. 
The CIPN-20 9 item sensory neuropathy subscale is added to the trial 
to harmonize with the SWOG1714 trial, and the subscale score will be 
analyzed in a similar way as the FACT/GOG-NTX score as supportive 
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PRO Objectives 
 
HRQoL 
The FACT/GOG-NTX questionnaire referenced above also contains 
27 core items (the FAT-G) that cover four areas of HRQoL: physical, 
social, emotional, and functional well-being. QOL will be measured by 
the summed total score of the 27 items, which will range from 0 to 
108. The HRQoL total score will be analyzed as a continuous variable 
and compared between low and high-risk genotypes groups of the 
paclitaxel arm, and between the paclitaxel arm and the docetaxel arm 
groups, using two-sample t tests. The primary comparison will be 
change in HRQoL total score between registration and treatment 
completion between two groups. With 77 patients (76%) in the high 
risk group and 24 patients (24%) in the low risk group in the paclitaxel 
arm (a total accrual of 120 patients in the paclitaxel arm and an 
assumed 10% misclassification rate and 5% missing data), we will 
have 80% power to detect an effect size of 0.67 in HRQoL score 
change between the high and low risk genotype groups at two-sided 
0.05 significance level using a two-sample t test.  
For comparison between the two treatment arms, with 102 evaluable 
patients in each arm (accrual of 120 with an assumption of 10% 
misclassification in race and 5% missing data), we will have 80% 
power to detect an effect size of 0.4 in HRQoL score change at two-
sided 0.05 significance level using a two-sample t test. In addition, 
multivariable linear mixed effect models will also be fit to evaluate the 
time trend of HRQoL and to estimate the average group difference in 
HRQoL after adjusting for other covariates. Group-by-time interaction 
will be tested to see whether the difference in HRQoL between groups 
depends on time. 
 
Physical Function 
Physical function will be assessed using PROMIS Physical Function 
v2.0 Short Form 10a. Summary scores are calculated as a T-score 
(with 50 = mean & 10 = SD of the reference population) and higher 
scores reflecting better physical function. The PROMIS Physical 
Function T score will be analyzed as a continuous variable, and it will 
be compared between the two treatment arms (A&B) and for the high 
risk vs. low risk genotypes (in arm A) using two-sample t tests. The 
primary comparison will be change in Physical Function T-scores 
between registration and treatment completion between two groups. 
The power calculation and analysis plan will be similar with that for the 
above HRQoL endpoint measured via FACT/GOG-NTX 
questionnaire. 
 
Financial Toxicity 
Financial toxicity will be assessed via the 11-item Comprehensive 
Score for Financial Toxicity (COST-FACIT) questionnaire. The level of 
financial toxicity will be measured by the total score (range: 0-44), 
which will be analyzed as a continuous variable. Higher COST scores 
represent better financial well-being.66 The COST-FACIT total score 
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sample t tests. The primary comparison will be change in COST-
FACIT scores between registration and treatment completion between 
the two groups. The power calculation and analysis plan will be similar 
with that for the above HRQoL endpoint measured via FACT/GOG-
NTX questionnaire. 
 
PRO-CTCAE Items 
The PRO-CTCAE items we have selected (#39a-b – numbness & 
tingling and #48a-c – general pain) include ratings of severity (none-
very severe) and interference with usual activities (not at all- very 
much)); the pain item also includes a frequency rating (never- almost 
constantly). We will present PRO-CTCAE scores for each attribute 
(frequency, severity and/or interference) separately and compare 
PRO-CTCAE severity (coded 0-4) with CTCAE grades for the 
corresponding time periods. In addition, the two patient-reported 
neuropathic-related PRO-CTCAE items will be compared between the 
two taxane regimens (Arm A vs. Arm B) and the two genotype risk 
groups in arm A. The association between PRO-CTCAE neurotoxicity 
and dose reduction and early treatment discontinuation will also be 
explored (Of note, the analyses will be exploratory in nature and the 
purpose of the analysis is hypothesis generating). 
 
Social Economic Determinants 
The five social determinants of health items from the Alliance Patient 
Questionnaire for Clinical Trials in Oncology (education, marital 
status, health insurance status income, and current zip code), will be 
collected at baseline. We will explore the association between these 
factors with treatment completion per protocol, dose reduction, 
toxicities (PRO-CTCAE, FACT/GOG-NTX neurotoxicity & CIPN 
sensory neuropathy scores) and HRQoL (Physical Function & FACT-
G scores). Of note, all these analyses will be exploratory in nature, 
and the purpose of the analysis is hypothesis generating. 
 
Safety Monitoring 
Adverse events and study progress are monitored twice yearly for all ECOG-
ACRIN studies. Reports of these analyses are sent to the ECOG-ACRIN 
Principal Investigator or Senior Investigator at the participating institutions. 
Expedited reporting of certain adverse events is required, as described in Section 
5.2. 
 
Gender and Ethnicity  
This study will be open only to self-identified African American women. Men are 
not eligible for the study. Women with race other than African American are not 
eligible for the study. The anticipated accrual in subgroups defined by gender 
and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
10 
0 
10 
Not Hispanic or Latino 
230 
0 
230 

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The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data and Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston. 
Ethnic Category: Total of all subjects 
240 
0 
240 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
240 
0 
240 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
0 
0 
0 
Racial Category: Total of all subjects 
240 
0 
240 

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10. 
Specimen Submissions 
Peripheral blood must be submitted for defined laboratory research studies. These 
studies are defined in Section 11. 
Plasma and the residual cells are to be submitted for future undefined laboratory 
research studies per patient consent. 
Detailed instructions to obtain study kits, as well as specimen collection, processing, and 
shipping guidelines can be found in the EAZ171 Biospecimen Manual of Procedures 
which can be found on the CTSU website under ‘Education and Promotion’ tab and will 
also be included with the kits.  
Kits are available to order and will include materials necessary for the preparation and 
shipment of the specimens. Please allow two weeks for delivery. Kits can be ordered 
using Indiana University’s online kit module for institutions that have the protocol open 
for patient enrollment: http://kits.iu.edu/EAZ171 
All specimens must be logged and tracked via the ECOG-ACRIN Sample Tracking 
System (Section 10.3). An STS shipping manifest form and IU Sample Record form 
(http://j.mp/2XBbnEo) must be included with every submission. 
All specimens must be labeled clearly with the ECOG-ACRIN protocol number 
(EAZ171), ECOG-ACRIN patient sequence number, patient initials, date and time of 
collection, time point, and specimen type. 
 
Submissions to Indiana University 
 
Collection and Submission Schedule 
Peripheral blood for the mandatory laboratory research studies must 
be collected at baseline (after registration, prior to start of taxane 
treatment) and submitted day of collection.  
Plasma for the optional future undefined research studies is to be 
collected at baseline (after registration, prior to start of taxane 
treatment and six (6) months post treatment per patient consent. 
If you have any questions concerning specimen collection and 
shipment please contact Indiana University (IU) at (317)274-2840. 
 
