A Randomized Phase II Trial of Neoadjuvant Cisplatin vs. Doxorubicin/Cyclophosphamide (AC) in Women With Newly Diagnosed Breast Cancer and Germline BrCa Mutations
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Beth Israel Deaconess Medical Center

 
 
Title: RANDOMIZED PHASE II TRIAL OF NEOADJUVANT CISPLATIN VS. 
DOXORUBICIN/CYCLOPHOSPHAMIDE (“AC”) IN WOMEN WITH NEWLY DIAGNOSED 
BREAST CANCER AND GERMLINE BRCA MUTATIONS 
 
 
NCT Number: NCT01670500 
 
 
IRB Approval Date: 8/16/2018 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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TABLE OF CONTENTS    
1. 
OBJECTIVES .................................................................................................................................................... 1 
1.1 
Study Design .................................................................................................................................................... 1 
1.2 
Primary Objective ........................................................................................................................................... 1 
1.3 
Secondary Objectives ...................................................................................................................................... 1 
2. 
BACKGROUND ................................................................................................................................................ 2 
2.1 
BRCA-related Breast Cancer .......................................................................................................................... 2 
2.2 
Cisplatin in Breast Cancer .............................................................................................................................. 3 
2.3 
Neoadjuvant Chemotherapy ............................................................................................................................ 4 
2.4 
Cisplatin in BRCA-related Breast Cancer ....................................................................................................... 4 
2.5 
Tissue Biomarkers of Response to Cisplatin ................................................................................................... 5 
2.6 
Doxorubicin and Cyclophosphamide “AC” in BRCA-related Breast Cancer ................................................ 7 
2.7 
Tissue Biomarkers of Response to Anthracyclines .......................................................................................... 8 
2.8 
Rationale for Current Study ............................................................................................................................ 8 
3. 
PARTICIPANT SELECTION .......................................................................................................................... 9 
3.1 
Eligibility Criteria ........................................................................................................................................... 9 
3.2 
Exclusion Criteria ......................................................................................................................................... 11 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 12 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 12 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ......................................................................... 12 
4.2 
Registration Process for Dana Farber/Harvard Cancer Center (DF/HCC) and Dana Farber/Partners 
Cancer Care (DF/PCC) Institutions ............................................................................................................. 12 
4.3 
Guidelines for External and TBCRC Sites .................................................................................................... 13 
4.4 
Registration Process for External  and TBCRC Sites ................................................................................... 13 
5. 
TREATMENT PLAN ...................................................................................................................................... 14 
5.1 
Randomization ............................................................................................................................................... 14 
5.2 
Pre-chemotherapy Surgical Evaluation ........................................................................................................ 14 
5.3 
Pre-chemotherapy Research Core Biopsy (see Appendix E) ......................................................................... 14 
5.4 
Overview of Preoperative Chemotherapy ..................................................................................................... 16 
5.5 
Pre-treatment Criteria ................................................................................................................................... 16 
5.6 
Agent Administration ..................................................................................................................................... 17 
5.7 
Second Core Biopsy Sample .......................................................................................................................... 19 
5.8 
Additional Pre-operative Chemotherapy....................................................................................................... 20 
5.9 
Definitive Breast Surgery .............................................................................................................................. 20 
5.10 
Post-operative Chemotherapy ....................................................................................................................... 20 
5.11 
General Concomitant Medication and Supportive Care Guidelines ............................................................. 20 
5.12 
Duration of Therapy ...................................................................................................................................... 21 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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5.13 
Criteria for Removal from Protocol Therapy ................................................................................................ 21 
5.14 
Duration of Follow Up .................................................................................................................................. 22 
5.15 
Criteria for Taking a Participant Off Study .................................................................................................. 22 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 22 
6.1 
Anticipated Toxicities .................................................................................................................................... 23 
6.2 
Toxicity Management .................................................................................................................................... 25 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 30 
7.1 
Availability and Preparation ......................................................................................................................... 31 
7.2 
Stability and Storage ..................................................................................................................................... 31 
8. 
STUDY CALENDAR AND BIOSPECIMEN COLLECTION .................................................................... 33 
8.1 
Required Data ............................................................................................................................................... 33 
8.2 
Research Specimen Submission ..................................................................................................................... 36 
8.3 
Research Blood Sample Collection ............................................................................................................... 37 
8.4 
SPECIMEN BANKING.................................................................................................................................. 39 
9. 
MEASUREMENT OF EFFECT..................................................................................................................... 39 
9.1 
Target Lesions ............................................................................................................................................... 39 
9.2 
Pathologic Complete Response ..................................................................................................................... 39 
9.3 
Radiographic Assessment .............................................................................................................................. 40 
9.4 
Clinical Assessments ..................................................................................................................................... 40 
9.5 
Pathology Response Central Review and Archival Tissue for Future Correlative Studies ........................... 40 
9.6 
Biomarkers of Response to Cisplatin and AC chemotherapy ........................................................................ 42 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 43 
10.1 
Adverse Event Lists ....................................................................................................................................... 43 
10.2 
Adverse Event Characteristics ...................................................................................................................... 43 
 
Adverse Event Reporting ............................................................................................................................... 44 
10.3 
44 
10.4 
Reporting to Hospital Risk Management....................................................................................................... 45 
10.5 
Routine Adverse Event Reporting .................................................................................................................. 46 
11. 
DATA AND SAFETY MONITORING .......................................................................................................... 46 
11.1 
Data Reporting .............................................................................................................................................. 46 
11.2 
Safety Meetings ............................................................................................................................................. 47 
11.3 
Monitoring ..................................................................................................................................................... 47 
12. 
REGULATORY CONSIDERATIONS .......................................................................................................... 48 
12.1 
Protocol Review and Amendments ................................................................................................................ 48 
12.2 
Informed Consent .......................................................................................................................................... 48 
12.3 
Ethics ............................................................................................................................................................. 48 
12.4 
Study Documentation .................................................................................................................................... 49 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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12.5 
Records Retention ......................................................................................................................................... 49 
12.6 
Multi-center Guidelines ................................................................................................................................. 49 
13. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 50 
13.1 
Analysis of Primary Endpoint ....................................................................................................................... 50 
13.2 
Interim Analysis............................................................................................................................................. 50 
13.3 
Analysis of Secondary Endpoints .................................................................................................................. 51 
14. 
PUBLICATION PLAN .................................................................................................................................... 52 
15. 
REFERENCES ................................................................................................................................................. 53 
Appendix A: PERFORMANCE STATUS CRITERIA .......................................................................................... 58 
Appendix B: FORMULA FOR CREATININE CLEARANCE ............................................................................ 59 
Appendix C:  NCI COMMON TOXICITY CRITERIA FORADVERSE EVENTS (CTCAE) v4.03 ............... 60 
Appendix D: STUDY SPONSORED BRCA1/2 TESTING .................................................................................... 61 
Appendix E: TISSUE ACQUISITION AND SHIPPING GUIDELINES FOR RESEARCH BIOPSIES ......... 62 
Appendix F: DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN ................................. 63 
Appendix G:  12-258 SPECIMEN REQUISITION (Diagnostic and Surgery Blocks/Slides) ............................. 81 
Appendix H: 12-258 SPECIMEN REQUISITION (Research Biopsy and Blood) ............................................... 82 
Appendix I: INFORM/TBCRC031 Questionnaire for Annual Follow-Up after Breast Surgery ....................... 83 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                             
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
1 
1. OBJECTIVES 
1.1 
Study Design 
 
The study is a randomized phase II trial in women with breast cancer and a germline mutation in 
BRCA1 or BRCA2 comparing the pCR rate after doxorubicin (A) (60 mg/m2) and 
cyclophosphamide (C) (600 mg/m2) (AC) administered either every 2 or 3 weeks for 4 cycles 
(Arm A), to the pCR rate after neoadjuvant cisplatin (75 mg/m2) administered every 3 weeks for 
4 cycles (Arm B). The goal is to enroll 170 women total, 85 to each arm of the study. 
1.2 
Primary Objective 
 
The main goal of this study is to determine if the pathologic complete response (pCR) rate 
(determined by the Miller-Payne method 1) [pCR in breast and nodes (i.e. RCB 0) or pCR in 
breast (i.e. Miller Payne 5) if nodes are not evaluable (i.e. positive nodes were removed 
surgically before chemo)]  to neoadjuvant cisplatin is at least 20% greater than the pCR to 
doxorubicin/ cyclophosphamide (AC) in women with newly diagnosed breast cancer and a 
germline BRCA mutation.  
1.3 
Secondary Objectives 
 
• To determine Residual Cancer Burden (RCB)2 and compare the rates of RCB 0 as well as 
RCB 0 and RCB 1 (combined, with the inclusion of pCR in the breast when nodes are not 
evaluable, i.e. Miller-Payne 5 when positive nodes were removed prior to chemo) after 
neoadjuvant cisplatin or doxorubicin/ cyclophosphamide (AC) in women with newly 
diagnosed breast cancer and a germline BRCA mutation.  
• To compare the rates of Miller Payne 4 (near pCR) and 5 (pCR) combined between those 
subjects who received neoadjuvant cisplatin and those who received neoadjuvant AC.1 
• To determine the clinical response rate, defined as the number of partial and complete 
responses, after preoperative therapy with either cisplatin or AC in participants with a 
germline BRCA mutation and breast cancer.  
• To compare the toxicities of cisplatin and AC preoperative chemotherapy in BRCA 
mutation carriers with newly diagnosed breast cancer. 
• To collect pre-chemotherapy biopsies for future analyses of biomarkers that predict for 
response to cisplatin or AC chemotherapy in BRCA mutation carriers, including 
homologous recombination deficiency (HRD) using an assay developed by Myriad 
Genetic Laboratories. 
• To determine if 3-year recurrence-free survival (RFS) is significantly better for germline 
BRCA mutation (gBRCAm) carriers with newly diagnosed HER2-negative breast cancer 
allocated to cisplatin vs.AC chemotherapy.  
• To determine if 3-year RFS is significantly improved for gBRCAm carriers who achieved 
pCR compared with those who did not. 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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2. BACKGROUND  
2.1 
BRCA-related Breast Cancer 
 
Breast cancers that develop in women with germline mutations in the genes BRCA1 or BRCA2 
comprise approximately 5% of all breast cancers3 and women with these mutations have up to a 
90% chance of developing breast cancer.4,5 BRCA1 and BRCA2 are essential to multiple aspects 
of DNA repair, including the repair of double strand (DS) DNA breaks through the process of 
homologous recombination (HR), and in preventing apoptosis.6 
 
Approximately 80% of BRCA1-associated breast cancers lack estrogen receptor (ER), 
progesterone receptor (PR), and amplification of the growth factor receptor HER2, thus being 
known as “triple-negative” breast cancers (TNBC).7,8 BRCA1-related breast cancers share 
several phenotypic and molecular features with sporadic TNBC, including low or absent 
expression of hormone receptors and HER2, high histologic and nuclear grade, high mitotic 
index and expression of basal cytokeratins and EGFR.8-12 In addition, by gene expression 
profiling, the majority of BRCA1-related and sporadic TNBC cluster within the basal 
subgroup.13 Furthermore, there seems to be a set of characteristic cytogenetic changes in BRCA1-
associated breast cancers, a number of which have been described in sporadic basal-like cancers, 
including loss of 5q and frequent p53 mutations.14-20  
 
BRCA1 is rarely mutated in sporadic breast cancers,21 but the pathological and molecular 
parallels described above have led to speculation that BRCA1, or associated pathways, can 
become inactivated in triple-negative tumors via other mechanisms. In fact, recent studies have 
shown that a proportion of sporadic basal-like breast cancers may have a dysfunctional BRCA1 
pathway due to gene promoter methylation or transcriptional inactivation. While there are 
conflicting reports regarding the function of BRCA1 and the methylation status of the 
corresponding gene promoter in relation to the phenotype of sporadic breast cancers,22-24 one 
report did indicate that BRCA1 mRNA expression was twofold lower in 37 basal-like sporadic 
breast cancers than in controls matched for age and grade (p=0.008).25 Additionally, ID4, a 
negative regulator of BRCA1, was expressed at a 9-times higher level in basal-like breast 
cancers (p<0.0001).25 These findings suggest that a BRCA1 deficiency might underlie the triple-
negative phenotype in at least some sporadic cancers, but this deficiency might happen via 
several mechanisms. 
 
Several studies have shown that basal breast cancers are more aggressive than other molecular 
subtypes of breast cancer and are associated with a shorter survival and increased chance of 
relapse. 9,26,27 However, basal-like breast cancers have also been found to be more responsive to 
doxorubicin containing preoperative chemotherapy than luminal and normal-like breast 
cancers.28 
 
In contrast, there are no consistent pathologic features of BRCA2-associated breast cancers; like 
non-hereditary cancers, they are most often ER-positive (ER+). However, when compared to 
ER+ sporadic breast cancers, ER+ breast cancers in women with germline BRCA1 mutations are 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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more often of invasive ductal type with a high mitotic rate, pushing margins, and less tubule 
formation.29,30 
2.2 
Cisplatin in Breast Cancer 
 
Platinum was studied in breast cancer in the 1970s and was shown to be active when 
given early in the course of the disease, but it was not adopted, perhaps because of the 
superior therapeutic index of other drugs then under development (the taxanes). The drug 
was initially tested in patients with advanced breast cancer, both as a single agent and in 
combination with other drugs. Small studies demonstrated objective response rates ranging from 
42% to 54% with the use of cisplatin as a single agent, but response rates were lower in women 
who had received prior chemotherapy for metastatic disease.31-33 When cisplatin was given after 
other chemotherapy, the response rate fell to 0-9%.34-37 
 
Notably, these studies used cisplatin in patients regardless of ER, PR, and HER2 status. Several 
combination regimens were also explored, particularly cisplatin combined with taxanes, but there 
seemed little reason to continue these combinations when the taxanes were found to be so active 
and relatively nontoxic.38 There was also interest in the evaluation of combined treatment with 
docetaxel and platinum. In several studies in unselected cases of metastatic disease, the overall 
response rate with this combination regimen was around 50%, even with prior adjuvant 
anthracycline therapy.38 
 
There has recently been renewed interest in cisplatin for the treatment of breast cancer, in part 
because of improved strategies for managing its side effects, particularly nausea. A 2004 phase II 
study of preoperative paclitaxel and cisplatin demonstrated a 28% complete response rate and a 
63% partial response rate in patients enrolled without regard to ER, PgR, and HER2 status22.  
 
Because of the many biologic similarities between BRCA1-associated breast cancers and 
sporadic (non-BRCA-associated) TNBC, and the rationale for cisplatin therapy in BRCA1 
deficient breast cancers (see section 2.3 below), two prior DF/HCC studies have evaluated the 
pathologic complete response (pCR) rate of pre-operative cisplatin in TNBC. Silver et al 
demonstrated that six (22%) of 28 patients achieved pathologic complete responses, including 
both patients with BRCA1 germline mutations; 18 (64%) patients had a clinical complete or 
partial response.39 In the second trial, cisplatin and bevacizumab were administered pre-
operatively to women with TNBC; both BRCA1 and BRCA2 mutation carriers achieved pCR, as 
did 15% of women without mutations.40 Of note, in neither pre-operative cisplatin trial did 
women receive only cisplatin as their systemic therapy.  All women received standard adjuvant 
chemotherapy after surgery, because there are no data that a pCR with cisplatin alone is 
sufficient to ensure good long-term outcome.  
 
Several ongoing studies are evaluating the benefit of platinum agents in sporadic breast cancer. 
For example, the current CALGB neoadjuvant trial (CALGB 40603) in women with TNBC 
includes an assessment of the role of carboplatin in addition to standard AC/T chemotherapy 
with or without bevacizumab. 
 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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2.3 
Neoadjuvant Chemotherapy 
 
For patients with operable breast cancer, chemotherapy can be administered either after surgical 
resection of the cancer (i.e., adjuvant therapy) or prior to tumor excision, as neoadjuvant, or 
preoperative chemotherapy. While there is no survival advantage associated with use of 
preoperative compared to adjuvant chemotherapy41, there are several theoretic advantages to 
neoadjuvant chemotherapy including: downstaging the cancer to allow breast preservation in a 
patient who would otherwise require mastectomy; the ability to assess response to chemotherapy; 
decreasing drug resistance by earlier exposure of the tumor (including micrometastases) to 
chemotherapy.42 Several studies have shown that breast cancer patients, including those with 
basal-like breast cancers, who achieve a complete pathologic response (pCR) to preoperative 
chemotherapy have improved disease free and overall survival compared to those with residual 
disease at surgery. 42-46 
2.4 
Cisplatin in BRCA-related Breast Cancer 
 
As predicted by cell line, animal and human tumor data, and based on the recognition of  the 
importance of BRCA1 and BRCA2 in DNA repair pathways, it has been hypothesized that 
BRCA-deficient cancers, including breast cancers, may be particularly vulnerable to 
chemotherapy, such as platinum agents, that create DS DNA breaks through interstrand cross-
links. 
 
Several groups have demonstrated that tumor cell lines (human breast and ovary) deficient in 
BRCA1 are unusually sensitive to the DNA cross-linking agents, including cisplatin and 
mitomycin, and that this sensitivity is reversed with either BRCA1 upregulation or restoration of 
BRCA1 function 4-8, 24.47 In one study, treatment with cisplatin produced a dose-dependent 
reduction in cell growth in breast cell lines after 48 hours of treatment 8.47-51 The BRCA1 
defective cell line was 2-3 fold more sensitive to cisplatin compared with BRCA1 competent cell 
lines. This data suggests that cisplatin may be a good agent for BRCA1- mutated breast cancer.  
 
A mouse model with knockout of p53 and BRCA1 in mammary tissue has been developed by 
Jonkers. These mice develop ER-negative, high grade invasive ductal cancers that stain for basal 
cytokeratins, similar to the BRCA1-associated breast cancers found in humans. The tumors that 
develop in these mice do not develop resistance to cisplatin, though resistance does develop to 
doxorubicin.52,53 
 
Cisplatin has been shown to be effective in treating newly diagnosed breast cancer in BRCA 
mutation carriers in clinical trials, but data are limited. In a DF/HCC neoadjuvant trial using 
cisplatin in women with TNBC both women with BRCA1 mutations in the trial achieved a 
pCR.39  In a second trial using cisplatin and bevacizumab in women with TNBC, 2 of 7 BRCA1 
and 1 of 1 BRCA2 mutation carriers achieved pCR.40 These studies formed the basis of a trial of 
neoadjuvant cisplatin in women with BRCA1 founder mutations in Poland. In that ongoing trial, 
18 of 25 (72%) BRCA1 carriers reported to date have had a pCR using cisplatin.54  However, 
neither in the DF/HCC cisplatin trials nor in the Polish trial did women receive only cisplatin as 
their systemic therapy.  All women received standard adjuvant chemotherapy after surgery, 
because there were and are no data that a pCR with cisplatin alone would be sufficient to ensure 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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good long-term outcome.  Further, all three of these trials were single arm trials, so there have 
been no studies directly comparing response to cisplatin alone to response to more standard 
combination chemotherapy regimens.   
 
Of note, almost no data exists regarding the efficacy of cisplatin in BRCA2-associated or BRCA-
related ER-positive breast cancers. However, the previously mentioned Dana-Farber/Harvard 
Cancer Center (DF/HCC) study evaluating preoperative cisplatin in patients with TNBC 
included 3 patients with a BRCA2 mutation. Results showed that women with TNBC and a 
BRCA2 mutation were responsive to cisplatin, but at least one progressed through treatment 
(unpublished data). The DF/HCC trial evaluating ciplatin in combination with bevacizumab in 
patients with TNBC also included one patient with a BRCA2 mutation; that patient achieved a 
pCR after cisplatin/bevacizumab therapy (manuscript pending). 
 
Despite the lack of data addressing the efficacy of cisplatin in BRCA2 and/or BRCA-related ER-
positive breast cancers, the same biologic defect thought to predict for the responsiveness of  
BRCA1-related breast cancers to cisplatin—a defect in homologous recombination (HR)—also 
exists in BRCA2-related breast cancers. In addition, poly(ADP-ribose) polymerase (PARP) 
inhibitors are novel agents that exploit a defect in HR through synthetic lethality. A phase 2 
study evaluating olaparib, a PARP inhibitor, as monotherapy in women with germline BRCA 
mutations and advanced breast cancer resulted in a 41% response rate when used at the optimal 
dose.55 Responses were achieved in both BRCA1 and BRCA2 breast cancers, underscoring the 
shared biologic defect in these cancers that also predicts for sensitivity to cisplatin. Likewise, 
responses were seen in both ER-negative and ER-positive BRCA-related breast cancers. 
2.5 
Tissue Biomarkers of Response to Cisplatin 
 
In BRCA1 or BRCA2 germline mutation carriers, functionally relevant defects in homologous 
recombination are thought to occur only upon loss of the remaining wild type allele of either 
BRCA1 or BRCA2.  Studies on carefully microdissected tumor samples and quantitative 
analysis of mutant vs. wild type allelic copy number have found that a majority (81-89%) of both 
ER+ and ER- breast cancers in BRCA1 mutation carriers have loss of the wild type allele of 
BRCA1 56.  Thus, a sizable minority of tumors from BRCA mutation carriers does not have loss 
of the wild type BRCA1 and would not be expected to have functional defects in HR or be 
sensitive to drugs targeting defective HR such as cisplatin. Therefore, assays for loss of 
heterozygosity or loss of wt BRCA alleles may be predictive of response to cisplatin based 
therapy. 
 
Loss of functional BRCA1 causes the spontaneous formation of triradial and quadriradial 
chromosome structures, which are cytologic indications of aberrant chromosome break repair 
and recombination 57. The resolution of these chromosome rearrangements at mitosis can lead to  
loss of large regions of maternal or paternal chromosomes resulting in allelic imbalance (AI) 
extending from the breakpoint to the telomere 58,59. In a recent study analyzing the pretreatment 
tumor tissue from two DF/HCC cisplatin-based neoadjuvant therapy trials in TNBC 39,40, we 
report that the number of regions of telomeric allelic imbalance (NtAI) was significantly 
associated with cisplatin sensitivity as determined by pathologic response in both trials (Fig 1) 60.  
 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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Figure 1. NtAI and cisplatin response in breast 
cancer. In two clinical trials, TNBC patients were 
given preoperative cisplatin (Cisplatin-1, Fig. 1 A-B) 
or cisplatin and bevacizumab (Cisplatin-2, Fig. 1 C-D). 
Cisplatin resistant tumors are indicated in black, 
cisplatin sensitive tumors are indicated in red. Tumors 
with germline mutations in BRCA1/2 are indicated 
with triangles. A and C. Box plots showing NtAI 
distribution in cisplatin resistant and sensitive tumors. 
B and D. Receiver operating characteristic curves 
showing the ability of NtAI to predict for sensitivity to 
cisplatin. 
 
Among the few tumors from BRCA1 or 
BRCA2 mutation carriers that were analyzed 
in this study, those that achieved a pCR also 
displayed a high NtAI in pretreatment tumor 
samples whereas tumors with low levels of 
NtAI were resistant to cisplatin. Although the 
case numbers are limited, the results suggest 
that NtAI may be also predictive of cisplatin 
response among BRCA mutation carriers.  
We performed a parallel analysis of the 
cisplatin trial samples to identify specific DNA copy number differences and gene expression 
(mRNA) differences associated with cisplatin sensitivity. We found that only copy number gain 
of chr 15q26 and overexpression of both Bloom helicase (BLM) and Fanconi Anemia 
complimentation group I (FANCI) from this chromosome region were consistently and 
significantly associated with increased sensitivity to cisplatin therapy in both trials (unpublished 
results).   
 
Myriad Genetic Laboratories has developed a Homologous Recombination Deficiency (HRD) 
Assay that detects homologous recombination deficiency regardless of etiology or mechanism, as 
measured by levels of genomic instability and loss of heterozygosity. The assay is compatible 
with formalin-fixed paraffin-embedded (FFPE) tumor tissue. Statistically significant correlation 
with response to platinum in breast cancer in a neoadjuvant study of gemcitabine, carboplatin 
and iniparib was recently reported61 
 
The HRD Assay score was assessed in a cohort of 77 patients enrolled on PrECOG 0105 where 
pathologic response was assessed using the residual cancer burden (RCB) index.23 Forty-four 
tumors were obtained from responders (RCB 0/I) and 33 tumors were from non-responders 
(RCB II/III). Genome-wide SNP data was generated from Affymetrix MIP arrays (n=15), a 
custom Agilent SureSelect XT capture followed by sequencing on an Illumina HiSeq 2500 
(n=21), or using both assays (n=41). Sequencing scores were used for analysis when available 
and the correlation coefficient for samples analyzed using both assays was 0.76. Tumors were 
sequenced for BRCA1 and BRCA2 and variants classified as deleterious or suspected 
deleterious. Read coverage across each exon was used to detect large rearrangements. The HRD 
score was derived by count of the number of LOH regions (>15 Mb and < whole chromosome) 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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observed in the tumor genome. Germline and somatic BRCA1/2 mutation status was known in 
all patients and 19 tumors were classified as BRCA1/2 deficient: germline BRCA1 mutation 
(n=12), germline BRCA2 mutation (n=4), germline BRCA1&2 mutation (n=1), somatic BRCA1 
mutation (1), and somatic BRCA2 (1) mutation. Three mutation carriers had ER+/PR+ (>5%) 
breast cancer. The average HRD score for responders was 16.2 and the average score for 
nonresponders 11.2 (p=0.0003). 60 patients had HRD scores ≥10. No differences were noted 
between BRCA1/2 mutant vs. intact responders. If BRCA1/2 deficient samples were excluded 
(n=58), the association between response to treatment and HRD score remained significant 
(p=0.0006). In this group, out of 28 responders, 26 had HDR scores ≥ 10. Seventy-four percent 
of TNBC tumors had an HRD score of < 10 (n=74). Overall, 70% of patients with an HRD score 
of ≥10 or BRCA1/2 mutation responded compared with 12% of patients with an HRD score of < 
10 and intact BRCA1/2 (p=0.00002). Correlations between response and stage were not 
significant61. 
 
Among TNBC cases with BRCA intact (n = 56), the standard deviation (sd) for HRD score was 
5.7, and in the subset that received neoadjuvant chemotherapy, scores did not vary between 
responders (n=10, sd = 5.4) and non-responders (n=17, sd = 5.7). 
 
Three methods to evaluate HRD score have subsequently been developed: HRD-LOH, HRDTAI, 
and HRD-LST. Each of the three individual HRD scores measures HRD in a slightly different 
way. Depending on the cohort analyzed (Stanford Platinum, Birkbak cisplatin, BBL BRCA 
subtypes), the individual methods perform slightly differently. A Mean HRD Score can be 
calculated using the arithmetic mean of the three individual HRD scores. In each cohort 
analyzed, the Mean HRD score provides superior performance, and as the Mean HRD score is 
not optimized to any particular cohort, it is may be more generalizable than any one testing 
method (Myriad, internal communication). 
2.6 
Doxorubicin and Cyclophosphamide “AC” in BRCA-related Breast Cancer 
 
There is limited information regarding the effectiveness of combination alkylator and 
anthracycline-based chemotherapy in BRCA-associated breast cancers  In a retrospective analysis 
of patient records conducted in Poland, Byrski et al found that 11 of 51 (22%) BRCA1 mutation 
carriers treated for breast cancer with conventional neoadjuvant doxorubicin and 
cyclophosphamide (“AC”) had a pCR.62 Chappius et al reported that 4 (2 BRCA1 and 2 BRCA2) 
of 9 (44%) mutation carriers had a pCR to anthracycline-based neoadjuvant chemotherapy 
compared to 1 of 27 (4%) non-carriers (p=0.009), though the distribution of breast cancer 
subtype was not uniform  between these groups.63 In women with metastatic breast cancer, 
Kriege et al found no difference in the responsiveness of breast cancers to anthracycline 
chemotherapy between BRCA1 mutation carriers and those without a mutation. BRCA2 carriers, 
however, had a significantly increased response rate (89% vs 50%; P=.001), an unexpected 
result.64 
 
Recently, Arun et al 65 reported a retrospective analysis of  preoperative chemotherapy 
administered to 317 women who had undergone BRCA testing; 18% were BRCA1 mutation 
carriers, 7% BRCA2 carriers and 75% were non-mutation carriers. Ninety-five percent of the 
patients had received anthracycline-based chemotherapy. The pCR rate was significantly higher 

Neoadjuvant Cisplatin vs. AC in BRCA-positive breast cancer 
Protocol chair: Nadine Tung 
DF/HCC 12-258/TBCRC031                               
 
 
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in the BRCA1 carriers, 46%, compared to 13% in BRCA2 carriers and 22% in non-carriers (p = 
0.0008). Interestingly, the pCR rate among triple negative breast cancers was not different 
between BRCA1 mutation carriers and non-carriers. In multivariate logistic regression, both ER-
negativity and BRCA1 mutation were significant predictors of a pCR. The odds ratio for a pCR 
in BRCA1 carriers was 3.10 (p = 0.002). 
 
The disparate results between these studies may be related to the retrospective nature of these 
studies as well as to the relatively small number of BRCA mutation carriers evaluated. 
2.7 
Tissue Biomarkers of Response to Anthracyclines 
 
In 2010, we reported the identification of chr 8q22 amplification as a poor prognostic marker for 
ER-negative breast cancers despite adjuvant treatment with anthracycline-based chemotherapy.  
In vitro studies showed that siRNA knockdown of two genes from the 8q22 region, LAPTM4B 
and YWHAZ, resulted in increased sensitivity to anthracyclines but no change in sensitivity to 
taxanes or cisplatin. YWHAZ is a known anti-apoptotic protein possibly explaining its role in 
resistance to chemotherapy.  Overexpression of LAPTM4B, a lysosomal protein, resulted in 
retention of the anthracycline, doxorubicin, in the lysosomal compartment, delaying its 
appearance in the nucleus.  Finally, overexpression of these two 8q22 genes in pretreatment 
tumor biopsies was significantly associated with poor tumor response to neoadjuvant epirubicin 
monotherapy in women with primary ER-negative breast cancer (Li Y, Zou L.,Li Q, Haibe-
Kains B, et al. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance 
and recurrence of breast cancer.  Nat Med. 2010 Feb;16(2):214-8.). The BRCA mutation status 
of the patients from this trial is unknown; however, this mechanism of anthracycline resistance is 
plausible for tumors arising in BRCA mutation carriers as well. 
 
Tumor-associated Lymphocytes 
Several studies have shown the association between lymphocytic infiltrates in breast cancer 
and improved outcomes, including within the TNBC subgroup66,67. 
 
Loi et al. demonstrated that after anthracyline and taxane -based adjuvant chemotherapy in the 
BIG 02-98 trial, those patients whose TNBC had a higher degree of lymphocytic infiltration had 
a significantly better disease-free and overall survival66. Likewise, a retrospective analysis of 
TNBC from ECOG studies 2197 and 1199 demonstrated that stromal lymphocytic infiltration 
was a strong and independent prognostic factor for improved DFS, DRFI and OS after 
anthracycline and taxane-based adjuvant therapy67. 
2.8 
Rationale for Current Study 
Due to the variable response rates reported with anthracycline-based chemotherapy in BRCA-
associated breast cancers and the limited data using cisplatin in this population, it is important to 
directly compare cisplatin to a standard chemotherapy in women with BRCA-associated breast 
cancer.   The fact that the small single-arm cisplatin trial 62,54 has led some to call for the 
addition or even the substitution of cisplatin or carboplatin to the adjuvant or neoadjuvant 
treatment of women with BRCA mutations seems premature and underscores the need for 
prospective, randomized data.  