Preparation Guidelines 
Blood draw order is sodium heparin (10mL green top), EDTA for 
plasma (10mL purple top) and then EDTA for whole blood (6mL 
purple top). Peripheral blood samples are to be shipped Monday 
through Thursday only. Please note full list of holidays and closures in 
in the Biospecimen Manual. 
10.1.2.1 
Peripheral Blood – Green Top (MANDATORY) 
• 
Draw 10mL of peripheral blood into one (1) green top 
sodium heparin tube 
• 
Immediately after blood draw, invert tube 8-10 times 
• 
Package and ship day of collection at ambient 
temperature during the cool season and on cool packs 
during the hot season 

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• 
Do not collect on Fridays, Weekends, or days before a 
holiday. 
10.1.2.2 
Peripheral Blood – Purple Top (MANDATORY) 
• 
Draw 6mL of peripheral blood into one (1) 6mL purple 
top EDTA tube 
• 
Immediately after blood draw, invert tube 8-10 times 
• 
Store tube upright at -80ºC until batch shipment 
overnight on dry ice. If specimens cannot be stored at 
–80ºC, store at –20ºC and ship on dry ice within one 
(1) week of collection. 
10.1.2.3 
Plasma – EDTA Purple Top (Submit from patients who 
answer “Yes” to “I agree to provide additional samples for 
research”) 
• 
Draw 10mL of peripheral blood into one (1) 10mL 
purple top EDTA tube 
• 
Immediately after blood draw, invert tube 8-10 times 
• 
Centrifuge within 30 minutes of draw at room 
temperature at 1500g for 15 minutes 
• 
Aliquot plasma into four (4) cryovials 
Cryovial 
Cap Color 
Specimen Type 
Purple 
Plasma, 1.5mL 
Blue 
Plasma, residual 
• 
Replace the cap on the purple top tube 
• 
Freeze cryovials and residual cells at –80ºC until 
shipment. Batch ship overnight on dry ice. If specimens 
cannot be stored at –80ºC, store at –20ºC and ship on 
dry ice within one (1) week of collection.  
 
Shipping Procedures 
Peripheral blood specimens are to be shipped PRIORITY overnight 
the day of collection at ambient temperature. 
Ship ambient specimens Monday – Thursday only, do not ship on 
Fridays, weekends or day before a holiday. 
Frozen specimens are to be batch shipped overnight on dry ice. 
Ship frozen specimens Monday, Tuesday, and Wednesday only. Do 
not ship the day before the weekend or holiday. 
Notify Indiana University of all incoming shipments prior to 
shipping the specimens by emailing wbobb@iu.edu the copy of 
the completed Shipping Manifest Form. 
Ship to: 
EAZ171 Study 

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IU Genetics Biobank 
351 W. 10th Street, TK342 
Indianapolis, IN 46202-4118 
An STS shipping manifest form and IU Sample Record form 
(http://j.mp/2XBbnEo) must be generated and shipped with all 
specimen submissions. 
 
Use of Specimens in Research 
See Section 11 for the description of the laboratory research studies to be 
performed at Indiana University. 
Specimens from patients who consented to allow their specimens to be used for 
future undefined ECOG-ACRIN approved research studies, including the 
residuals and derivatives of the specimens used for the EAZ171 protocol-defined 
laboratory research studies, will be routed to the ECOG-ACRIN Central 
Biorepository and Pathology Facility (CBPF) at MD Anderson and stored for 
future use.  
Specimens submitted will be processed for the purposes of the defined research 
studies and, if possible, to maximize their utility for current and future research 
projects and may include, but not limited to, extraction of plasma, serum, DNA 
and RNA. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. 
 
ECOG-ACRIN Sample Tracking System 
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
Generic Specimen Submission Form (#2981v3) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. 

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Retroactively enter all specimen collection and shipping information when STS is 
available. 
 
Sample Inventory Submission Guidelines  
Inventories of all specimens submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized for the approved laboratory research studies 
will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office - Boston. 

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11. 
Laboratory Research Studies 
Results of these studies are for the purposes of the trial only and will not be returned to 
the institution or reported to the patient. 
 
To prospectively validate & discover additional germline predictive biomarkers for 
paclitaxel-induced peripheral neuropathy in EAZ171. 
 
Rationale & strategy 
There are no prospectively validated and clinically implemented 
predictive biomarkers for TIPN. Our previously discovered, genetically 
categorized high- and low-risk populations have the strongest level of 
evidence to date for prediction of TIPN in patients of African descent. 
These genetic predictors will be prospectively validated or refuted in 
the prospective clinical trial, EAZ171. EAZ171 also provides the 
perfect opportunity to further assess the impact of genetic variation on 
risk; specifically, the role of non-coding variants throughout the 
genome. 
 
Experimental design 
We will prospectively test for associations between genotypes and 
phenotypes as outlined below. The primary objective will be to 
validate the genetically determined high/low-risk category for TIPN. 
This will assume that those who had TIPN in EAZ171 will have the 
high-risk genotype and those who did not have TIPN will have the 
low-risk genotype. A secondary objective will be to evaluate for 
associations between non-coding variants throughout the genome 
with TIPN. For the secondary objective, we will evaluate for an 
association with genotypes using a case/control analysis plan. For 
analyses, we will first call all variants but subsequently use 
bioinformatic algorithms to prioritize functional variants to minimize 
multiple testings and to improve statistical power. Finally, the top non-
coding variant candidates will be subsequently validated or refuted in 
patients of African descent patients from E5103 (n=386) using 
TaqMan genotyping. 
11.1.2.1 
Phenotypes 
Phenotypes will be formally assessed and reported in 
prospective fashion using two definitions. The primary 
definition will be physician-reported CTCAE grade 2-4 
TIPN. The secondary definition will be patient-reported 
TIPN, which is considered more sensitive, using the 
validated FACT/GOG-NTX & CIPN 20 sensory neuropathy 
subscale.26,28 Controls (for the secondary objectives) will 
include patients who did not experience Grade 2+ TIPN 
and received the fully intended dose of paclitaxel. 
11.1.2.2 
Whole Genome Sequencing (WGS) 
Genotyping will be completed through WGS as outlined 
below using germline DNA derived from 120 patients in 
EAZ171. The primary genotype for evaluation will be the 

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composite high- and low-risk categories (Table 1). This 
categorical classification will include the combination of 
protective, common variants in FCAMR and permissive, 
rare variants in SBF2. The secondary analyses will include 
non-coding variants across the genome. The genetic 
variants in the promoter regions are all known to have 
biological significance, including the enhancer regions; 3’-
untranslated regions (UTR) that are enriched in microRNA 
targeting sites; and intronic regions that have an impact on 
splicing regulation. To date, no data have previously been 
reported in this arena. 
 