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To date, germline BRCA testing in women with newly diagnosed breast cancer has provided 
information used primarily for decisions about surgical choices (i.e. prophylactic mastectomies 
and bilateral salpingo-oophorectomies) and surveillance practices (e.g., breast MRI). Thus far, 
BRCA status has not influenced the choice of chemotherapy and the same regimens are used to 
treat breast cancer in BRCA mutation carriers and non-carriers. Therefore, genetic testing is 
often performed during or after chemotherapy administration. If, however, a non-standard 
chemotherapy regimen such as cisplatin is demonstrated to be superior to current standard 
regimens, management of newly diagnosed breast cancer would change since earlier BRCA 
testing would be necessary in order to select the optimal chemotherapy. 
 
3. PARTICIPANT SELECTION 
3.1 
Eligibility Criteria 
 
3.1.1 Participant must have a confirmed germline deleterious BRCA mutation. Participants 
with a BRCA1 or BRCA2 classified as “variant, suspected deleterious” by Myriad Genetics 
are also eligible for the trial. Participants with only a BRCA1 or BRCA2 VUS (variant of 
uncertain significance) are not eligible for this study.  
 
If a potential subject is considered high risk for carrying a BRCA1/BRCA2 mutation by 
NCCN criteria but does not have insurance coverage for testing or if results from available 
testing options will not be ready in time for enrollment in the study Myriad Genetic 
Laboratories may cover the cost of the test. Genetic testing does not have to be performed 
by Myriad Genetic Laboratories but a study-specific test request form is available for tests 
submitted to Myriad. This form may also be used for genetic testing which will be covered 
by the participant’s insurance and may lead to more expedited testing. 
 
3.1.2 Histologic documentation: Pathologic confirmation of invasive breast cancer by core or 
surgical biopsy (FNA alone is not adequate).   
 
3.1.3 Stage: Clinical T1 > 1.0 cm, T2 or T3, N0-3, M0.  
 
Participants with multicentric or bilateral disease are eligible if at least one lesion meets 
stage eligibility criteria for the study (i.e., ≥1.0 cm operable breast cancer) and no tumor 
is HER2-positive (3+ by IHC or ISH amplified > 2.0). In this circumstance, the 
investigator must determine which will represent the target lesion to be assessed for 
response. This should remain consistent throughout the study. The target lesion should be 
selected on the basis of its size (lesion with the longest diameter) and suitability for 
accurate repetitive measurements. 
   
3.1.4 HER 2 status: Tumors must be HER2 negative defined as HER2 0 or 1+ by 
immunohistochemical (IHC) assays and /or lack of gene amplification by FISH defined as 
a ratio < 2 on invasive tumor. A tumor is considered HER2+ if 3+ by IHC or ISH amplified 
> 2.0. (For questions about HER2 status, investigators are advised to refer to the most 
recent ASCO guidelines.68 )  

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3.1.5 ER and PgR status by immunohistochemistry must be known.   ER positive tumors are 
allowed in patients for whom the treating investigator has determined neoadjuvant 
chemotherapy is appropriate. 
 
3.1.6 Breast imaging should include imaging of the ipsilateral axilla. For subjects with a 
clinically negative axilla, a sentinel lymph node biopsy will be performed either up front or 
after preoperative therapy at the discretion of the subject’s physicians; for subjects with a 
clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be 
performed prior to registration to confirm the presence of metastatic disease in the lymph 
nodes. While not mandated by the protocol, it is strongly recommended that participants 
with positive lymph nodes undergo a level I and II lymph node dissection at the time of 
definitive surgery.   
 
Participants with axillary adenopathy only are not eligible for this study.   
 
3.1.7 Cardiac ejection fraction (LVEF) > institutional lower limit of normal by MUGA/RVG or 
ECHO  
 
3.1.8 Women or men > 18 years of age 
 
3.1.9 ECOG performance status 0 or 1 
 
3.1.10 Laboratory Evaluation 
 
• Absolute neutrophil count (ANC) 
> 1,500 / mm3 
• Platelet count 
> 100,000/ mm3 
• Bilirubin 
< 1.5 x institutional upper limits of normal (ULN); 
if patient has documented Gilbert’s syndrome 
bilirubin must be < 3 X institutional ULN 
• ALT, AST, ALK Phos 
< 2.5 x institutional ULN 
• Glucose 
< 200 mg/dl 
• Hemoglobin 
> 9 g/dl 
• Creatinine  
< 1.5 mg/dl 
OR 
 
• Creatinine clearance (can be 
calculated by 24 hour urine or by  
the Cockroft-Gault formula in 
Appendix B) 
 
> 60 cc/min 
3.1.11 Life expectancy of greater than six months 
 
3.1.12 Use of an effective means of contraception is required in subjects of childbearing potential 
since cisplatin, doxorubicin and cyclophosphamide agents are known to be teratogenic. 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately.  Women of child-bearing 

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potential and men must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of study participation 
3.1.13 Ability to understand and the willingness to sign a written informed consent document 
3.1.14 Individuals with a history of other malignancies are eligible if they have been disease-free 
for at least 5 years and are deemed by the investigator to be at low risk for recurrence of 
that malignancy and did not receive prior chemotherapy. Individuals with the following 
cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, 
and basal cell or squamous cell carcinoma of the skin. 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
 
3.2.1 Any prior anthracycline or platinum based therapy at any time. 
 
3.2.2 Any prior treatment for the current breast cancer, including chemotherapy, hormonal  
therapy, radiation or experimental therapy. 
 
3.2.3 Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for DCIS or 
breast-conserving treatment and hormonal therapy for DCIS or invasive cancer. 
 
3.2.4 Peripheral neuropathy of any etiology that exceeds grade 1 
 
3.2.5 Significant hearing loss that would prevent cisplatin administration.  
 
3.2.6 Renal dysfunction for which exposure to cisplatin would be unsafe or require cisplatin dose 
modification (i.e., Cre > 1.5 mg/dl or GFR < 60 cc/min). 
 
3.2.7 Use of any other investigational or study agents. 
 
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to study drugs (e.g. cisplatin).  
 
3.2.9 Uncontrolled intercurrent illness including, but not limited to ongoing or active systemic 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, steroid dependent asthma, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.10 Any condition that would prohibit administration of corticosteroids 
 
3.2.11 Pregnancy or breast-feeding because the chemotherapy agents in this study have the 
potential for teratogenic or abortifacient effects as well as unknown but potential risks in 
nursing infants.  
 

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3.2.12 Uncontrolled diabetes (If non-fasting blood sugar > 200 mg/dl, perform a fasting blood 
sugar which must be < 200mg/dl).  
 
3.2.13 Any pre-existing medical condition that would represent toxicity in excess of grade 1 as 
measured by CTCAE (NCI Common Toxicity Criteria for Adverse Events version 4.03) 
unless the symptom is not considered medically significant by the treating investigator 
(e.g., alopecia) 
 
3.2.14 Known HIV-positive individuals on combination antiretroviral therapy are ineligible 
because these individuals are at increased risk of lethal infections when treated with 
marrow-suppressive therapy. 
 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age 
or race in the clinical trial outlined.  This trial is open to the accrual of men and women. 
 
 
4. REGISTRATION PROCEDURES 
4.1 
 General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (ODQ) central registration system. Registration must occur prior to the 
initiation of therapy. Any participant not registered to the protocol before treatment begins 
will be considered ineligible and registration will be denied.  
 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the ODQ protocol-specific eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a 
participant does not receive protocol therapy following registration, the participant’s registration 
on the study may be canceled. Notify the ODQ Registrar of registration cancellations as soon as 
possible. 
4.2 
Registration Process for Dana Farber/Harvard Cancer Center (DF/HCC) and 
Dana Farber/Partners Cancer Care (DF/PCC) Institutions 
 
The ODQ registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin treatment during 
off-hours or holidays, call the ODQ registration line at 
and follow the instructions 
for registering participants after hours. 
   
The registration procedures are as follows: 
 

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1. Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments. 
 
2. Complete the ODQ protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. 
To be eligible for registration to the protocol, the participant must meet all inclusion 
and exclusion criterion as described in the protocol and reflected on the eligibility 
checklist.   
  
3. Fax the eligibility checklist(s) and all pages of the consent form(s) to the ODQ at 
 
  
4. The ODQ Registrar will (a) review the eligibility checklist, and (b) register the 
participant on the protocol, and (c) randomize the participant when applicable. 
  
5. An email confirmation of the registration will be sent to the Overall PI, study 
coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration. 
4.3 
Guidelines for External and TBCRC Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Project Manager.   
 
Following registration, participants must begin protocol treatment within 7 days. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
4.4 
Registration Process for External  and TBCRC Sites 
 
To register a participant, the following documents should be completed by the research nurse or 
data manager and emailed to the Project Manager at 
or faxed to 
 
• Confirmation of BRCA1 and/or BRCA2 mutation 
• Copy of required laboratory tests including: Hematology (CBC w/differential), 
Serum Chemistries (potassium, BUN, creatinine, magnesium, total bilirubin, SGOT 
(AST), SGPT (ALT), and Alkaline Phosphatase, and pregnancy test (for women of 
child-bearing potential only). 
• Signed informed consent form 
• HIPAA authorization form (if separate from the informed consent document) 
• Completed ODQ Eligibility Checklist 
• Breast imaging documentation (MRI/US/Mammogram) 
• MUGA or Echocardiogram report 
• EKG report 
• Pathology report and documentation of ER/PR and HER2+ status 

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• Clinic visit note documenting history and physical exam 
  
To complete the registration process, the Project Manager will 
• Register the participant on the protocol with the ODQ 
• E-mail the confirmation of registration with the participant study number to the 
participating site 
• Call the research nurse or data manager at the participating site and verbally confirm 
registration 
 
NOTE: Registration and randomization with the ODQ can only be conducted during the 
business hours of 8:00 AM and 5:00 PM Eastern Standard Time Monday through Friday. 
Same day treatment registrations will only be accepted with prior notice and discussion with the 
DF/HCC Project Manager. 
 
 
5. TREATMENT PLAN  
5.1 
Randomization 
 
Participants will be randomized to either preoperative cisplatin or doxorubicin plus 
cyclophosphamide (AC) in a ratio of 1:1 using block randomization. Randomization will be 
stratified by ER status (positive or negative). 
5.2 
Pre-chemotherapy Surgical Evaluation 
 
Prior to neoadjuvant chemotherapy, some clinicians may choose to determine the pathologic 
axillary node status. This can be done by whatever means the surgeon feels is appropriate. This 
decision should be made in consultation with the treating surgeon and radiation therapist. For 
participants with clinically involved axillary nodes by exam or imaging, axillary metastases 
should be confirmed by FNA, core biopsy or axillary surgery prior to chemotherapy. 
5.3 
Pre-chemotherapy Research Core Biopsy (see Appendix E) 
 
Research breast core biopsies of the target lesion for all participants prior to initiating protocol 
chemotherapy are desired, but are optional. It is strongly recommended that core biopsies be 
image-guided. A clip should be placed in the target lesion at the time of diagnostic biopsy. If it 
was not, a clip should be placed at the time of the research biopsy. If staging is to be done, 
research biopsy is to be performed after staging is completed. 
 
Ideally six (6) core biopsies will be obtained: 
 
• Two cores should be frozen in OCT; each core should be frozen in a separate cassette. 
The individual preparing the frozen cores should read appendix E and watch the 
teaching video which has been made available to participating sites. (see 
 

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All research biopsy samples should arrive during the week by Friday morning. If a biopsy 
must be performed at one of the non-Boston sites on Friday, the specimens should be stored over 
the weekend and shipped on Monday.  Frozen specimens should be stored in a -80 freezer until 
shipment; specimens in RNA Later and formalin should be stored at room temperature until 
shipment. 
 
The frozen cores should be shipped on dry ice.  Cores in RNA Later and in formalin should be 
shipped at room temperature. It is recommended that all research biopsies be shipped together in 
the mailing kit provided by the study. If so, the bottom of the shipping container should have dry 
ice for the frozen specimens; no dry ice should be put in the top section for the specimens in 
RNA Later and formalin.  
 
All biopsy samples will be stored in the DF/HCC Core Blood and Tissue Bank indefinitely.  
Protocol defined assays will be performed during the course of this study.  If any tissue remains 
after the protocol-defined assays are complete, it may be used for future correlative studies until 
all supplies are exhausted.   
5.4 
Overview of Preoperative Chemotherapy 
 
This study includes a preoperative phase with participants randomized to either cisplatin or 
doxorubicin and cyclophosphamide (AC), followed by surgery. Treatment will be administered 
on an outpatient basis. Protocol treatment must begin with 7 days of randomization. Expected 
toxicities and potential risks as well as dose modifications for cisplatin, doxorubicin and 
cyclophosphamide are described in Section 6 (Expected Toxicities and Dosing Delays/Dose 
Modification).  
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
 
Preoperative Chemotherapy 
 
Arm A “AC”: 
Doxorubicin: 60 mg/m2 IV q 2-3 weeks* x 4 cycles plus 
Cyclophosphamide: 600 mg/m2 q 2-3 weeks* x 4 cycles  
 
OR  
 
Arm B: 
Cisplatin: 75 mg/m2 IV q 3 weeks x 4 cycles  
5.5 
Pre-treatment Criteria 
   
Requirements for Day 1 for any cycle for cisplatin or AC: 
 
• ANC must be > 1,000 /mm3 
• Platelets must be > 100,000 /mm3 

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• Creatinine must be < 1.5 mg/dl or creatinine clearance ≥ 50 cc/min. (can be 
calculated by 24 hour urine or by  the Cockroft-Gault formula in Appendix B) 
• All non-hematologic toxicities must be < grade 1 (unless considered medically 
insignificant by the treating investigator) 
 
Chemotherapy may be delayed up to 3 weeks. If chemotherapy cannot be delivered after a 3 
week delay, because of toxicity, the participant must be removed from the study. 
5.6 
Agent Administration  
 
Note: Doses should be based on actual body weight. The participant should be weighed each 
cycle. 
 
Minor schedule changes owing to observed holidays, inclement weather, and so forth are 
permitted (+/- 3 days). 
5.6.1 Arm A: Doxorubicin, Cyclophosphamide (AC) 
 
Table 5.1: Arm A: Doxorubicin plus Cyclophosphamide (AC) 
Agent 
Pre-
medications; 
Precautions 
Dose 
Route 
Schedule 
Supportive 
Therapy 
Doxorubicin 
N/A 
60 mg/m2  
IV push or 
infuse 
according to 
local policy 
q 2-3 
weeks* 
x 4 
cycles 
• GCSF if 
receiving AC 
q 2 weeks** 
• Anti-emetic 
therapy at 
MD 
discretion 
Cyclophos-
phamide 
N/A  
600 mg/m2 
IV infusion 
according to 
local policy 
q 2-3 
weeks* 
x 4 
cycles 
*Scheduling of AC: Participants with ER-negative breast cancers randomized to Arm A must 
be treated with AC on an every 2 week schedule. For ER-positive breast cancers, the choice of 
a two or three week schedule for AC is left to the treating physician’s discretion.   
** GCSF [i.e Filgrastim (5 μg/kg SQ) days 3-10, pegfilgrastim (6 mg SQ) day 2 of each cycle, 
filgrastim-sndz or other biosimilars per institutional guidelines] is mandatory if AC is 
administered every 2 weeks. If AC is administered every 3 weeks, growth factor may be 
administered at the physician’s discretion. 
 
• Dose: Doxorubicin 60 mg/m2 IV bolus plus 
Cyclophosphamide 600 mg/m2 IV  
 
• Scheduling of AC: Participants with ER-negative breast cancers randomized to Arm 
A must be treated with AC on an every 2 week schedule. For ER-positive breast 

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cancers, the choice of a two or three week schedule for AC is left to the treating 
physician’s discretion.   
 
• AC chemotherapy may be administered per institutional guidelines. 
 
• Supportive Care:  
 
o GCSF is mandatory if AC is administered every two weeks. If AC is 
administered every 3 weeks, growth factor use is optional. GCSF may 
include Filgrastim (5μg/kg) days 3-10, pegfilgrastim (6 mg SQ) day 2 of 
each cycle, filgrastim-sndz or other biosimilars per institutional guidelines.  
o Anti-emetics: subjects may be given anti-emetics per institutional 
guidelines. 
5.6.2 Arm B: Cisplatin 
 
Table 5.2: Arm B: Cisplatin 
Agent 
Pre-medications; 
Precautions 
Dose 
Route 
Schedule 
Supportive Therapy 
Cisplatin 
Hydration and 
magnesium 
supplementation 
are given per 
institutional 
guidelines 
 
75 mg/m2 
IV bolus 
over 60 
minutes 
q 3 
weeks 
for 4 
cycles 
• Post-treatment 
hydration 
• Growth factors at 
MD discretion 
• Magnesium and/or 
potassium 
supplementation at 
MD discretion 
• Antiemetic therapy 
*See section 5.6.2 for an example Cisplatin treatment schedule and pre-medication details. 
** Use of GCSF is left to the treating physicians’ discretion. 
 
• Dose: Cisplatin 75 mg/m2 IVB q 3 weeks for 4 cycles 
 
• Cisplatin may be administered according to institutional guidelines at 
participating sites. An example schedule for Cisplatin administration is available 
upon request.   
• Supportive Care: It is important for the participant to remain well hydrated after 
cisplatin administration, especially for the next 24 hours. Oral hydration should be 
encouraged and nausea/vomiting must be well controlled. 
o Magnesium supplementation: At the physician’s discretion, participant may 
take 500mg Magnesium Gluconate QD for 7 days (or equivalent). Magnesium 
level will be checked on day 7-10 and if < 1.8mg/dl, then magnesium 
supplementation should be continued and adjusted at the physician’s discretion. 
The schedule of supplementation is at the treating physician's discretion and is not 
mandatory. 

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Subjects may receive intravenous fluids on study. Institutional guidelines should be 
followed for AC and cisplatin. Specific guidelines for cisplatin (one possible regimen) 
are outlined in section 5.6.2.  
5.11.4 Growth Factors 
Growth factor support with GCSF (i.e. filgrastim, pegfilgrastim, filgrastim-sndz or other 
biosimilars per institutional guidelines) must be used during treatment with AC if 
administered every two weeks. Growth factor support may be used with cisplatin or AC 
administered every 3 weeks, at the treating physician’s discretion. 
 
Erythropoietin and related congeners may be administered for anemia associated with 
therapy or otherwise at the discretion of the treating physician. 
5.12 Duration of Therapy 
 
Preoperative therapy with cisplatin or AC is planned for 8-12 weeks (i.e., 8 weeks for dose dense 
AC and 12 weeks for cisplatin or AC administered every 3 weeks). Preoperative therapy will be 
followed by surgery no later than 42 days after the last dose of AC or cisplatin.  
5.13 Criteria for Removal from Protocol Therapy  
 
Participants will be removed from the protocol therapy for any of the following: 
 
• Any grade 4 non-hematologic toxicity 
• Progression of tumor by physical exam or imaging study 
• Treatment delay of more than 3 weeks for any toxicity-related reason 
• A toxicity develops which, in the opinion of the investigator, precludes further 
therapy, or 
• For safety reasons the investigator considers it to be in the best interest of the 
participant that they be withdrawn, or 
• Participant decides to withdraw consent from the study 
• Patient non-compliance 
 
The reason for treatment removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with the participant.   
 
A ODQ Treatment Ended & Off Study Form should also be filled out when a participant 
completes study treatment and again when they come off study. Participants are considered 
off treatment either on the date of the last protocol chemotherapy treatment or the date a 
cross-over (alternative) treatment decision was made.  
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Nadine Tung MD at 
 
 and the Coordinating Center designee.   

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5.14 Duration of Follow Up  
 
All patients will be followed for 3 years after surgery or until death, whichever occurs first. For 
patients who change to cross-over/alternative neoadjuvant therapy, data on type of post-protocol 
treatment and response to therapy at definitive surgery will be collected.  
 
During follow up, information on survival, recurrence, additional treatment, surgery, and 
radiation will be collected from a participant’s medical record via progress notes and results from 
any routine tests or procedures, when available.  For participants that are no longer being seen at 
their treating institution, they may be contacted directly for survival assessment and to report any 
further anti-cancer treatment, annually for a total of 3 years. A participant’s current treating 
physician or designee may also be contacted for this follow up information. The questionnaire in 
Appendix I outlines the specific information that should be captured by the study team. 
 
Adverse events will be followed until 30 days after last dose of protocol treatment. Any 
treatment-related grade 3 or 4 AEs present 30 days after the last dose of protocol treatment 
should be followed until resolved to < grade 2. This AE follow up can occur via phone call.  
5.15 Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Three year follow up completed 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, 
must be documented in the case report form (CRF).  
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the Coordinating Center.  
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Version of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE version 4.03) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 

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toxicity has resolved or is deemed irreversible. Participants may not come off study until all 
treatment related AEs have resolved to < grade 2. 
6.1 
Anticipated Toxicities 
6.1.1 Cisplatin 
 
Nephrotoxicity 
The major dose-limiting toxicity of cisplatin is cumulative nephrotoxicity. Tubular 
necrosis of both proximal and distal renal tubules has been noted in 28% to 36% of 
subjects treated with a single dose of 50 mg/m2. It is first noted during the second week 
after a dose and is manifested by elevations in BUN and creatinine, serum uric acid 
and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and 
severe with repeated courses of the drug. Renal function must return to normal before 
another dose of cisplatin can be given. Nephrotoxicity can be reduced by IV hydration 
and mannitol diuresis as well as avoidance of nephrotoxic drugs such as aminoglycoside 
antibiotics. 
 
Nausea and Vomiting 
Cisplatin causes moderate to severe nausea and vomiting in almost all subjects treated. 
Nausea and vomiting usually begin within 1 to 4 hours after treatment and last up to 24 
hours. Various degrees of vomiting, nausea, and/or anorexia may persist for up to 1 week 
after the treatment. Delayed nausea and vomiting (beginning 24 hours or more after 
chemotherapy) has occurred with complete emetic control on the day of cisplatin therapy. 
The use of prophylactic and continuing antiemetic medication reduces these adverse 
effects. 
 
Hypomagnesemia 
Hypomagnesaemia have been reported in subjects treated with cisplatin and is probably 
related to renal tubular damage. It may become severe enough to cause tetany. Generally, 
serum electrolytes return to normal levels when cisplatin is discontinued and 
supplemental electrolytes are administered. 
 
Ototoxicity 
Ototoxicity has been observed in up to 31% of subjects treated with a single dose of 
cisplatin (50 mg/m2) and is manifested by tinnitus and/or hearing loss in the high 
frequency range (4000 to 8000 Hz). Decreased ability to hear normal conversational 
tones may occur occasionally. Ototoxicity can be more severe in children than in adults 
and more frequent and severe with repeated administration. Hearing loss can be unilateral 
or bilateral and is usually not reversible. During treatment with cisplatin, it is necessary to 
monitor hearing at each visit. An audiogram is recommended after a cumulative dose of 
300 mg/m2. Subsequent doses of cisplatin should not be given until an audiometric 
analysis indicates that auditory acuity is within normal limits. 
 
Myelosuppression 
Myelosuppression occurs in 25% to 30% of subjects treated with cisplatin. The nadirs in 

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circulating platelets and leukocytes occur between days 18 and 23, with most subject 
recovering by day 39. Leukopenia and thrombocytopenia are more pronounced at higher 
doses (>50 mg/m2). Anemia (a decrease in hemoglobin of 2 g/100 ml) occurs at 
approximately the same frequency and with the same timing as leukopenia and 
thrombocytopenia. 
 
Neurotoxicity 
Cisplatin neurotoxicity is characterized by peripheral neuropathies, which are sensory in 
nature but can also include motor difficulties such as reduced deep-tendon reflexes and 
leg weakness. The symptoms usually occur after prolonged therapy (4 to 7 months). 
Cisplatin therapy should be discontinued when serious neuropathy develops. The 
neuropathy, however, may progress further even after discontinuation of treatment. 
 
Drug Interactions 
Aminoglycosides: Cisplatin may enhance the nephrotoxic effect of Aminoglycosides. 
Loop Diuretics: May enhance the nephrotoxic effect of Cisplatin. Loop Diuretics may                            
enhance the ototoxic effect of Cisplatin. Phenytoin: Cisplatin may decrease the serum 
concentration of Phenytoin. 
6.1.2 Doxorubicin  
 
Hematologic 
Leucopenia (dose-limiting), thrombocytopenia, anemia nadir in 10-14 days with recovery 
usually in 21 days. In this study, doxorubicin is given every 14 days, as dose dense 
AC(ddAC). Growth factor support is required. 
 
Dermatologic 
Alopecia (usually complete; reversible); radiation recall reactions; increased sensitivity to 
sunlight. 
 
Gastrointestinal 
Nausea and vomiting (doxorubicin is generally considered moderately to highly 
emetogenic), anorexia, diarrhea, mucositis (stomatitis, esophagitis). 
 
Cardiovascular 
Cardiomyopathy may occur and is related to total cumulative lifetime dose. This risk for 
cardiomyopathy increases with total doses greater than 450 mg/m2. 
 
ECG changes and less often, arrhythmias are seen. Rarely, sudden death has occurred. 
 
Other 
Red discoloration of urine for 24-48 hours after drug administration.  
Doxorubicin is a vesicant and can cause tissue necrosis if extravasated.  
6.1.3 Cyclophosphamide  
 
Myelosuppression 

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Primarily leucopenia, but also thrombocytopenia. 
 
Gastrointestinal 
Nausea and vomiting (cyclophosphamide is considered moderately to highly emetogenic; 
onset of symptoms is somewhat delayed at 6-10 hours after administration). 
 
Genitourinary 
Sterile hemorrhagic cystitis (related to the accumulation of the acrolein metabolite in the 
bladder; minimize with hydration). 
 
Endocrine 
Amenorrhea and possible sterility 
6.2 
Toxicity Management 
 
All toxicities should be graded according to the Common Terminology Criteria for Adverse Events 
(version 4.03). 
 
The goal is to attempt to administer full doses of chemotherapy on schedule. All dose 
reductions are maintained in subsequent cycles. Any participant whose treatment is delayed 
must be evaluated on a weekly basis until adequate hematologic and non-hematologic 
parameters have been met.  
 
Once a chemotherapy dose has been decreased for toxicity, that dose should be maintained 
through subsequent cycles and should not be re-escalated. 
 
No more than two dose reductions are allowed. If further dose reduction is required, participant 
should be removed from the study. 
 
If chemotherapy is delayed > 3 weeks for any toxicity, participant must be removed from study 
6.2.1 Dose Delay: chemotherapy must be delayed if the following criteria are not met on Day 1 
of any cycle: 
 
• ANC must be > 1,000 /mm3 
• Platelets must be > 100,000 /mm3 
• Creatinine < 1.5 mg/dl or creatinine clearance ≥ 50 cc/min (can be calculated by 24 
hour urine or by  the Cockroft-Gault formula in Appendix B) 
• All non-hematologic treatment-related toxicities must be < grade 1 (unless considered 
medically insignificant by the treating investigator). See table 6.2.2.  
 
6.2.2 Dose modifications for Hematologic toxicity (cisplatin and AC) 
Toxicity 
Grade 
Guideline for 
management 
Dose modification  
HEMATOLOGIC (Occurring any time during previous cycle or on Day 1 of current cycle) 
Neutropenia (based 
Grade 3 (which resulted in 
 
Delay all treatment 

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Toxicity 
Grade 
Guideline for 
management 
Dose modification  
on ANC, not WBC) 
a delay of < 1 week) 
until ANC > 1000/mm3 
and treat at previous 
dose level. 
Grade 4* 
OR  
Any grade resulting in a  
delay of next cycle  by > 1 
week due to ANC* 
OR  
Febrile Neutropenia: 1st 
occurrence*  
 
*without use of growth 
factor in prior cycle 
Begin growth 
factors 
Delay all treatment 
until ANC > 1000/mm3 
and treat at previous 
dose level.  
Grade 4*  
OR  
Any grade resulting in a  
delay of next cycle  by > 1 
week due to ANC* 
OR  
Febrile Neutropenia: 1st 
occurrence* 
 
*with use of growth 
factors  
 
Delay all treatment 
until ANC > 1000/mm3 
and reduce dose 25%. 
Grade 4*  
OR  
Any grade resulting in a  
delay of next cycle  by > 1 
week due to ANC* 
OR  
Febrile Neutropenia: 2nd  
occurrence*  
 
*with use of growth 
factors 
 
Delay all treatment 
until ANC > 1000/mm3 
and reduce dose 25%. 
Grade 4*  
OR  
Any grade resulting in a  
delay of next cycle  by > 1 
week due to ANC* 
OR  
Febrile Neutropenia: 3rd  
occurrence*  
 
Discontinue protocol 
therapy. 

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Toxicity 
Grade 
Guideline for 
management 
Dose modification  
 
*with use of growth 
factors 
Platelets 
Grade 1-2 
Re-check CBC 
weekly (or 
more often at 
physician’s 
discretion) 
Delay all treatment 
until Platelets > 
100,000/mm3 and treat 
at previous dose level. 
Any grade resulting in  a 
delay of > 1 week)  
 
Delay all treatment 
until Platelets > 
100,000/mm3 and 
reduce dose by 25%. 
Grade 3 or 4: 1st 
occurrence 
 
Delay all treatment 
until Platelets > 
100,000/mm3 and 
reduce dose 25%. 
Grade 3 or 4: 2nd  
occurrence 
 
Delay all treatment 
until Platelets > 
100,000/mm3 and 
reduce dose 25%. 
Grade 3 or 4: 3rd 
occurrence 
 
Discontinue protocol 
therapy. 
NON-HEMATOLOGIC 
Diarrhea (on Day 1 
of new cycle or 
anytime during 
previous cycle) 
Grade 1 
 
No dose modifications 
Grade 2 
 
Delay all treatment 
until diarrhea has 
resolved to Grade 1. 
Grade 3 or 4 
 
Delay all treatment 
until diarrhea has 
resolved to Grade 1. 
Reduce all treatment 
doses by 25%. 
Bilirubin (on Day 1 
of a new cycle) 
Grade 2 (> 1.5-3.0 x ULN)  
Decrease doxorubicin 
dose by 50% 
Grade 3 (> 3.0-5.0 x ULN)  
Decrease doxorubicin 
dose by 75% 

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Toxicity 
Grade 
Guideline for 
management 
Dose modification  
Grade 3 or 4 (> 5.0 x 
ULN) 
 
Delay doxorubicin and 
cyclophosphamide until 
bilirubin < 5.0 x ULN 
and then reduce dose 
by 75%.  
Neurosensory 
Toxicity (on Day 1 of 
a new cycle) 
Grade 0-1 
 
No dose modification 
Grade 2 
 
Delay cisplatin until 
neuropathy is < grade 
1. Reduce cisplatin 
dose by 50%. 
> Grade 3 
 
Discontinue protocol 
therapy. 
Tinnitus/ Significant 
Hearing Loss 
>Grade 2 
 
Delay cisplatin until 
tinnitus or hearing loss 
has resolved to < grade 
1.  Dose reductions are 
at the discretion of the 
treating physician.  
Mucositis 
> Grade 3 
 
Delay treatment until 
mucositis < grade 1.  
Reduce cisplatin dose 
by 25%; reduce 
doxorubicin and 
cyclophosphamide 
doses by 20%. 
 