 
Methodology 
11.1.3.1 
Whole genome sequencing (WGS) in EAZ171 
WGS will be performed in the IUSM Center for Medical 
Genomics (CMG) laboratory, directed by Dr. Yunlong Liu 
(co-PI). We have established standard operating 
procedures and by following industry standards, we will 
ensure 30X average depth for over 90% of the human 
genome from the blood. The sequencing data will be 
analyzed following standard pipelines including quality 
control (QC), sequence alignment (including refined 
alignment), variant calling, and variant annotation. A key 
component analysis will be conducted using Sentieon 
DNA-seq pipeline, which uses identical algorithms as 
Broad Institute’s BWA-GATK Best Practice Workflow, but 
is over 10X faster for generating variant call format (VCF) 
file from FASTQ sequencing data. We will further conduct 
vigorous QC to ensure the integrity of the data. Major 
metrics include the transition-transversion ratios and the 
percentage of variants that are documented in the latest 
dbSNP release. Findings on significant genomic loci will be 
examined visually using the Integrative Genomic Viewer 
(IGV) software. 
11.1.3.2 
Validation of high/low-risk genotypes 
EAZ171 is designed to serve as an independent cohort to 
replicate the previous GWAS/WES findings1,7and is 
powered to validate a difference in risk of TIPN between 
our “high-risk” and “low-risk” categories based on FCAMR 
and SBF2 mutation status (Table 1). We will extract the 
genotyping data for the candidate common variants in 

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FCAMR and the deleterious variants in SBF2 based on our 
previous GWAS and WES data, respectively.  
11.1.3.3 
Prioritization of non-coding variants 
The secondary objectives are to identify non-coding 
variants that are associated with TIPN. In order to reduce 
the total number of hypotheses to be tested, we will first 
use a broad array of bioinformatics tools to prioritize the 
candidate variants, based on their genomic loci and the 
predicted impact on gene regulation, such as detlaSVM, 
CADD, and deepSeq. We will further conduct burden test 
focusing on the variants that are predicted to be 
functionally important. This strategy will effectively reduce 
the non-functional variants before conducting statistical 
analysis, and therefore increase statistical power.  
We will use our own computational algorithms45,46 in 
predicting functions of various genetic variants, including 
promoter variants, micro-INDELs, and intronic variants. 
Top functionally associated variants in the gene promoter 
and enhancer regions of the genes within expression 
quantitative trait loci (eQTL) regions will be further 
analyzed for their roles in transcriptional regulation using 
data generated in the ENCODE and Epigenomic Roadmap 
consortia as outlined below. 
Cis-regulatory element: We will focus our analysis on the 
variants identified in gene promoter and enhancer regions 
of the genes within expression quantitative trait loci (eQTL) 
regions. In recent years, many studies reported that 
genetic variants in the key regulatory regions are causal 
variants for complex disease. For instance, a recent study 
reports that a Parkinson-associated risk variant in distal 
enhancer of α–synuclein affects disease phenotype 
through modulating target gene expression.47 The 
candidate promoter and enhancer regions will be derived 
from the data generated in the ENCODE and Epigenomic 
Roadmap consortia. In addition, we will also include the 
regions identified from ATAC-seq data that is proposed in 
Aim 3 (Section 11.3). The eQTL regions will be derived 
from the data generated in the GTEx consortium, which 
provided a comprehensive transcriptome profile on 17 
tissues of neuronal origin in dozens to hundreds of 
individuals. These data will offer comprehensive 
measurements on the expression levels of the transcription 
factors and variant target genes in tissues relevant to 
neuropathy. We will also extend our prior data on regSNPs 
(which prioritizes the functional impact of promoter SNPs) 
to neuropathy, using variants in open chromatin regions 
that are enriched with regulatory regions. We expect to find 
functional variants that will alter the likelihood of TIPN by 
affecting transcription factor binding in promoter and 
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using the RNA-seq data available in the public domain 
(e.g., GTEx; https://www.gtexportal.org/).  
11.1.3.4 
Association analysis of non-coding variants 
The top variants from prioritization will be further evaluated 
for their association with TIPN in EAZ171. Variants located 
in a gene promoter or 3’-UTR region, or predicted to 
disrupt or create a transcription factor-binding motif that 
cis-regulate that gene, will be aggregated to a variant set, 
and the gene based on Sequence Kernel Association Test 
(SKAT)48 will be applied to the variant sets in the 
association with TIPN. Similarly, variants predicted to alter 
the splicing outcome in the intron or exon region of a gene 
will be aggregated to a variant set. The tests will be 
adjusted for clinical covariates including age, body surface 
area or principal components (from WGS data) that are 
significantly associated with TIPN in a multi-variate logistic 
regression model at α=0.05 significance level. The 
Bonferroni correction for multiple comparisons will be 
applied to the gene-based multi-variant tests. 
11.1.3.5 
Validation of top candidate non-coding genetic variants in 
E5103 
The top candidate genes with non-coding variants 
identified from EAZ171 will be validated/refuted in the 
African American patients (n=386) from E5103.18 151 out 
of 386 African Americans in E5103 experienced grade 2-4 
TIPN, and DNA is available for genotyping.7 TaqMan 
assays will be used for validation of non-coding variants. 
The number of candidates will be based on statistical 
power after effect size is established in EAZ171 (See 
below). 
11.1.3.6 
Sample Size and Power Calculations 
Primary objective: Based on our prior published data 
(Table 1),1,7 76% of patients of African descent in EAZ171 
will be expected to be in the high-risk category and 24% in 
the low-risk category. For the proposed validation study 
with 120 patients, our power calculation demonstrates that 
there is at least 80% power to validate that the high-risk 
group will be more likely to have TIPN than those in the 
low-risk group using a one-sided t-test at α=0.05 
significance level.  
Secondary objective and validation: The top 5 genes from 
the SKAT analysis will be validated in E5103 (151 cases 
and 235 controls). If we assume the average length of the 
transcriptional regulation region will be 5,000 base pairs, 
and 30% of the variants will be causal variants with an 
odds ratio of 4.5, there will be 80% power to validate an 
association at the statistical significance level of α=0.01 
with Bonferroni correction. Similarly, if we assume the 

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average length of splicing regulation region will be 10,000 
base pairs, there will be 82% power to validate an 
association between gene splicing mutations and TIPN at 
the significance level of α=0.01. 
 
To determine the impact of germline variability on paclitaxel-induced phenotypic 
changes in patient derived iPSC-iSNs and compare and contrast the accuracy 
and sensitivity of these changes with clinical outcomes in EAZ171.  
 