Nephrotoxicity 
(creatinine)  
See section 6.2.3  

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Toxicity 
Grade 
Guideline for 
management 
Dose modification  
Cardiac: If the 
participant has any of 
the following: 
 Symptoms of 
CHF and a 
diagnosis of CHF 
is confirmed 
 Myocardial 
infarction 
 > 15% decline in 
LVEF from 
baseline, or > 
10% decline from 
baseline to below 
lower limits of 
normal 
 
 
 
Discontinue protocol 
therapy 
Cardiac: PACs or 
PVCs without cardiac 
dysfunction during 
and shortly after 
doxorubicin infusion  
 
 
No dose modification 
Fatigue 
 
 
No dose modification 
Alopecia 
 
 
No dose modification 
Transaminase 
elevations 
 
 
No dose modification 
Nausea and/or 
vomiting 
 
 
 
No dose modification 
Other non-
hematologic 
Grade 1  
 
No dose modification 
Grade 2 
 
All non-hematologic 
treatment-related 
toxicities must be < 
grade 1 (unless 
considered medically 
insignificant by the 
treating investigator)** 
> Grade 3 
 
Delay treatment until 
toxicity improves to < 
grade 1. Reduce 
cisplatin dose by 25%; 
reduce doxorubicin and 
cyclophosphamide 

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Toxicity 
Grade 
Guideline for 
management 
Dose modification  
doses by 20%. ** 
**Veno-thrombotic events are excluded from dose modifications; dose modifications 
are per investigator discretion 
6.2.3 Nephrotoxicity (Cisplatin only; no dose modification for AC) 
 
Cisplatin may be associated with renal toxicity. The likelihood of this toxicity may be 
decreased by adequate hydration and prevention of nausea and vomiting. 
 
In the event that Creatinine is > 1.5 mg/dl, measure or calculate creatinine clearance. If 
creatinine clearance ≥ 50 cc/min, chemotherapy may be administered. If creatinine 
clearance < 50 cc/min the creatinine (+/or creatinine clearance) should be checked 
weekly until the creatinine is < 1.5 mg/dl and/or creatinine clearance is ≥ 50 cc/min. 
 
If chemotherapy is delayed > 1 week because of decreased renal function, the cisplatin 
dose should be reduced in the following manner: 
 
• 1st dose reduction: Reduce Cisplatin by 25% (56 mg/m2) 
• 2nd dose reduction: Reduce Cisplatin by 50% (of initial dose) (37 mg/m2) 
• If 3rd dose reduction is required, participant must be removed from study. 
 
If the Creatinine is still > 1.5 mg/dl but < 2.0 mg/dl and creatinine clearance is < 50 
cc/min but ≥ 40 cc/min after treatment has been held for two weeks, the treating 
physician may consult the PI to discuss proceeding with cisplatin dose reduction of 50%. 
No cisplatin will be administered if Creatinine is > 2.0 or creatinine clearance is < 40 
cc/min. 
6.2.4 Hypersensitivity Reaction 
Hypersensitivity reactions including anaphylaxis have been reported within minutes of 
administering cisplatin. If a hypersensitivity reaction occurs, the patient must be 
evaluated by appropriate clinicians per institutional standards prior to any further 
cisplatin administration. Subsequent cisplatin administration should be administered 
through a desensitization protocol under the supervision of appropriate clinicians.  
 
7. DRUG FORMULATION AND ADMINISTRATION  
 
• Qualified personnel who are familiar with procedures that minimize undue exposure 
to themselves and to the environment should undertake the preparation, handling, 
and safe disposal of chemotherapeutic agents in a self-contained, protective 
environment. 
 
• As all agents are commercially available, each study site is responsible for 
prescribing and ordering study drugs for study participants enrolled at their site. 

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• Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or that are prepared with unpreserved diluents (i.e., sterile water 
for injection, USP, or 0.9% sodium chloride for injection, USP) within 8 hours of vial 
entry to minimize the risk of bacterial contamination. 
 
• The total administered dose of chemotherapy may be rounded up or down within a 
range of 5% of the actual calculated dose. 
 
7.1 
Availability and Preparation 
 
Cisplatin 
Commercially available cisplatin injection (1 mg/ml): Each ml of sterile, unpreserved solution 
contains: cisplatin 1.0 mg of cisplatin with 9 mg of sodium chloride and 1 mg of mannitol in 
water for injection. Hydrochloric acid is added to adjust the pH. Single-dose glass vials of 10, 
50, and 100 ml contain 10, 50, and 100 mg of cisplatin, respectively. None of the injection 
components, such as IV needles, syringes, and sets, should have aluminum components, 
because aluminum is incompatible with cisplatin. Please refer to the FDA-approved package 
insert for complete product information. 
 
Preparation of cisplatin is per institutional standards.  
 
Doxorubicin 
Doxorubicin is commercially available as a lyophilized powder for reconstitution in 10, 20, 
and 50mg vials. Also available as 2 mg/ml solution for injection in 10, 20, 50, 75 and 200 mg 
vials. Please refer to the FDA-approved package insert for complete product information. 
 
Reconstitute the vials of doxorubicin powder with 5, 10, 25, 50 or 75 ml, respectively, of 
sodium chloride for injection, USP, resulting in a concentration of 2 mg/ml. 
 
Preparation of doxorubicin is per institutional standards.  
 
Cyclophosphamide 
Cyclophosphamide is commercially available as powder for reconstitution in 500mg, 1g and 
2g vials. Please refer to the package insert for complete product information. 
 
Reconstitute 500mg, 1g and 2g vials with 25, 50, or 100ml of sterile water for injection for a 
final concentration of 20mg/ml. Vigorous shaking and/or gentle warming may be necessary. 
 
Preparation of cyclophosphamide is per institutional standards.  
7.2 
Stability and Storage 
 
Cisplatin 

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Vials of cisplatin injection, USP, are stored at room temperature between 4°C  - 25°C. Do not 
refrigerate or freeze cisplatin solutions, since a precipitate will form. IV needles, syringes, 
or sets having aluminum components should not be used in preparing or administering 
cisplatin solutions. An interaction will occur between aluminum and platinum from cisplatin, 
causing a black precipitate that is visible in the cisplatin solution. Diluted solution of 
carboplatin is physically and chemically stable for up to 8 hours at ambient room temperature. 
The solution should be discarded after 8 hours as no antibacterial preservative is contained in 
the formulation. 
 
Doxorubicin 
Intact vials of doxorubicin solution should be stored in the refrigerator. Intact vials of powder 
for reconstitution should be stored at room temperature. Reconstituted solutions are stable for 7 
days at room temperature and 15 days under refrigeration when protected from light. 
Commercially available solutions labeled as such are intended to be multi-dose vials. 
 
 
Cyclophosphamide 
Store intact vials of powder at room temperature (15-30°C). Reconstituted solutions are stable 
for 24 hours at room temperature or for 6 days in the refrigerator (2-8°C). Solutions further 
diluted for infusion in 0.9% NaCl or D5W are stable for 24 hours at room temperature and 6 
days under refrigeration. 

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8. STUDY CALENDAR AND BIOSPECIMEN COLLECTION 
 
8.1 
Required Data 
 
Table 8.1 outlines the required data. Case Report Forms or Electronic Data Capture (EDC) will 
be completed for each participant and submitted to the DF/HCC ODQ. 
 
After a participant has been determined to be eligible for this study and has provided signed and 
written informed consent, a pre-study baseline evaluation is required as indicated on Table 8.1 
prior to initiation of cycle 1. This evaluation must be completed within 28 days prior to starting 
therapy, except as indicated.  

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Table 8.1 Required Data 
Parameter 
Pre-
study 
(within 28 
days) 
Prior to 
Neo-
adjuvant 
therapy 
Day 1 of 
cycles 
1-4 
Day 7-10 
of cycle 
1-4 
Pre-surgery 
(2-4 weeks after 
last protocol 
chemo)r 
30 days 
post 
treatment 
(Day 30-33 
post tx) 
Within 42 
days of last 
chemo  
(Day 30-42 
post tx) 
 
Follow-Up 
(annually x 
3 years) 
Informed consent 
X 
 
 
 
 
 
 
 
Confirmation of BRCA1 
and/or BRCA2 mutation 
 
X 
 
 
 
 
 
 
 
Confirmation of invasive 
cancer on diagnostic 
biopsy a 
 
X 
 
 
 
 
 
 
 
Sentinel node biopsy or 
needle aspiration if 
clinically suspicious 
axillary nodes a 
 
 
X 
 
 
 
 
 
 
 
Mammogram +/or MRI 
+/or ultrasound  
X b 
 
 
 
X c 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
Complete physical exam 
including tumor 
measurement  
X 
 
Xo 
 
X d 
 
 
 
Weight, vital signs, 
height n  
X 
 
X 
 
 
 
 
 
Performance status 
(ECOG) 
X 
 
 
 
 
 
 
 
Adverse Event evaluation 
 
 
X 
  
Xp 
Xp 
Xp 
 
Hematology (CBC, 
differential, platelets) 
X 
 
Xo 
Xe 
(Cycle 1 
only)  
 
 
 
 
Serum Glucose 
X 
 
 
 
 
 
 
 
Liver function tests  
(AST/ALT, Alk Phos, 
Bili) 
X 
 
Xf,o 
 
 
 
 
 
Serum BUN, Cre, K, Mg 
X 
 
Xg,o 
Xh 
 
 
 
 
MUGA scan or 
echocardiogram 
X 
 
 
 
 
 
 
 
EKG (12 lead) 
X 
 
 
 
 
 
 
 
Pregnancy test i 
X 
 
 
 
 
 
 
 
Excision of tumor or 
mastectomy and axillary 
nodes  
 
 
 
 
 
 
X j 
 
Research biopsy k  
 
X k 
 
 
Xq  
 
 
 
Research blood samplem 
 
X 
 
 
 
X 
 
 
 
 
Bone scan, CT scan, 
(chest/abd/pelvis) or 
PET-CT l 
 
X 
 
 
 
 
 
 
 
Survival Assessment  
(See section 5.14) 
 
 
 
 
 
 
 
X 
 

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a Pathology report is required for eligibility; 28 day window does not apply.  Slides and tumor block of the 
diagnostic biopsy (and node evaluation if done) can be sent to the coordinating center per section 9.5 at the same 
time as the specimens from definitive surgery. 
b Affected breast imaging that measures the tumor must be done within 28 days prior to study start; MRI is 
strongly recommended, although other imaging modalities (mammogram, ultrasound) are permitted. See Section 9. 
c Affected breast imaging is required prior to breast surgery, between C4D1 and 4 weeks after the last 
chemotherapy. Mammogram, MRI or ultrasound may be used if being compared to baseline study prior to 
chemotherapy.  
d Tumor measurement should be assessed by physical exam prior to surgery, 2-4 weeks after the last protocol 
chemotherapy.   
e Participants receiving growth factor support do not need this nadir CBC. A nadir CBC is only required for Cycle 1. 
This blood draw may be performed at the treating hospital or closer to home.  
f  For participants receiving AC only 
g  For participants receiving Cisplatin only  
h  For participants receiving Cisplatin only; the blood draw may be performed at the treating hospital or closer to 
home 7-10 days after chemo each cycle. If K or Mg levels are low, supplementation should be administered. If Cre 
is elevated, this should be managed per institutional guidelines. 
i Women of childbearing potential only if there is a suspicion of possible pregnancy. 
j  Slides and tumor block of the tumor excision should be sent to BIDMC per section 9.5 within 60 days of surgery. 
k Optional; prior to beginning study therapy. (See section 5.3 and Appendix E).   
l   Staging Studies are not required for this protocol and are at the discretion of the treating physicians. It is recommended 
that NCCN guidelines for staging patients receiving pre-operative chemotherapy be followed. 
m See Section 8.2 and 8.3 
n Height should only be collected at baseline.  
o  Physical exam and Labs may be performed up to 48 hours prior to the start of a new cycle.  
p The pre-surgery AE assessment may be performed by surgeons trained on the study or by telephone call. Any AEs 
documented at pre-surgery should be recorded on the Cycle 4 AE form. The 30 day post AE assessment and any 
continuing AE follow-up may occur via phone call. See Section 5.13 and Section 10.  
q This biopsy is required for patients who receive additional therapy prior to definitive surgery. It must be performed 
prior to the initiation of additional therapy. 
r For patients with significant residual disease after 4 cycles of assigned protocol chemotherapy who will receive 
additional treatment. These assessments should be obtained 2-4 weeks after the last protocol assigned chemotherapy 
and before additional non-protocol assigned chemotherapy is administered. 

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8.2 
Research Specimen Submission  
 
Table 8.2 Required Specimen Submissions 
Specimen Type 
Time Point 
Shipping 
Condition 
Ship to 
Pre-study 
(Diagnostic 
biopsy) 
Pre-
treatment 
(Optional 
Research 
biopsy) 
Post 
protocol 
treatment  
Definitive 
Surgery  
Representative H&E 
slide from each block 
from diagnostic 
biopsy* 
X 
 
 
 
Room 
temperature 
 at 
BIDMC 
Tumor block from 
diagnostic biopsy* 
X 
 
 
  
Room 
temperature 
 at 
BIDMC 
Biopsy core frozen in 
OCT** 
 
X 
 
 
Store in -80C 
freezer; ship on 
dry ice 
DF/HCC Core 
Blood and 
Tissue Bank 
Biopsy core in RNA 
Later** 
 
X 
 
 
Room 
temperature 
DF/HCC Core 
Blood and 
Tissue Bank 
Biopsy core in 
formalin 
 
X** 
X# 
 
Room 
temperature 
DF/HCC Core 
Blood and 
Tissue Bank 
Two 10mL lavender 
top (EDTA) tubes of 
blood*** 
X 
 
 
Use thermos 
provided in 
research kit 
DF/HCC Core 
Blood and 
Tissue Bank 
Two 10 mL Streck 
tubes of blood*** 
 
X 
X 
 
Room 
temperature- 
DO NOT 
FREEZE/ 
REFRIGERATE 
DF/HCC Core 
Blood and 
Tissue Bank 
H&E slides from 
definitive surgery* 
 
 
 
X 
Room 
temperature 
 at 
BIDMC 
H&E slides from 
axillary lymph node 
dissection* 
 
+/- X 
 
+/- X 
Room 
temperature 
 at 
BIDMC 
Tumor block from 
definitive surgery* 
 
 
 
X 
Room 
temperature 
 at 
BIDMC 
Block of normal breast 
tissue, skin or 
uninvolved LN* 
 
 
 
X 
Room 
temperature 
 at 
BIDMC 
* For more information see protocol section 9.5.  
** For more information see protocol section 5.3 
*** For more information see protocol section 8.3  
# Only required for patients who received additional chemotherapy before surgery; a biopsy to 
prove residual cancer is encouraged in this situation. H&E slides will be reviewed by the study 
team in lieu of definitive surgery slides.  

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8.4 
SPECIMEN BANKING 
 
Any leftover study blood and tissue samples may be stored for future research studies.  The 
subjects will consent to the future use of samples in the consent form for the study.  Any samples 
will only be released for use in future studies after approval by the Principal Investigator and 
other regulatory bodies, as appropriate. 
 
The study PI and collaborators have approval by the TBCRC to use all research bio-specimens 
collected during the conduct of this trial to address the research questions described in the 
protocol document.  All future use of residual or repository specimens collected in this trial for 
purposes not prospectively defined will require review and approval by the TBCRC according to 
its established policies, whether the specimens are stored in a central site or at a local institution 
in a virtual repository. 
 
Secondary use of bio-specimens for new endpoints must be submitted to the TBCRC Central 
Office for possible review by the TBCRC Correlative Science Review Committee. 
 
9. 
MEASUREMENT OF EFFECT  
 
A baseline and presurgical radiographic study of the breast is required; MRI is recommended. 
The same radiographic modality should be used consistently. The baseline scan must be obtained 
within 28 days of beginning therapy. The presurgical scan should occur between C4D1 and up to 
4 weeks after the last chemotherapy administration. If the participant clinically progresses, repeat 
imaging is required. If there is discordance (clinical progression, but radiographic stable disease 
or response), contact the study chair. 
9.1 
Target Lesions 
 
In the event of multifocal or multicentric disease in the breast, the investigator must determine 
which will represent the target lesion. This should remain consistent throughout the study. The 
target lesion should be selected on the basis of its size (lesion with the longest diameter) and 
suitability for accurate repetitive measurements (either by imaging techniques or clinically). 
9.2 
Pathologic Complete Response 
 
Pathological Complete Response (pCR): 
Complete disappearance of invasive tumor 
(Miller-Payne method)1                                      in the breast at the time of surgery. Pathologic 
complete response in the lymph nodes is 
defined as no detectable invasive tumor by 
H&E. 
 
 
Pathological Complete Response (pCR):  
 
Complete disappearance of invasive tumor 
    (MD Anderson RCB method)2                          in the breast and axillary nodes at the time of            
                                                                                  surgery. 
 

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All patients with significant residual disease who proceed to alternative chemotherapy will be 
considered to belong to the poor response group. 
9.3 
Radiographic Assessment 
 
Each participant will have a pre-therapy baseline radiographic tumor measurement, preferably by 
MRI, however if logistic, financial, or practical issues preclude MRI use, mammogram or 
ultrasound may be substituted, as long as the tumor lesion can be adequately measured. The 
longest diameter (LD) of the target lesion at the time of study initiation will be reported as the 
baseline LD. The baseline LD of the target lesion will be used as reference to further characterize 
the objective tumor response of the measureable dimension of the disease. 
 
Response criteria are based on the RECIST 1.1 criteria: 
 
 
Radiographic Complete Response (CR):  
Complete disappearance of the target lesion 
 
Radiographic Partial Response (PR):   
 
 
Greater than or equal to 30% decrease in the 
longest diameter (LD) of the target lesion 
taking as reference the baseline LD. 
 
Radiographic Progressive Disease (PD):  
Greater than or equal to 20% increase in the 
LD of target lesion taking as reference the 
baseline LD or the appearance of one or more 
new lesions 
. 
Radiographic Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD 
taking as reference the baseline LD  
9.4 
Clinical Assessments 
 
Both target and, in the event of multifocal or multicentric invasive cancer, nontarget lesions 
should be followed clinically and their clinical size recorded at baseline. Measurements 
thereafter are required; these lesions should be categorized at subsequent visits regarding 
whether there is evidence of progression. If “yes”, the study chair should be notified in order to 
determine whether the participant should come off protocol treatment. 
9.5 
Pathology Response Central Review and Archival Tissue for Future Correlative 
Studies 
 
Central review of pathology will be performed by Dr. Stuart Schnitt of DF/HCC.  Dr. Schnitt 
will be blinded to the treatment assignment of each participant.   
 
For each participant, submit the following: 

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• Clinical material: 
a)  A representative H&E slide from each block from the diagnostic breast biopsy 
(pre-chemotherapy) 
b) All H&E slides from the definitive surgery (post-chemotherapy or mastectomy) 
c) All H&E slides from axillary nodes (if applicable) 
 
Pathologic complete response will be assessed. For those without a pCR, the semi-
quantitative pathologic response scores and grade will be determined using the 
Miller-Payne criteria and the Residual Cancer Burden measure.  
 
More slides may be requested from the participating site if needed to complete the 
pathology response central review.   
 
The clinical material will be returned to the site after the completion of the pathology 
central review.   
• Tumor Tissue for future research: 
a) One representative tumor block from the diagnostic breast biopsy (pre-
chemotherapy) 
b) One representative tumor block from the definitive surgery (post-chemotherapy or 
mastectomy) 
c) One block of normal breast tissue, skin or uninvolved axillary node   
 
This tissue will be used by the study pathologist for future correlative studies to 
identify biomarkers of response to cisplatin and doxorubicin and cyclophosphamide. 
 
*It is recommended that participating sites request all archival tissue specimens, including 
clinical material and tissue for future research after the definitive surgery clinical case has been 
signed out by pathology.   
 
**If an institutional policy exists that precludes release of tissue blocks, please send 15  sections 
(5 micron thickness) on charged slides from: a) the diagnostic tumor biopsy (pre-chemotherapy); 
b) the post-chemotherapy definitive surgery (excision or mastectomy); and c) normal breast 
tissue, skin or uninvolved lymph node (i.e. negative for cancer). 
 
Tumor blocks will be kept for future research at DF/HCC; however, if a tumor block is needed 
for clinical care purposes, the participating site should contact the coordinating center study 
coordinator to request that the applicable block be returned. 
 
The coordinating center study coordinator will maintain a specimen tracking log of all archival 
tissue specimens received.   

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Exploratory analysis will be performed to seek new measures of therapy response using the data 
from DNA copy number and gene expression profiles.  In addition, we will plan to perform 
whole exome and possibly whole genome sequencing of tumors to identify potential single gene 
modifiers of response to therapy and to measure global point mutation and insertion/deletion 
mutation burden.   
 
10. ADVERSE EVENT REPORTING REQUIREMENTS 
 
It is of the utmost importance that all staff involved in the study is familiar with the content of 
this section. The Protocol Chair is responsible for ensuring these guidelines are followed. 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 10.1) and the characteristics of an 
observed AE (Section 10.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
10.1 Adverse Event Lists 
10.1.1 Adverse Event (AE) Lists for Study Agents 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not considered to 
be related to the study.  
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study 
agent(s). 
10.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 

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10.3.4 DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
 
Other investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional AE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.   
 
 
 
 
Attribution 
DF/HCC Reportable Adverse Events(AEs) 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event. 
 
 
The Overall PI/Coordinating Center will submit AE reports from outside institutions to 
the DFCI OHRS according to DFCI IRB policies and procedures in reporting adverse 
events.  
10.3.5 Protocol Specific Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs listed below do not require expedited reporting to the 
Overall PI or the DFCI IRB. However, they still must be reported through the routine 
reporting mechanism (case report forms).  
 
Grade 4 expected events do not need to be reported by expedited reporting to the IRB, 
however, the Overall PI should be notified of any Grade 4 events within 24 hours of first 
awareness of event.  
 
Any events that are unequivocally due to progression of disease should not be reported as 
an adverse event. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 
10.4 Reporting to Hospital Risk Management 
 

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Participating investigators will report to their local Risk Management office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
10.5 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB) must also be reported in routine study data submissions. Any adverse events noted 
during the pre-surgery evaluation should be included on the cycle 4 Adverse Event form.  
 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention, throughout the study, and within 30 days of the last study intervention 
should be followed to their resolution, or until the participating investigator assesses them as 
stable, or the participating investigator determines the event to be irreversible, or the participant 
is lost to follow-up. The presence and resolution of AEs and SAEs (with dates) should be 
documented on the appropriate case report form and recorded in the participant’s medical record 
to facilitate source data verification. This AE evaluation can be documented by phone call.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the 
SAE report (e.g., hospital discharge summary, consultant report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. Participating investigators should notify the DF/HCC 
Overall Principal Investigator and their respective IRB of any unanticipated death or adverse 
event occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study.   
 
11. DATA AND SAFETY MONITORING 
11.1 Data Reporting 
11.1.1 Method  
The ODQ will collect, manage, and perform quality checks on the data for this study. 
11.1.2 Data Submission  
The schedule for completion and submission of electronic case report forms to the ODQ 
is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ 

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On Study Form 
Within approximately 14 days of registration 
Baseline Assessment Form 
Within approximately 14 days of registration 
Treatment Form 
Within approximately 10 days of the last day 
of the cycle 
Adverse Event Report Form 
Within approximately 10 days of the last day 
of the cycle 
Response Assessment Form 
Within approximately 10 days of the 
completion of the 4th cycle (or last cycle if 
subject does not complete 4 cycles of 
chemotherapy) of preoperative chemotherapy. 
Off Treatment/Off Study Form Within approximately 14 days of completing 
treatment or being taken off study for any 
reason 
 
11.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this trial. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information that 
raises any questions about participant safety or protocol performance will be addressed with the 
Principal Investigator, statistician and study team members.  Should any major concerns arise; the 
DSMB will offer recommendations regarding whether or not to suspend the trial. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual, treatment 
regimen information, adverse events and serious adverse events reported by category, summary 
of any deaths on study, audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
11.3 Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the DF/HCC 
Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or 
inspections is to examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately reported in 
accordance with the protocol, institutional policy, and any applicable regulatory requirements.  
 

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All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and will 
continue during protocol performance and completion. 
 
Refer to Appendix F, Sections 7.0 and 9.0, of the Data and Safety Monitoring Plan for a 
detailed description of the study’s auditing and monitoring plan. 
 
12. REGULATORY CONSIDERATIONS 
12.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
12.2 Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their participation 
in this study. The formal consent of a participant, using the IRB approved consent form, must 
be obtained before the participant is involved in any study-related procedure. The consent 
form must be signed and dated by the participant or the participant’s legally authorized 
representative, and by the person obtaining the consent. The participant must be given a copy 
of the signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file. 
12.3 Ethics  
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
• US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  

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o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  
• State laws 
• DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. In such case, the deviation must 
be reported to the IRB according to the local reporting policy. 
12.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays. 
12.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 
12.6 Multi-center Guidelines 
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard 
Cancer Center. The specific responsibilities of the DF/HCC Overall Principal Investigator 
(or Protocol Chair), Coordinating Center, and Participating Institutions are presented in the 
Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (see 
Appendix F). 
• The DF/HCC Overall Principal Investigator/Coordinating Center is responsible 
for distributing all IND Action Letters or Safety Reports to all participating 
institutions for submission to their individual IRBs for action as required.  

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• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.  
• Except in very unusual circumstances, each participating institution will order the 
agent(s) directly from the supplier. A participating site may order the agent(s) 
only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center.  
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 Analysis of Primary Endpoint 
 
The primary endpoint is pCR [pCR in breast and nodes (i.e. RCB 0) or pCR in breast (i.e. 
Miller Payne 5) if nodes are not evaluable (i.e. positive nodes were removed surgically 
before chemo)] assessed by the Miller-Payne method1 and to determine if the pCR rate after 
cisplatin chemotherapy is 20% higher than the pCR rate after doxorubicin and 
cyclophosphamide chemotherapy.  
 
We hypothesize that the incidence of pCR will be 50% among participants randomized to 
neoadjuvant cisplatin and 30% in the AC treatment arm62. Despite the pCR rate of 72% with 
cisplatin reported by Gronwald et al 54, it is anticipated that the response rate in a multicenter 
randomized phase 2 study will be lower than that reported initially in a single institution trial. In 
addition, the effect of introducing high grade ER+ breast cancers in BRCA2 carriers is not 
certain.  Assuming a two-sided alpha of 0.10 and accounting for the interim analysis described 
below, we would need 76 evaluable participants in each treatment arm to have 80% power to 
detect the specified difference (50% vs. 30%). We will aim to enroll 85 participants in each 
treatment arm to account for 10% potential drop out when not evaluable. We will compare the 
frequency of pCR in the two treatment arms using log-binomial regression to calculate the risk 
ratio and 95% confidence interval; we will include a term in the model for ER status to evaluate 
its effect on the outcome. It is anticipated that the duration of the study will be approximately 
three years.  
13.2 Interim Analysis 
 
One interim analysis is planned after 50% (43) of the participants in each arm have completed 
the study. Results of the interim analysis will be reported to the Dana-Farber/Harvard Cancer 
Center Data Safety Monitoring Board.  
 
The O’Brien-Fleming group sequential design was used to determine stopping boundaries for a 
two-sided hypothesis for the interim and final analyses (see table below). The probability of 
stopping at the first interim analysis under the alternative hypothesis is 0.27. The interim analysis 
of the primary endpoint will be conducted as described above in 13.1.   
 
 

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Interim Analysis 
Final Analysis 
Participants completed 
86 (50.6%) 
170 (100.0%) 
Boundary values 
(standardized Z) 
2.37 
1.68 
Accumulated alpha   
0.018 
0.10 
Accumulated beta  
0.0002 
0.2 
 
13.3 Analysis of Secondary Endpoints 
13.3.1 pCR and Residual Cancer Burden by MD Anderson RCB method 2  
 
The RCB method of assessing residual cancer burden, including pCR, requires 
assessment of both the breast as well as axillary nodes after neoadjuvant chemotherapy. 
Given the results of the Z0011 (Z-11) study by the American College of Surgeons 
Oncology Group69, it was felt that for those participants with one or two sentinel nodes 
involved with tumor prior to chemotherapy, completion axillary dissection could not be 
mandated. Therefore this objective was made a secondary rather than a primary objective.   
 
It is anticipated that very few subjects (< 5) in the study will not get a completion axillary 
dissection after chemotherapy if pre-chemotherapy sentinel nodes are involved with 
cancer since most subjects will not fit the criteria of subjects in the Z-11 study 69 . 
Therefore, it is believed that we will have adequate power to assess pCR by this method, 
though less than with the Miller-Payne method that requires only response in the breast.  
 
Therefore a secondary objective is to compare the rates of RCB 0 (i.e.pCR)  and RCB1 
combined in patients who have received cisplatin and AC neoadjuvant chemotherapy. 
There is data to support that long term outcomes in patients with RCB1 is equivalent to 
those with RCB 0.2 
 
There is also data that achievement of a near pCR after neoadjuvant therapy (i.e. Miller 
Payne 4) predicts for good outcomes in women with breast cancer. Therefore, a 
secondary objective is to assess the rate of Miller Payne 4 and 5 (combined) between 
those patients who received neoadjuvant cisplatin and those who received neoadjuvant 
AC1.  
13.3.2 Clinical complete response (CCR)  
The CCR to cisplatin and to AC neoadjuvant chemotherapy will be determined in this 
population. CCR will be determined with 95% confidence interval for both regimens.  
13.3.3 Toxicity: frequency and severity of adverse effects 
Analyses of safety will be completed for all participants who receive at least 1 dose of 
study treatment The National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) criteria version 4.03 will be used to classify and grade 
toxicities observed during and following treatment (up to 30 days after last 

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chemotherapy). Participants will be tabulated according to the maximum grade for each 
organ system or preferred term. Safety endpoints will be summarized with descriptive 
statistics for the participants in the safety analysis dataset.  
13.3.4 Biomarkers of response to cisplatin and AC chemotherapy 
We will conduct an exploratory analysis to evaluate the utility of NtAI, BLM+FANCI 
mRNA levels, chr 15q26 copy number, chr 8q22 copy number, and YWHAZ + 
LAPTM4B mRNA levels to predict response to chemotherapy. The comparison of the 
results in the two arms will be descriptive and we will not attempt to show marker 
interaction with a specific drug response or make further claims about the marker 
performance. Other exploratory analyses based on gene expression profiling, DNA 
profiling, or sequencing will be for discovery purposes and statistical planning for this 
part cannot be determined at this time. Other biomarkers of response to cisplatin and/or 
AC that will be assessed if sufficient tissue exists include: homologous recombination 
defect assay by Myriad Genetic Laboratories, assessment of BRCA mutation reversion, 
BRCA1/(avg BLM + FANCI) 3-gene mRNA signature, BLM/ chromosome 15q26 copy 
number, gene expression profiling to assess breast cancer subtype,  lymphocytic 
infiltration and circulating DNA. 
13.3.5 3-year Recurrence-Free Survival 
 
We will compare the frequency of recurrence between the two treatment arms of the 
INFORM trial (DF-HCC 12-258; TBCRC 031) using log-binomial regression to calculate 
the risk ratio and 95% confidence interval. We will also compare the frequency of 
recurrence between patients who achieved pathological complete response and those who 
did not using log-binomial regression to calculate the risk ratio and 95% confidence 
interval.  
 