Rationale & strategy 
The ability to evaluate for phenotypical changes in iPSC-iSNs from 
patients treated in EAZ171 will provide a real-world test of this ex vivo 
tool and increase our understanding of the biology of TIPN. 29,49,50 
While the assessment of peripheral nerves from patients before and 
after treatment would be ideal for mechanistic studies, these types of 
invasive biopsies are not possible. Data have suggested the fidelity of 
gene expression between the primary neuron dorsal root ganglion and 
the iPSC-iSNs generated by the method proposed below.32 Thus, the 
iPSC-iSNs proposed in the current study are the most relevant, 
genetically representative, human model available for studying TIPN. 
The patient-derived iPSC-iSNs have advantages over other animal 
models or lymphoblastoid cells models: 1). they will be directly derived 
from patients with matching clinical outcomes; 2). they will be 
differentiated in a way to mimic sensory-specific neurons; 3). they will 
allow for accurate integration of the complex role of genetic variation 
on TIPN in each individual patient. Importantly, these proposed 
studies might ultimately demonstrate that iPSC-iSNs can serve as an 
exemplary model for other types of therapy-induced neuropathies in 
cancer and other disease states. 
 
Experimental design 
iPSC-iSNs will be derived from all patients in the paclitaxel arm of 
EAZ171. Baseline peripheral blood cells will be reprogrammed to 
human induced pluripotent cells (iPSCs), and iPSCs will subsequently 
be differentiated to form sensory neurons (iPSC-iSNs). The cultured 
iPSCs-iSNs will be treated ex vivo with paclitaxel at 50nM for 48 
hours. Morphological changes in the iPSCs will be measured and 
compared with and without exposure to paclitaxel using the five most 
established neurite outgrowth phenotypes51 (serving as ex vivo 
surrogates for neuronal damage) including: 1. mean process length, 
2. median process length, 3. maximum process length, 4. total 
outgrowth, and 5. mean outgrowth intensity. A decrease in mean 
process length will serve as the primary phenotypic endpoint as it has 
been the most sensitive across the five phenotypes.51 In addition, we 
will develop a “composite score” which will comprehensively consider 
all five phenotypes simultaneously. Our primary objective for this aim 
will be to compare the development of conventional physician 
reported CTCAE grade 2+ TIPN in EAZ171 with ex vivo neuronal 
damage (from each patient’s own iPSC-iSNs). A secondary analysis 
will compare patient-reported TIPN 25,27using the FACT/GOG-NTX26,28 
with ex vivo neuronal damage. The patient-reported outcomes are 
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sensitivity of the ex vivo model in addition to its clinical validity. 
Another secondary analysis will compare evidence of ex vivo neuronal 
damage (using both individual and composite neurite outgrowth 
phenotypes) with high/low-risk genotypes. 
 
Methodology 
11.2.3.1 
Generation of patient derived iPSC-iSNs 
Baseline peripheral blood cells of individual patients from 
EAZ171 will be reprogrammed to human iPSCs following 
the protocol of StemCell Technologies. Erythroid 
progenitor cells will be isolated and expanded from 
peripheral blood for 7 days and subsequently 
reprogrammed into iPSCs with Epi5TM episomal vector 
through a transfection process. iPSC colonies will be 
obtained in 18-25 days and the pluripotent nature 
(trilineage differentiation) of the iPSC line will be confirmed 
using immunofluorescence markers. iPSCs will 
subsequently be differentiated to sensory neurons (iPSC-
iSNs) using the method as described by Cai et al.52 Briefly, 
iPSCs will be maintained in mTeSR™1 medium (StemCell 
Technologies) on Corning Matrigel®-coated dishes until 
reaching 80% confluency and then induced for iSN 
differentiation. On day 5, the cells will be passaged and 
seeded into Matrigel®-coated chamber slides at a density 
of 1 x 10 cells/well21 in neural induction media until day 8. 
The differentiation to sensory neurons will be confirmed by 
immunofluorescence staining. Patient derived iPSC-iSNs 
will then be maintained in neural maintenance media until 
exposed to paclitaxel. 
11.2.3.2 
Exposure of iPSC-iSNs to paclitaxel 
The iPSC-iSNs will be treated with paclitaxel at 50nM for 
48 hours. The duration and dose (50nM) of paclitaxel have 
been selected based on literature51,53,54 and our own 
preliminary data. The morphology will be assessed 
immediately before and after the 48-hour exposure to 
paclitaxel. Prior to the post-paclitaxel morphological 
analyses, we will assess for cell viability using CellTiter-Glo 
assay to re-confirm that the concentration of paclitaxel at 
50nM was not excessively high (< 80% viable) for that 
patient, to preclude proper morphological assessment. Our 
preliminary data indicated that iPSC-iSNs treated with 
50nM paclitaxel for 48 hours uniformly had > 90% viability 
compared to the untreated iPSC-iSNs. Fifty iPSC-iSNs 
from each patient will be used to collect data for each of 
the five neurite outgrowth phenotypes. If there are 
insufficient cells (n < 50) due to unexpected cell death for a 
given patient, we will repeat generation of iPSC-iSNs from 
that same patient. If the sum of the first and second set of 
viable iPSC-iSNs is not > 50, that patient’s sample will not 
be included in the planned analyses as apoptosis is not an 

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established parameter for assessing ex vivo neuropathy. 
Although we expect few to no cases of insufficient viable 
cells, we will perform an exploratory and descriptive 
assessment of cells with exceptional apoptosis/cell death 
to see if these correspond to patients with clinical evidence 
of exceptionally severe TIPN. 
11.2.3.3 
Quantification of morphological changes 
Five iPSC-iSN neurite outgrowth phenotypes and a 
composite score will be assessed and compared from 
baseline to post-paclitaxel treatment to determine ex vivo 
neuronal damage. The iPSC-iSNs will be stained with 
Hoechst 33342 (Life Technologies, Carlsbad, CA) and 
labeled with an immunofluorescent marker against 
peripherin (Abcam, San Francisco, CA) and imaged using 
EVOS Fl Cell Imaging System (Thermo Fisher Scientific) 
for measuring neurite outgrowth. At least nine fields will be 
imaged and neurite outgrowth phenotypes will be 
assessed using the Simple Neurite Tracer of the Image J 
(https://imagej.nih.gov/ij/). The changes of neurite 
outgrowth will be analyzed using individual cell data. Fifty 
cells will be quantified to obtain the five outgrowth 
phenotypes as follows 1). mean process length (primary 
phenotype)-the mean process length from each cell 
averaged over 50 cells; 2). median process length- the 
median process length from each cell averaged over 50 
cells; 3). maximum process length- the maximum process 
length from each averaged over 50 cells, 4). total 
outgrowth- the sum of the length of all processes from 
each cell averaged over 50 cells, and 5). mean outgrowth 
intensity- the mean thickness/diameter of all outgrowths 
from each cell averaged over 50 cells. 
11.2.3.4 
Neurite outgrowth composite score 
To develop a single ex vivo phenotype of neuronal 
damage that integrates all of the established five 
phenotypes, we will develop a “composite score” using a 
logistic regression model. Assuming the prevalence of 
TIPN in patients of African descent to be 39% based on 
the clinical data from E5103, we expect 47 patients will 
experience TIPN among the 120 patients enrolled in 
EAZ171. Depending on the number of variables selected, 
which could be from 5 (five individual phenotypes) to 2 
(neurite length and thickness) the resulting events per 
variable (EPV) will range from 9 to 24, respectively. At this 
level of EPV, we can expect stable estimates and thus 
decrease the chance of overfitting.55 The data will be split 
into 70% for training and 30% for testing, and the model 
will be evaluated using a stratified 10-fold cross-validation. 
The overall performance and discriminatory power of the 
model will be accessed using metrics such as the Brier 
score and receiver operating characteristic (ROC). The 