14. PUBLICATION PLAN 
 
It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to all participating sites prior to submission for publication or presentation. The 
Protocol Chair will be the final arbiter of the manuscript content.

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53 
15. REFERENCES  
 
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3. 
Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of 
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Risch HA, McLaughlin JR, Cole DE, et al. Population BRCA1 and BRCA2 mutation 
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van der Kolk DM, de Bock GH, Leegte BK, et al. Penetrance of breast cancer, ovarian 
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Lakhani SR, Reis-Filho JS, Fulford L, et al. Prediction of BRCA1 status in patients with 
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Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of 
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Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast 
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Lakhani SR, Jacquemier J, Sloane JP, et al. Multifactorial analysis of differences between 
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based neoadjuvant chemotherapy. J Clin Oncol. Feb 1999;17(2):460-469. 
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survival in patients with triple-negative breast cancer. J Clin Oncol. Mar 10 
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susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival 
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2000;275(31):23899-23903. 
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Husain A, He G, Venkatraman ES, Spriggs DR. BRCA1 up-regulation is associated with 
repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res. Mar 15 
1998;58(6):1120-1123. 

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Moynahan ME, Cui TY, Jasin M. Homology-directed dna repair, mitomycin-c resistance, 
and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 
Jun 15 2001;61(12):4842-4850. 
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Quinn JE, Kennedy RD, Mullan PB, et al. BRCA1 functions as a differential modulator 
of chemotherapy-induced apoptosis. Cancer Res. Oct 1 2003;63(19):6221-6228. 
52. 
Liu X, Holstege H, van der Gulden H, et al. Somatic loss of BRCA1 and p53 in mice 
induces mammary tumors with features of human BRCA1-mutated basal-like breast 
cancer. Proc Natl Acad Sci U S A. Jul 17 2007;104(29):12111-12116. 
53. 
Rottenberg S, Nygren AO, Pajic M, et al. Selective induction of chemotherapy resistance 
of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl 
Acad Sci U S A. Jul 17 2007;104(29):12117-12122. 
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Gronwald J BT, Huzarski T, Dent R, Bielick V, Zuziak D, Wisniowski R, Lubinski J,  
Narod S. Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients J 
Clin Oncol 27, 15s,  (suppl; abstr 502). 2009. 
55. 
Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib 
in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-
concept trial. Lancet. 2010;376(9737):235-244. 
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Tung N, Miron A, Schnitt SJ, et al. Prevalence and predictors of loss of wild type 
BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers. 
Breast Cancer Res. 2010;12(6):R95. 
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Silver DP, Dimitrov SD, Feunteun J, et al. Further evidence for BRCA1 communication 
with the inactive X chromosome. Cell. Mar 9 2007;128(5):991-1002. 
58. 
Luo G, Santoro IM, McDaniel LD, et al. Cancer predisposition caused by elevated 
mitotic recombination in Bloom mice. Nat Genet. Dec 2000;26(4):424-429. 
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Vrieling H. Mitotic maneuvers in the light. Nat Genet. Jun 2001;28(2):101-102. 
60. 
Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective 
DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. Apr;2(4):366-375. 
61. 
Telli M, Jensen K, Abkevich V, et al. Homologous Recombination Deficiency (HRD) 
score predicts pathologic response following neoadjuvant platinum-based therapy in 
triple-negative and BRCA1/2 mutation-associated breast cancer (BC). Cancer Research. 
December 17, 2012 2012;72(24 Supplement):PD09-04. 
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Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response rates in young 
women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin 
Oncol. 2010;28(3):375-379. 
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Chappuis PO, Goffin J, Wong N, et al. A significant response to neoadjuvant 
chemotherapy in BRCA1/2 related breast cancer. J Med Genet. 2002;39(8):608-610. 
64. 
Kriege M, Seynaeve C, Meijers-Heijboer H, et al. Sensitivity to first-line chemotherapy 
for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 
2009;27(23):3764-3771. 
65. 
Arun B, Bayraktar S, Liu DD, et al. Response to Neoadjuvant Systemic Therapy for 
Breast Cancer in BRCA Mutation Carriers and Noncarriers: A Single-Institution 
Experience. J Clin Oncol. Sep 6. 
66. 
Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating 
lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast 
cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based 
chemotherapy: BIG 02-98. J Clin Oncol. Mar 1 2013;31(7):860-867. 

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67. 
Adams S, Gray RJ, Demaria S, et al. Prognostic Value of Tumor-Infiltrating 
Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized 
Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199. J Clin Oncol. Jul 28 2014. 
68. 
Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced 
human epidermal growth factor receptor 2-positive breast cancer: American Society of 
Clinical Oncology clinical practice guideline. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. Jul 1 2014;32(19):2078-2099. 
69. 
Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph 
node dissection with or without axillary dissection in patients with sentinel lymph node 
metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. 
Ann Surg. Sep;252(3):426-432; discussion 432-423. 
70. 
National Comprehensive Cancer Network Clinical practice guidelines in breast cancer. 
Version 1.2012. (Accessed October 2012, at 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp ).  
http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix A: PERFORMANCE STATUS CRITERIA 
 

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Appendix B: FORMULA FOR CREATININE CLEARANCE 
Creatinine clearance may be calculated by 24 hour urine  
Or by the formula below: 
Creatinine clearance (CrCl) will be calculated with the Cockroft-Gault equation [47] as follows: 
CrCl ( ml/min) =  (140-age)(weight (actual) kg) 
[72 X serum creatinine (mg/dl)] 
 
 
If using this formula, use 85% of calculated CrCl value for females. 
 
 
 

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Appendix C:  NCI COMMON TOXICITY CRITERIA FORADVERSE EVENTS 
(CTCAE) v4.03 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 

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Appendix D: STUDY SPONSORED BRCA1/2 TESTING 
 
Participants must meet one of the following criteria to be eligible for genetic testing through the 
study (NCCN guidelines)70: 
 
• Breast cancer diagnosed at age ≤ 45 years; 
 
• Diagnosed at age ≤ 50 years with first-, second-, or third-degree blood 
relative with breast cancer diagnosis ≤ 50 years and/or epithelial 
ovarian/fallopian peritoneal cancer at any age; 
 
• Diagnosed at age < 60 years with a triple negative breast cancer; 
 
• Two breast primaries (i.e., bilateral disease or two or more clearly separate 
ipsilateral primary tumors) when first breast cancer diagnosis occurred 
prior to age 50; 
 
• Personal history of epithelial ovarian/fallopian tube/primary peritoneal 
Cancer. 
 
• 
Diagnosed at any age, with ≥ 2 first-, second-, or third-degree relatives 
with breast and/or epithelial ovarian/fallopian tube/primary peritoneal 
cancer at any age; 
 
• First- or second-degree relative of an individual known to carry a 
deleterious BRCA1 or BRCA2 mutation; 
 
• Ashkenazi Jewish descent; 
 
• Male breast cancer; or 
 
• First-, second-, or third-degree male relative with breast cancer. 
 
Note: Participants who pre-qualify with one or more of these criteria will be eligible 
to screen for BRCA1/BRCA2 mutation by Myriad Genetics through the study. These 
subjects may be eligible for randomization upon receipt of a confirmed deleterious 
germline BRCA1/BRCA2 mutation by Myriad Genetics. 
 
BRACAnalysis Test Request Forms will be provided by the Coordinating Center.  The genetic 
test request form should be submitted with BRCA specimen tubes. Genetic counselors or study 
coordinators should email 
 when a BRCA testing 
specimen is submitted to Myriad to ensure a quick turnaround time.  
 
 
 

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Appendix F: DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN 
 
 
 
 
 
 
DFCI IRB Protocol #: 12-258 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents  
 
1.0  Introduction 
 
 
 
 
1.1  Purpose 
1.2  Data and Safety Monitoring Plan Components 
 
2.0     General Roles and Responsibilities 
 
  
2.1  Protocol Chair 
 
 
 
2.2  Coordinating Center 
 
 
 
2.3  Participating Institution 
 
 
 
3.0 
Protocol Development 
 
 
 
3.1   Activation of a Protocol 
 
 
 
3.2   Coordinating Center Support Function 
 
 
4.0   Protocol Management 
 
 
4.1 Protocol Distribution 
 
 
 
4.2 Protocol Revisions and Closures 
 
 
4.3 Informed Consent Requirements 
 
 
4.4 IRB Documentation 
 
 
 
4.5 IRB Re – Approvals 
 
 
 
4.6 Participant Confidentiality and Authorization 
 
 
4.7 Participant Registration and Randomization 
 
 
 
4.8 DF/HCC Multi-center Protocol Case Number 
 
 
4.9 DF/HCC Multi-center Protocol Registration Policy 
 
 
4.10 Schedule of Data Submission 
 
 
 
4.11 Data Form Review 
 
 
 
4.12 Missing and Deficient Memorandum 
 
     5.0 Requisitioning Study Drug 
 
 
 

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 6.0   Safety Assessments and Toxicity Monitoring 
 
 
      
6.1 Serious Adverse Events 
 
 
 
6.2 Guidelines for Reporting Serious Adverse Events 
 
 
6.3 Guidelines for Processing IND Safety Reports 
 
 
 
 
 
7.0 Protocol Violations and Deviations 
 
          
7.1 Definitions   
 
 
 
7.2 Reporting Procedures 
  
 
 
8.0 Monitoring: Quality Control  
 
 
 
8.1 Ongoing Monitoring of Protocol Compliance 
 
 
  9.0 Evaluation of Participating Institution Performance 
 
 
      10.0 Auditing: Quality Assurance  
 
10.1 DF/HCC Sponsored Trials 
 
 
10.2 Participating Institution 
 
10.3 Coordinating Center 
 
10.4 Substandard Performance 
 

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1.0 INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol.  
 
1.1 Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) Multi-
center protocol will comply with Federal regulations; and Health Insurance Portability and 
Accountability Act (HIPAA) requirements in accordance with the CTEP Multi-center Guidelines.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Components 
 
The Multi-Center Data and Safety Monitoring Plan includes the following components: 
 
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with Dana-
Farber/Harvard Cancer Center on a research  protocol where DF/HCC is the Lead Institution. 
DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, BIDMC, 
CHB, BWH) will be the Lead Institution and will be responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the DFCI IRB and 
applicable regulatory guidelines (CTEP, FDA, OBA etc.).  The Lead Institution is the home of the 
Overall PI.   
 
DF/HCC Contract Principal Investigator:  Investigator located at the Lead Institution who will be 
charged with the responsibility of the administration of the DF/HCC Project. This most often will be 
the Protocol Chair, but occasionally this may be the overall grant or contract holder, as applicable. 
 
Protocol Chair:  The Protocol Chair is the Principal Investigator for the DF/HCC protocol submitted 
as the Lead Institution.  The Protocol Chair may also be referred to as the Overall Principal 
Investigator or DF/HCC Sponsor.  For applicable protocols, the Protocol Chair will be the single 
liaison with any regulatory agencies (i.e. CTEP Protocol and Information Office (PIO), FDA, OBA 
etc.).  
 
Participating Institution:  A Participating Institution is an institution that desires to collaborate with 
DF/HCC and commits to accruing participants to a DF/HCC protocol.  The Participating Institution 
acknowledges the Protocol Chair as having the ultimate authority and responsibility for the overall 
conduct of the study.    
 
Coordinating Center: In general, the Lead Institution is the Coordinating Center for the DF/HCC 
Multi-center Protocol. The Coordinating Center will provide the administrative support to the 
Protocol Chair in order that he/she may fulfill the responsibilities outlined in the DSMP and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines).  In addition to the 
Lead Institution, the Quality Assurance Office for Clinical Trials (ODQ) provides support services to 
assist the Protocol Chair.  

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Clinical Trials Office: The clinical trials offices of the DF/HCC consortium members support 
investigators and their study teams with the coordination, submission and ongoing conduct of 
research protocols involving human subjects.  Specifically, these offices support four core service 
areas including; pre-review of PI initiated protocols; assistance in the preparation and management of 
Investigational New Drug (IND) applications and subsequent required reporting to the FDA; 
regulatory consultation and guidance in the interpretation of local, federal, and ICHguidelines and 
policies; and the orientation and ongoing training support of clinical research personnel.  
 
DF/HCC Quality Assurance Office for Clinical Trials: The DF/HCC ODQ is a unit that has been 
developed to computerize, manage, and QC & QA data and DF/HCC trials.  The DF/HCC ODQ is 
located administratively in the office of the Senior Vice President for Clinical Research, at Dana-
Farber Cancer Institute.  The ODQ uses DF/HCC computerized institutional databases for participant 
registrations and for the management of trial data as well as a set of quality assurance programs 
designed to audit DF/HCC trials.   
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 
In accordance with the CTEP Multi-center Guidelines, the Protocol Chair, Coordinating Center (Lead 
Institution or designee), and the Participating Institutions will all agree to the general responsibilities 
as follows (specific procedures for these general responsibilities are detailed in the DSMP): 
 
2.1 Protocol Chair (DF/HCC Principal Investigator) 
 
The Protocol Chair, Dr. Nadine Tung, will accept responsibility for all aspects of the  
Multi-Center Data and Safety Monitoring Plan to: 
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the 
protocol. 
• Assure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team receives adequate protocol 
training and/or a Site Initiation Visit prior to enrolling subjects. 
• For international trials, assure that the protocol is provided to Participating Institutions 
in the primary language spoken at the site.    
• Monitor progress and overall conduct of the study at all Participating Institutions. 
• Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.  
• Ensure all DFCI IRB and DF/HCC requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
 
2.2   Coordinating Center (Lead Institution) 
 

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The Coordinating Center is the DF/HCC Lead Institution’s study team or designee (i.e Medical 
Monitor, Clinical Research Organization). The DF/HCC Lead Institution Dana-Farber Cancer 
Institute will ensure that all Participating Institutions within the Multi-Center Protocol 
demonstrate their intent and capability of complying with Federal Regulations and HIPAA 
requirements. To assist the Protocol Chair in meeting his/her responsibilities as required by the 
DSMP, the DF/HCC Lead Institution’s study team or designee will assume the following general 
responsibilities: 
• Assist in protocol review. 
• Maintain copies of FWA and Institutional Review Board (IRB) approvals from all 
Participating Institutions. 
• Maintain correspondence, as applicable. 
• Maintain updated roster of participants.  
• Verify eligibility. 
• Verify response. 
• Collect data on protocol specific CRFs. 
• Prepare all submitted data for review by the Protocol Chair. 
• Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to Protocol Chair for timely review.   
• Distribute Serious Adverse Event safety reports (both IND Safety reports and protocol 
specific SAEs).  
• Monitor at Participating Institutions either by on-site inspection of selected participant 
records and/or with source documents and research records submitted to the Lead 
Institution.  
    
In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical Trials 
provides the following support services to assist the Protocol Chair: 
• Develop protocol specific case report forms (eCRFS). 
• QA/QC data of protocol specific CRFs.  
• Provide Central Participant Registration. 
• Verify that eligibility has been confirmed by the investigator and that appropriate 
consent has been obtained.  
• Provide auditing services (funding and ODQ approval required). 
 
2.3   Participating Institution 
 
Each Participating Institution will provide to the Coordinating Center a list of the key personnel 
assigned to the role for oversight of data management at their site. All sites must have office 
space, office equipment, and internet access that meet HIPAA standards. 
The general responsibilities for each Participating Institution are as follows: 
 
• Commit to accrual to the Lead Institution’s (DF/HCC) protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain a regulatory binder. 
• Update Coordinating Center with research staff changes on a timely basis. 

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• Register participants through the Coordinating Center.  
• Submit source documents, research records, and CRFs per protocol specific submission 
guidelines to the Coordinating Center. 
• Submit Serious Adverse Event reports to local IRB and directly to the Coordinating 
Center.  
• Submit deviations and violations to local IRB and the Coordinating Center. 
 