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results will be compared with the clinical measures of TIPN 
from the donor patients. This process will also provide 
insights on the preferential influence of paclitaxel on each 
of the five phenotypes. Changes in neurite outgrowth 
composite score before and after treatment will ultimately 
be compared with mean process length (primary ex vivo 
phenotype) in an exploratory fashion to determine whether 
this score outperforms the primary ex vivo phenotype. 
11.2.3.5 
Data analysis and statistics 
Power analysis for the number of cells required to detect 
morphological changes: Based on our preliminary data, the 
average length of neurite processes is 250µm with a 
standard deviation of 159µm in the control cells, and an 
average length of 123µm with a standard deviation of 
58µm after the treatment with 50nM paclitaxel for 48 hours. 
50 cells in each group will be measured in order to have at 
least 95% power to detect the decrease in paclitaxel-
induced neurite process length, using a t-test at a 
significance level of α=0.05. 
Primary and secondary analyses: For the primary analysis, 
we will compare grade 2+ TIPN with a change in mean 
process length using a one-sided t-test. Based on the 
clinical data from E5103, there will be 47 patients (39%) 
who develop TIPN and 73 patients (61%) who won’t. 
Assuming the standard deviance in neurite length is 58 µm 
based on our preliminary data, there will be at least 80% 
power to test for a > 28µm decrease (an effect size of 
0.48) in the paclitaxel-induced neurite process length 
between those with grade 2+ TIPN and the control group 
at the α=0.05 significance level. Similarly, we will use a t-
test for our secondary analyses, including: patient-reported 
TIPN vs. change in mean neurite length; high/low-risk 
genotype group vs. change in mean neurite length; grade ≥ 
2 TIPN vs. composite score; high/low-risk genotype group 
vs. composite score; and patient-reported TIPN vs. 
composite score. 
 
To assess the impact of paclitaxel on gene expression, DNA methylation, and 
chromatin accessibility in patient-derived iPSC-iSNs 
 
Rationale & strategy 
Despite substantial prior work, the molecular mechanism for TIPN has 
not been completely elucidated. A deeper understanding of the 
mechanism has the potential to uncover therapeutic targets to prevent 
and treat this toxicity; which in turn can improve the therapeutic index 
of the paclitaxel and quality of life for patients. We will use cutting-
edge high-throughput technologies to measure paclitaxel-induced 
changes in gene expression, DNA methylation, and chromatin 
accessibility. Using a systems biology approach, these experiments 
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characterizations in a well-controlled patient-derived system as shown 
below: 
 
 
Experimental design 
We will perform ATAC-seq, MethylCap-Seq, and RNA-seq 
experiments in patient derived (from EAZ171) iPSC-iSNs, before and 
after paclitaxel exposure to assess the chromatin accessibility, DNA 
methylation in promoter/enhancer/CpG island regions, and gene 
expression. The iPSC-iSNs will be derived from each of 120 patients 
recruited in EAZ171.  
 
Methodology 
11.3.3.1 
Molecular characterization of patient-derived iPSC-iSNs 
Gene expression: We will use RNA-seq technology to 
measure the global gene expression levels in patient-
derived iPSC-iSNs, with or without 50nM paclitaxel 
exposure. The library will be constructed from total RNA 
isolated from the cells using the Illumina “TruSeq Stranded 
mRNA Library Prep Kit” and followed by sequencing 
(HiSeq 4000). To capture the gene expression differences 
with or without drug exposure, sequencing will be 
conducted using 75 base pair (bp) paired-end 
configuration with more than 30 million clusters (read pairs) 
per sample. This coverage will reliably measure the 
variability in gene expression, and capture splicing variants 
at the transcriptome level. This will allow investigation of 
other possible molecular mechanisms that could impact 
the response of neuronal cells to paclitaxel exposure. 
DNA Methylation: As one of the most stable epigenetic 
signals, DNA methylation plays key roles in modulating the 

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activity of DNA elements and typically acts to repress gene 
transcription through inactivating promoters and 
enhancers. Analysis of DNA methylation will be achieved 
using MethylCap-seq, a robust procedure for genome-wide 
profiling that readily allows detection of DNA methylation in 
known and novel regions as previously described by our 
group.56-58 Enrichment of methylated DNA will be 
performed using the Methylminer kit (Invitrogen). Libraries 
will be generated using the Illumina TruSeq protocol, and 
further sequenced using the 75bp paired-end protocol. 
Chromatin accessibility: ATAC-seq will be used to examine 
the chromatin accessibility at gene promoters and 
enhancers in iPSC-iSNs. It will also help us to define 
neuronal-specific enhancer regions that will be used 
Section 11.1. This approach will allow for the assessment 
of key regulatory regions (promoters and enhancers) that 
may be altered by paclitaxel exposure. The sequencing will 
be done on HiSeq 4000 with 50 million 75bp paired-end 
reads per sample, which will be adequate for identifying 
open chromatin regions. 
11.3.3.2 
Bioinformatic processing and statistical analyses 
RNA-seq: The overarching informatics approach for RNA-
seq is composed of multiple key components including 
read QC and pre-processing (TrimGalore), sequence 
alignment (STAR59), post-alignment QC (NGSUtils60), and 
gene expression quantification (NGSUtils60). The derived 
RNA-seq counts in each gene will be normalized to the 
total number of sequencing reads falling into all the 
annotated gene regions in each sample, and will be further 
scaled based on a trimmed mean of log transformed 
counts per million (CPM) value.61 The scaled CPM or 
CPM_RNA will then be used as a gene level quantification 
in each sample and will be the base for the further 
association analyses on paclitaxel induced neuronal 
damage. Taxane-induced changes in gene expression 
levels will be identified using edgeR,62 based on a 
generalized linear model assuming negative binomial 
distribution. In this model, sample identity will be treated as 
a random variable, which effectively increases the 
statistical power by pairing the measurements of pre- and 
post-taxane treatment. Effects of multiple comparisons will 
be corrected using Benjamini and Hochberg's (BH) 
method.  
MethylCap-seq: MethylCap-seq data will be processed as 
previously described.56-58 Briefly, after QC and pre-
processing with TrimGalore, sequencing reads will be 
mapped to human reference genome hg38 using Burrows-
Wheeler Aligner (BWA). Genome-wide methylation will be 
identified using MACS263,64 and methylation-enriched 
regions will be derived from the union of all the regions 

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identified across all samples. The derived MethylCap-seq 
counts in each region will then be normalized to the total 
number of sequencing reads falling into all the identified 
methylation enriched regions, and further scaled based on 
a trimmed mean of log transformed counts per million 
(CPM) value. The scaled CPM or CPM_methyl, will be 
used as a region-specific quantification of methylation in 
each sample. Taxane-induced methylation changes will be 
calculated using edgeR,61 followed by correction for 
multiple comparisons using BH method.  
ATAC-seq: Chromatin accessibility will be quantified with 
the ATAC-seq data using a similar analysis plan to the 
MethylCap-seq (above). We will also use the combination 
of BWA (sequence alignment), MACS2 (region 
identification), and edgeR (differential chromatin changes) 
algorithms. In our preliminary data from ~50,000 cells, we 
identified 25,525 open chromatin regions overlapping with 
promoter regions of 16,368 genes (within 3000-bp 
upstream of transcriptional start site). Chromatin 
accessibility will be quantified by counting reads falling into 
identified regions, following proper normalization and 
scaling procedures, as described above. Similar to RNA-
seq and MethylCap-seq, the scaled counts per million 
CPM, or CPM_ATAC, will be used as a region-specific 
quantification of chromatin accessibility in each sample. 
The paclitaxel-induced changes in chromatin accessibility 
will be calculated using edgeR, followed by correction for 
multiple comparisons using BH method. 
Statistical power: If we assume 10,000 genes that passed 
QC will be tested for an association between paclitaxel 
induced changes of the transcriptome or epigenome and 
paclitaxel induced ex vivo neuronal damage, there will be  
> 80% power to detect this association at the significance 
level of 5×10-6. This also assumes that > 21% of ex vivo 
neuronal damage variance will be explained by changes in 
the transcriptome or epigenome. 
Impact of the baseline epigenome on TIPN: We will 
evaluate whether the molecular signals, including gene 
expression, DNA methylation patterns and/or chromatin 
accessibility of key genes, at the baseline level (pre-
Taxane treatment) can predict TIPN. This analysis goes 
beyond traditional association studies that merely examine 
the genetic markers that are associated with a phenotype, 
and will shed insight on the role of epigenetic markers on 
TIPN. Specifically, we will calculate the basal level 
differences of gene expression and epigenetic factors on 
the iPSC-iSNs between patients with TIPN and those 
without, through the quantification of gene expression 
(CPM_RNA), chromatin accessibility (CPM_ATAC) and 
DNA methylation levels (CPM_methylation). A standard 

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differential analysis will be calculated using edgeR. Finally, 
correction for multiple comparisons will be made using the 
BH method. If an excessive number of candidate genes 
are identified, we will conduct pathway analyses (as 
outlined above) to maintain adequate power.  
Statistical power: Based on the preliminary data and power 
calculations for EAZ171, there will be 47 patients with 
TIPN and 73 without TIPN. We will assume that we can 
reliably detect the expression of 10,000 genes from the 
iPSC-SNs, and 5% of these genes will be differentially 
expressed. Thus with 120 samples (47 cases and 73 
controls), there will be >90% power to identify genes 
differentially expressed with >1.25 fold-change at the 
significance level of 5% false-discovery rate (FDR). Similar 
levels of statistical power will be applicable to the 
Methylcap-seq and ATAC-seq data. 
Impact of germline genetic variants on paclitaxel-induced 
epigenetic and gene expression alterations: Taxane-
induced epigenetic and gene expression changes serve as 
an important molecular endophenotype that can be used 
for stratifying TIPN. We will examine whether DNA variants 
identified in Section 11.1 are associated with these 
changes. For each patient, edgeR-reported log fold 
changes of CPM_RNA, CPM_ATAC, and CPM_methyl will 
be used for the analysis. Due to the limited sample size, 
we will focus our analysis on genes significantly associated 
with neuronal damage, and on variants with cis-acting 
effects, in which only variants in the putative regulatory 
regions (promoters, enhancers, and 3’-UTR regions) will 
be evaluated. These regions will be derived from the 
existing gene annotations, as well as the union of the 
enriched regions identified using the ATAC-seq and 
methylCap-seq assays above. Variants will be clustered to 
gene sets as discussed above. Additional follow-up studies 
will be warranted for validation of these specific findings.  
Statistical power: Assuming the log fold change in either 
gene expression or epigenetic data follows a standard 
normal distribution, 20% of the variances can be explained 
by germline genetic variants. If we assume the possibility 
that an extraordinarily high number of genes 
(maximum=1000) impact ex vivo neuronal damage, we will 
still maintain > 80% power to detect an association with a 
message or epigenetic changes after paclitaxel exposure 
with 120 patients using a 2-sided test. 
 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the Investigator. 

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12. 
Electronic Data Capture 
Please refer to the EAZ171 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the Clinical Data Update System  (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. 
Schneider BP, Li L, Radovich M, et al. Genome-Wide Association Studies for 
Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199. Clinical 
cancer research : an official journal of the American Association for Cancer 
Research 2015;21:5082-91. 
2. 
Schneider BP, Shen F, Jiang G, et al. Impact of genetic ancestry on outcomes in 
ECOG-ACRIN-E5103. J Clin Oncol PO 2017 (Accepted). 
3. 
Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment 
of breast cancer. The New England journal of medicine 2008;358:1663-71. 
4. 
Dietze EC, Sistrunk C, Miranda-Carboni G, O'Regan R, Seewaldt VL. Triple-
negative breast cancer in African-American women: disparities versus biology. Nat 
Rev Cancer 2015;15:248-54. 
5. 
Sparano JA, Wang M, Zhao F, et al. Race and hormone receptor-positive breast 
cancer outcomes in a randomized chemotherapy trial. Journal of the National 
Cancer Institute 2012;104:406-14. 
6. 
Sparano JA, Zhao F, Martino S, et al. Long-Term Follow-Up of the E1199 Phase III 
Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2015;33:2353-60. 
7. 
Schneider BP, Lai D, Shen F, et al. Charcot-Marie-Tooth gene, SBF2, associated 
with taxane-induced peripheral neuropathy in African Americans. Oncotarget 
2016;7:82244-53. 
8. 
Bach PB, Schrag D, Brawley OW, Galaznik A, Yakren S, Begg CB. Survival of 
blacks and whites after a cancer diagnosis. Jama 2002;287:2106-13. 
9. 
Albain KS, Unger JM, Crowley JJ, Coltman CA, Jr., Hershman DL. Racial 
disparities in cancer survival among randomized clinical trials patients of the 
Southwest Oncology Group. Journal of the National Cancer Institute 2009;101:984-
92. 
10. 
Keenan T, Moy B, Mroz EA, et al. Comparison of the Genomic Landscape 
Between Primary Breast Cancer in African American Versus White Women and the 
Association of Racial Differences With Tumor Recurrence. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 
2015;33:3621-7. 

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11. 
DeSantis CE, Siegel RL, Sauer AG, et al. Cancer statistics for African Americans, 
2016: Progress and opportunities in reducing racial disparities. CA: a cancer 
journal for clinicians 2016;66:290-308. 
12. 
Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival 
in the Carolina Breast Cancer Study. Jama 2006;295:2492-502. 
13. 
Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with 
differences in survival among black and white women with breast cancer. Jama 
2013;310:389-97. 
14. 
DeSantis C, Jemal A, Ward E. Disparities in breast cancer prognostic factors by 
race, insurance status, and education. Cancer causes & control : CCC 
2010;21:1445-50. 
15. 
Tichy JR, Deal AM, Anders CK, Reeder-Hayes K, Carey LA. Race, response to 
chemotherapy, and outcome within clinical breast cancer subtypes. Breast cancer 
research and treatment 2015;150:667-74. 
16. 
Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of 
chemotherapy-induced peripheral neuropathy in survivors of adult cancers: 
American Society of Clinical Oncology clinical practice guideline. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 
2014;32:1941-67. 
17. 
Vicini F, Nancarrow-Tull J, Shah C, et al. Increasing accrual in cancer clinical trials 
with a focus on minority enrollment: The William Beaumont Hospital Community 
Clinical Oncology Program Experience. Cancer 2011;117:4764-71. 
18. 
Miller K, O'Neill AM, Dang CT, et al. Bevacizumab (Bv) in the adjuvant treatment of 
HER2-negative breast cancer: Final results from Eastern Cooperative Oncology 
Group E5103. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2014;32:Abstr 500. 
19. 
Bryc K, Durand EY, Macpherson JM, Reich D, Mountain JL. The genetic ancestry 
of African Americans, Latinos, and European Americans across the United States. 
American journal of human genetics 2015;96:37-53. 
20. 
Cobb RJ, Thomas CS, Laster Pirtle WN, Darity Jr WA. Self-identified race, socially 
assigned skin tone, and adult physiological dysregulation: Assessing multiple 
dimensions of “race” in health disparities research. SSM - Population Health 
2016;2:595-602. 
21. 
Rivera E, Cianfrocca M. Overview of neuropathy associated with taxanes for the 
treatment of metastatic breast cancer. Cancer Chemother Pharmacol 2015;75:659-
70. 
22. 
Sucheston-Campbell LE, Clay-Gilmour AI, Barlow WE, et al. Genome-wide meta-
analyses identifies novel taxane-induced peripheral neuropathy-associated loci. 
Pharmacogenet Genomics 2018;28:49-55. 
23. 
Mathis S, Goizet C, Tazir M, et al. Charcot–Marie–Tooth diseases: an update and 
some new proposals for the classification. Journal of Medical Genetics 
2015;52:681-90. 
24. 
Ballinger TJ, Kassem N, Shen F, et al. Discerning the Clinical Relevance of 
Biomarkers in Early Stage Breast Cancer. Breast cancer research and treatment 
2017 (accepted). 

ECOG-ACRIN 
EAZ171 
Cancer Research Group 
Version Date: February 26, 2021 
84 
Rev Add2 
25. 
(U.S. Department of Health and Human Services FaDA. 
http://wwwfdagov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM193282pdf 2009. 
26. 
Hershman DL, Weimer LH, Wang A, et al. Association between patient reported 
outcomes and quantitative sensory tests for measuring long-term neurotoxicity in 
breast cancer survivors treated with adjuvant paclitaxel chemotherapy. Breast 
cancer research and treatment 2011;125:767-74. 
27. 
Kluetz PG, Papadopoulos EJ, Johnson LL, et al. Focusing on Core Patient-
Reported Outcomes in Cancer Clinical Trials-Response. Clinical cancer research : 
an official journal of the American Association for Cancer Research 2016;22:5618. 
28. 
Kushner DM, Connor JP, Sanchez F, et al. Weekly docetaxel and carboplatin for 
recurrent ovarian and peritoneal cancer: a phase II trial. Gynecol Oncol 
2007;105:358-64. 
29. 
Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Nature 
reviews Neurology 2010;6:657-66. 
30. 
Sterneckert JL, Reinhardt P, Scholer HR. Investigating human disease using stem 
cell models. Nature reviews Genetics 2014;15:625-39. 
31. 
Wing C, Komatsu M, Delaney SM, Krause M, Wheeler HE, Dolan ME. Application 
of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy. Stem cell 
research 2017;22:79-88. 
32. 
Young GT, Gutteridge A, Fox HD, et al. Characterizing human stem cell-derived 
sensory neurons at the single-cell level reveals their ion channel expression and 
utility in pain research. Molecular therapy : the journal of the American Society of 
Gene Therapy 2014;22:1530-43. 
33. 
Newman LA, Kaljee LM. Health Disparities and Triple-Negative Breast Cancer in 
African American Women: A Review. JAMA Surg 2017;152:485-93. 
34. 
Postma TJ, Heimans JJ, Muller MJ, Ossenkoppele GJ, Vermorken JB, Aaronson 
NK. Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. 
Ann Oncol 1998;9:739-44. 
35. 
Hay JL, Atkinson TM, Reeve BB, et al. Cognitive interviewing of the US National 
Cancer Institute's Patient-Reported Outcomes version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE). Qual Life Res 2014;23:257-69. 
36. 
Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of the 
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-
Neurotoxicity (FACT/GOG-NTX) questionnaire for patients receiving systemic 
chemotherapy. International journal of gynecological cancer : official journal of the 
International Gynecological Cancer Society 2003;13:741-8. 
37. 
Basch E, Pugh SL, Dueck AC, et al. Feasibility of Patient Reporting of 
Symptomatic Adverse Events via the Patient-Reported Outcomes Version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a 
Chemoradiotherapy Cooperative Group Multicenter Clinical Trial. International 
journal of radiation oncology, biology, physics 2017;98:409-18. 
38. 
Hile E, Levangie P, Ryans K, Gilchrist L. Oncology Section Task Force on Breast 
Cancer Outcomes: Clinical Measures of Chemotherapy‐induced Peripheral 
Neuropathy—A Systematic Review. Rehabilitation Oncology 2015;33:32-41. 

ECOG-ACRIN 
EAZ171 
Cancer Research Group 
Version Date: February 26, 2021 
85 
39. 
Cella D, Peterman A, Hudgens S, Webster K, Socinski MA. Measuring the side 
effects of taxane therapy in oncology: the functional assesment of cancer therapy-
taxane (FACT-taxane). Cancer 2003;98:822-31. 
40. 
Monfort SM, Pan XJ, Patrick R, et al. Longitudinal changes in patient-reported 
symptoms and physical function during taxane-based chemotherapy in breast 
cancer patients. Journal of Clinical Oncology 2016;34. 
41. 
Sasane M, Tencer T, French A, Maro T, Beusterien KM. Patient-Reported 
Outcomes in Chemotherapy-Induced Peripheral Neuropathy: A Review. The 
Journal of Supportive Oncology 2010;8:e15-e21. 
42. 
Ward E, Jemal A, Cokkinides V, et al. Cancer disparities by race/ethnicity and 
socioeconomic status. CA: a cancer journal for clinicians 2004;54:78-93. 
43. 
Pollitt RA, Swetter SM, Johnson TM, Patil P, Geller AC. Examining the pathways 
linking lower socioeconomic status and advanced melanoma. Cancer 
2012;118:4004-13. 
44. 
Rini BI, Powles T. Biology and treatment of advanced renal cell carcinoma: a 
global perspective. Semin Oncol 2013;40:419-20. 
45. 
Teng M, Ichikawa S, Padgett LR, et al. regSNPs: a strategy for prioritizing 
regulatory single nucleotide substitutions. Bioinformatics 2012;28:1879-86. 
46. 
Zhang X, Li M, Lin H, et al. regSNPs-splicing: a tool for prioritizing synonymous 
single-nucleotide substitution. Hum Genet 2017;136:1279-89. 
47. 
Soldner F, Stelzer Y, Shivalila CS, et al. Parkinson-associated risk variant in distal 
enhancer of alpha-synuclein modulates target gene expression. Nature 
2016;533:95-9. 
48. 
Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X. Rare-variant association testing for 
sequencing data with the sequence kernel association test. American journal of 
human genetics 2011;89:82-93. 
49. 
Hu BY, Weick JP, Yu J, et al. Neural differentiation of human induced pluripotent 
stem cells follows developmental principles but with variable potency. Proc Natl 
Acad Sci U S A 2010;107:4335-40. 
50. 
Xie Y, Schutte RJ, Ng NN, Ess KC, Schwartz PH, O'Dowd DK. Reproducible and 
efficient generation of functionally active neurons from human hiPSCs for 
preclinical disease modeling. Stem cell research 2017;26:84-94. 
51. 
Wheeler HE, Wing C, Delaney SM, Komatsu M, Dolan ME. Modeling 
chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived 
neuronal cells. PLoS One 2015;10:e0118020. 
52. 
Cai S, Han L, Ao Q, Chan YS, Shum DK. Human Induced Pluripotent Cell-Derived 
Sensory Neurons for Fate Commitment of Bone Marrow-Derived Schwann Cells: 
Implications for Remyelination Therapy. Stem Cells Transl Med 2017;6:369-81. 
53. 
Nokihara H, Yamamoto N, Ohe Y, Hiraoka M, Tamura T. Pharmacokinetics of 
Weekly Paclitaxel and Feasibility of Dexamethasone Taper in Japanese Patients 
with Advanced Non-small Cell Lung Cancer. Clin Ther 2016;38:338-47. 
54. 
Zasadil LM, Andersen KA, Yeum D, et al. Cytotoxicity of paclitaxel in breast cancer 
is due to chromosome missegregation on multipolar spindles. Sci Transl Med 
2014;6:229ra43. 

ECOG-ACRIN 
EAZ171 
Cancer Research Group 
Version Date: February 26, 2021 
86 
Rev Add1 
55. 
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of 
the number of events per variable in logistic regression analysis. J Clin Epidemiol 
1996;49:1373-9. 
56. 
Huang RL, Gu F, Kirma NB, et al. Comprehensive methylome analysis of ovarian 
tumors reveals hedgehog signaling pathway regulators as prognostic DNA 
methylation biomarkers. Epigenetics 2013;8:624-34. 
57. 
Rao X, Evans J, Chae H, et al. CpG island shore methylation regulates caveolin-1 
expression in breast cancer. Oncogene 2013;32:4519-28. 
58. 
Tang J, Fang F, Miller DF, et al. Global DNA methylation profiling technologies and 
the ovarian cancer methylome. Methods Mol Biol 2015;1238:653-75. 
59. 
Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq 
aligner. Bioinformatics 2013;29:15-21. 
60. 
Breese MR, Liu Y. NGSUtils: a software suite for analyzing and manipulating next-
generation sequencing datasets. Bioinformatics 2013;29:494-6. 
61. 
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for 
differential expression analysis of digital gene expression data. Bioinformatics 
2010;26:139-40. 
62. 
Robinson MD, Oshlack A. A scaling normalization method for differential 
expression analysis of RNA-seq data. Genome biology 2010;11:R25. 
63. 
Feng J, Liu T, Qin B, Zhang Y, Liu XS. Identifying ChIP-seq enrichment using 
MACS. Nature Protocols 2012;7:1728-40. 
64. 
Zhang Y, Liu T, Meyer CA, et al. Model-based analysis of ChIP-Seq (MACS). 
Genome biology 2008;9:1-9. 
65. 
Garcia, S. F., Cella, D., Clauser, S. B., Flynn, K. E., Ladd, T., Lai, J-S, Reeve, B., 
Smith, A. W., Stone, A. A., & Weinfurt, K. (2007). Standardizing patient-reported 
outcomes assessment in cancer clinical trials: A PROMIS initiative. Journal of 
Clinical Oncology, 25, 5106-5112. 
66. 
https://www.assessmentcenter.net/ac_scoringservice 
67. 
de Souza JA, Yap BJ, Wroblewski K, et al: Measuring financial toxicity as a 
clinically relevant patient-reported outcome: The validation of the COmprehensive 
Score for financial Toxicity (COST). Cancer 123:476-484, 2017 
68. 
Hershman DL, Weimer LH, Wang A, Kranwinkel G, Brafman L, Fuentes D, Awad 
D, Crew KD. Association between patient reported outcomes and quantitative 
sensory tests for measuring long-term neurotoxicity in breast cancer survivors 
treated with adjuvant paclitaxel chemotherapy. Breast Cancer Research and 
Treatment 2011;125(3):767-74 
69. 
Jensen RE, Potosky AL, Reeve BB, et al. Validation of the PROMIS physical  
function measures in a diverse US population-based cohort of cancer patients. 
Quality of life research: an international journal of quality of life aspects of 
treatment, care and rehabilitation. 2015;24(10):2333-2344 
70. 
Postma TJ, Aaronson NK, Heimans JJ, et al. The development of an EORTC 
quality of life questionnaire to assess chemotherapy-induced peripheral 
neuropathy: the QLQ-CIPN20. European journal of cancer. 41(8):1135-1139, 2005 
71. 
Lavoie Smith EM, Barton DL, Qin R, Steen PD, Aaronson NK, Loprinzi CL. 
Assessing patientreported peripheral neuropathy: the reliability and validity of the 
European Organization for Research and Treatment of Cancer QLQ-CIPN20 

ECOG-ACRIN 
EAZ171 
Cancer Research Group 
Version Date: February 26, 2021 
87 
Questionnaire. Quality of life research : an international journal of quality of life 
aspects of treatment, care and rehabilitation. 22(10):27872799, 2013 
72. 
Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy 
Scale: development and validation of the general measure. J Clin Oncol 1993; 
11:570-79. 

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Appendix I 
 
ECOG-ACRIN Generic Specimen Submission Form (#2981v3) 
 

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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 

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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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Appendix III 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.