 
3.0 PROTOCOL DEVELOPMENT 
 
3.1 Activation of a Protocol 
 
The Protocol Chair is responsible for the coordination, development, and approval of the protocol 
as well as its subsequent amendments, and reporting SAEs, violations and deviations per DFCI 
IRB guidelines.  
 
To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards: 
 
• Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the protocol 
as an appendix. 
• Identify, qualify and initiate Participating Institutions and obtain accrual commitments.  
• Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the Protocol Chair. 
• Ensure that there is only one version of the Protocol and that all Participating 
Institutions use the correct version.  
• Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the Participating Institutions.  
 
 3.2 Coordinating Center Support Function 
  
The DF/HCC Lead Institution’s study staff or designee will provide administrative and clerical 
support to the Protocol Chair for the development and distribution of the protocol.  
 
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee include: 
• Maintain Regulatory documents for all Participating Institutions.  
• Review of the protocol and consent to check for logistics, spelling, and consistency.  
Provide the Protocol Chair a list of queries related to any inconsistencies. 
• Provide necessary administrative sections, including paragraphs related to registration 
logistics, data management schedules, and multi-center guidelines.  
• Maintenance of contact list of all Participating Institutions in the DF/HCC Multi-center 
Protocol and the distribution of updates to the sites as needed.  
• Derivation of the study calendar, if applicable. 
•  Assistance in preparation and maintenance of case report forms. 

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• Conduct regular communications with all Participating Institutions (conference call, 
emails, etc)   
• Maintain documentation of all communications.  
 
 
 
 
4.0 PROTOCOL MANAGEMENT 
 
The Coordinating Center is responsible for assuring that each Participating Institution has the 
appropriate assurance on file with the Office of Human Research Protection (OHRP).   Additionally, 
the Coordinating Center must maintain copies of all IRB approvals, for each Participating Institution.  
 
 
4.1 Protocol Distribution 
 
The Coordinating Center will distribute the final approved protocol and any subsequent amended 
protocols to all Participating Institutions.    
 
4.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive phone, fax, mail or e-mail notification of protocol 
revisions from the Lead Institution or designee.  It is the individual Participating Institution’s 
responsibility to notify its IRB of these revisions. 
 
Non life-threatening revisions: Participating Institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Lead Institution or designee. 
Non-life-threatening protocol revisions should be IRB approved and implemented within 90 days 
from receipt of the notification. 
 
Revisions for life-threatening Causes: Participating Institutions will receive telephone 
notification from the Lead Institution or designee concerning protocol revisions required to 
protect lives with follow-up by fax, mail or e-mail.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval 
 
Protocol Closures and Temporary Holds: Participating Institutions will receive fax, e-mail, or 
phone notification of protocol closures and temporary holds from the Lead Institution or 
designee. Closures and holds will be effective immediately.  In addition, the Lead Institution or 
designee will update the Participating Institutions on an ongoing basis about protocol accrual data 
so that they will be aware of imminent protocol closures. 
 
4.3 Informed Consent Requirements 
 
 
 

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The DF/HCC approved informed consent document will serve as a template for the informed 
consent from participating institutions. As best a possible, the template should be followed with 
the specifications outlined in the DF/HCC guidance document on Model Consent Language.   
 
Participating sites are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Lead Site for their revision prior to submission to the 
participating site's IRB.  
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. It is DF/HCC policy that only attending physicians can obtain 
informed consent and re-consent to drug and/or device trials.   
 
 
4.4 IRB Documentation 
 
The following must be on file with the DF/HCC Lead Institution or designee and must be 
submitted and approved by the DFCI IRB prior to participant registration: 
 
• Approval Letter of the institution's IRB  
• Copy of the Informed Consent Form approved by the Participating Institution’s IRB  
• IRB approval for all amendments 
 
It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the DF/HCC Lead Institution 
their IRB approval for Amendments to a protocol.    
 
 
 
4.5 IRB Re-Approval 
          
Annual IRB re-approval from the Participating Institution is required in order to continue research 
and register participants onto a protocol.  There is no grace period for continuing approvals. 
 
Protocol registrations will not be completed if a re-approval letter is not received by the DF/HCC 
Lead Institution from the Participating Institutions on or before the anniversary of the previous 
approval date.   
 
 
4.6 Participant Confidentiality and Authorization Statement 
 
The HIPPA of 1996 contains, as one of its six major components, the requirement to create 
privacy standards for health care information that is used or disclosed in the course of treatment, 
payment or health care operations.  The original Privacy Rule, as it has come to be known, was 
published in December 2000.  The Final Rule was published on August 14, 2002, which modified 
the privacy rule in significant ways vis-à-vis research. 

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In order for covered entities to use or disclose protected health information during the course of a 
DF/HCC Multi-Center Protocol, the study participant must sign an Authorization.  This 
Authorization may or may not be separate from the Informed Consent.  The DF/HCC Multi-
Center Protocol, with the approval from the DFCI IRB and if applicable NCI/CTEP, will provide 
an Informed Consent template, which covered entities (DF/HCC Multi-Center Protocol 
Participating Institutions) must use.  
 
The DF/HCC Multi-Center Protocol will use all efforts to limit its use of protected health 
information in its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per National Cancer Institute requirements. These are the primary 
reasons why DF/HCC has chosen to use Authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements.   
 
 
4.7 Participant Registration and Randomization  
Refer to section 4 of the protocol for information regarding participant registration and 
randomization.  
 
4.8 DF/HCC Multi-center Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five digit protocol case number.  This number is unique to the participant on this trial 
and must be used for ODQ CRF/eCRF completion and written on all data and ODQ 
correspondence for the participant. 
 
4.9 DF/HCC Multi-center Protocol Registration Policy 
 
4.9.1 Initiation of Therapy: Participants must be registered with the DF/HCC ODQ before 
receiving treatment.  Treatment may not be initiated until the Participating Institution 
receives a faxed or e-mailed copy of the participant’s Registration Confirmation memo from 
the DF/HCC ODQ. Therapy must be initiated per protocol guidelines.  The Protocol Chair 
and DFCI IRB must be notified of any exceptions to this policy.  
 
4.9.2 Eligibility Exceptions: The DF/HCC ODQ will make no exceptions to the eligibility 
requirements for a protocol without DFCI IRB approval.  In addition, the Cancer Therapy 
Evaluation Program (CTEP) specifically prohibits registration of a participant on any NCI 
Sponsored protocol that does not fully and completely meet all eligibility requirements. The 
DF/HCC ODQ requires each institution to fully comply with this requirement. 
 
4.9.3 Verification of Registration, Dose Levels, and Arm Designation: A registration 
confirmation memo for participants registered to DF/HCC Multi-Center Protocol will be 
faxed or emailed to the registering institution within one working day of the registration. 

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Treatment may not be initiated until the site receives a faxed or e-mailed copy of the 
registration confirmation memo.  
 
4.9.4 Confidentiality: All documents, investigative reports, or information relating to the 
participant are strictly confidential. Whenever reasonably feasible, any participant specific 
reports (i.e. Pathology Reports, MRI Reports, Operative Reports, etc.) submitted to the Lead 
Institution or designee must have the participant’s full name & social security number 
“blacked out” and the assigned DF/HCC ODQ case number and protocol number written in 
(with the exception of the signed informed consent document). Participant initials may only 
be included or retained for cross verification of identification. 
  
 
4.10 Schedule of Data Submission 
 
The DF/HCC ODQ develops a set of either paper or electronic case report forms, (CRF/eCRFs) 
for use with the DF/HCC Multi-Center Protocol.  ODQ provides a web based training for eCRF 
users.  These forms are designed to collect data for each study.  
Note: It is necessary to send only ONE copy of all paper Case Report Forms, if applicable.  
 
4.10.1 Eligibility Checklist 
 
Purpose - Outlines protocol-specific eligibility criteria and includes the following: 
              
Participant Demographics (address, zip code, sex, race, ethnicity, initials, date of birth) 
1) Parameters for eligibility 
2) Parameters for exclusion 
3) Parameters for stratifications 
If a time frame is not specified in the protocol, tests must be completed as follows: 
• Lab tests required for eligibility must be completed within 28 days prior to study 
enrollment by the ODQ. 
• Non-lab tests required for eligibility must be performed within 30 days prior to study 
entry. Example: radiological scans 
 
4.10.2 On-study Form(s) 
 
Purpose - documents the following items: 
• Demographic data 
• Prior therapy 
• Past medical and surgical history 
• Description of participant’s physical status at protocol registration 
• Disease site specific data 
 
4.10.3 Baseline Assessment Form(s) 
 

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Purpose – Documents objective and subjective disease status as defined by the protocol. 
Records all pertinent radiographic and laboratory measurements of disease utilized in 
determining response evaluations.  
 
4.10.4  Treatment Form(s) 
 
Purpose - Records the following information related to the time the participant receives 
protocol treatment: 
• Participant, Protocol information 
• Protocol treatment and supportive therapy per treatment cycle 
• Protocol specific laboratory values per treatment cycle 
• All medications other than protocol chemotherapy agents used to treat concomitant   
diagnoses, if applicable 
 
4.10.5 Adverse Event Report Form(s) 
 
Purpose – Documents adverse events that occur while the participant is receiving treatment 
and for up to 30 days after the last dose of treatment.  All adverse events are to be graded by 
number using the toxicity grading scale required by the protocol. This form is not for IRB 
submission, but for recording the AE in the research database. 
 
 
4.10.6   Off Treatment and Off Study Form(s) 
 
Purpose - The Off Treatment and Off Study Forms are submitted when the participant is  
removed from the study or has completed all protocol treatment.  Note: If the participant 
dies while on protocol, the Off Study Form is the last form submitted. 
 
 
 4.11 Data Form Review 
 
When data forms arrive at the DF/HCC ODQ, they are reviewed for: 
   
 
 
Completeness:  
Is all the information provided as required per protocol? 
 
Protocol Treatment Compliance:  
Are the body surface area (BSA) and drug dosage calculations correct?  The dose must be within 
10% of the calculated protocol dose. 
  
Adverse Events (Toxicities):  
Did the participant experience adverse events (toxicities or side effects) associated with the 
treatment? Was the treatment delayed due to the adverse event? What was the most severe degree 
of toxicity experienced by the participant? 
 

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Notations concerning adverse events will address relationship to protocol treatment for each 
adverse event grade.  All adverse events encountered during the study will be evaluated according 
to the NCI Common Toxicity Criteria assigned to the protocol and all adverse events must be 
noted on the participant's Adverse Event (Toxicity) Forms. 
 
Response:  
Did the participant achieve a response?  What level of response did they achieve?  On what date 
did the participant achieve the response and how was the response determined? 
 
Response criteria are defined in the protocol.  A tumor assessment must be performed prior to the 
start of treatment and while the participant is on treatment as specified by the protocol.   
 
Objective responses must have documentation such as physical measurements, x-rays, scans, or 
laboratory tests.   
 
A subjective response is one that is perceived by the participant, such as reduction in pain, or 
improved appetite. 
 
 
4.12 Missing and Deficient Memorandum 
 
Data submissions are monitored for timeliness and completeness of submission. Participating 
Institutions are notified of their data submission delinquencies in accordance with the following 
policies and procedures: 
 
Incomplete or Questionable Data 
 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written query from the DF/HCC ODQ Data Analyst.  Responses to the query should be 
completed and returned within 14 days.  Responses may be returned on the written query or on an 
amended case report form. In both instances the query must be attached to the specific data being 
re-submitted in response.   
 
Missing Forms 
 
If study forms are not submitted on schedule, the Participating Institution will receive a Missing 
Form Report from the DF/HCC ODQ noting the missing forms.  These reports are compiled by 
the DF/HCC ODQ and distributed a minimum of three times a year.  
 
5.0 REQUISITIONING STUDY DRUG 
      
All study drugs are commercially available. Participating Institutions are responsible for checking 
with the local Director of Pharmacy to ensure that the agent is in stock.   
 
6.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING 

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All participants receiving investigational agents will be evaluated for safety.   The safety parameters 
include all laboratory tests and hematological abnormalities, physical examination findings, and 
spontaneous reports of adverse events reported to the investigator by participants.  All toxicities 
encountered during the study will be evaluated according to the NCI criteria specified in the 
protocol and recorded prior to each course of therapy.  Life-threatening toxicities should be reported 
immediately to the Protocol Chair and Institutional Review Board (IRB).  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
6.1 Serious Adverse Events 
 
A serious adverse event (SAE) is any adverse drug experience at any dose that results in any of 
the following outcomes: death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions in a participant who has 
never had seizure activity in the past that do not result in inpatient hospitalization, or the 
development of drug dependency or abuse. 
 
6.2 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is delineated in the 
protocol in section 10. 
 
 
 
 
 
The Lead Institution will maintain documentation of all Participating Institution Adverse Event 
reports and be responsible for communicating all SAEs to all sites conducting the trial. 
 
Participating Institutions must report the AEs to the Protocol Chair and the Coordinating Center 
following the DFCI IRB SAE Reporting Requirements.  
 
6.3 Guidelines for Processing IND Safety Reports  
 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. The Protocol Chair will review 
all IND Safety Reports and is ultimately responsible for forwarding the IND Safety Reports to the 
Participating Institutions.  The Participating Institutions will review and submit to their IRB 
according to their institutional policies and procedures.  
 
 
7.0 PROTOCOL VIOLATIONS AND DEVIATIONS 

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Neither the FDA nor the ICH guidelines define the terms “protocol violation” or “protocol 
deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the DFCI IRB, 
the definitions for protocol violation and deviation as described by the DFCI IRB will be 
applied for reporting purposes for all Institutions Participating in the DF/HCC Multi-center 
Protocol.  
  
7.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. enrollment   
of a subject who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB prior 
to its initiation or implementation.  
 
 
 
 
7.2 Reporting Procedures 
 
The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations and 
violations.  
The Protocol Chair will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from DFCI IRB. 
The Participating institution must submit the deviation request to the Protocol Chair or 
designee, who will submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the 
deviation should be submitted to the Participating Institution’s own IRB, per its institutional 
policy. 
A copy of the Participating Institution’s IRB report and determination will be forwarded to the 
DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail within 10 business days 
after the original submission.  
 
All protocol violations must be sent to the DF/HCC Lead Institution Protocol Chair or designee 
in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the DF/HCC Lead Institution or designee will submit the report to the Protocol 
Chair for review. Subsequently, the Participating Institution’s IRB violation/deviation report 
will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 

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8.0 MONITORING: QUALITY CONTROL 
      
1) The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. As the Coordinating Center, the DF/HCC Lead Institution or designee with the aid of the 
ODQ provides quality control oversight for the DF/HCC Multi-center Protocol. 
 
8.1  Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions will be required to submit participant source documents to the 
DF/HCC Lead Institution or designee for monitoring. Also, the Participating Institution may be 
subject to on-site monitoring conducted by the DF/HCC Lead Institution or designee.   
 
The DF/HCC Lead Institution will implement on-going monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and subject safety.  Additional monitoring practices may include but are not limited to; source 
verification, review and analysis of the following: eligibility requirements of all participants , 
informed consent procedures, adverse events and all associated documentation, study drug 
administration / treatment, regulatory records and site trial master files, protocol deviations, 
pharmacy records, response assessments, and data management.  Additionally, a plan will be 
formulated to provide regular and ongoing communication to Participating Institutions about 
study related information which will include participation in regular coordinating center initiated 
teleconferences.  Teleconferences will occur approximately once a month beginning as soon as 
external sites are activated and will continue regularly until the completion of accrual.  Upon 
completion of accrual, teleconferences will occur quarterly thereafter until study completion.  
Additional communication may be distributed via “Newsletter” or email as deemed appropriate 
by the protocol chair. 
 
Monitoring will occur before the clinical phase of the protocol begins and will continue during 
protocol performance through study completion.  Each participating site will have one on-site 
monitoring visit after at least 3 participants have been enrolled at the site.  Virtual monitoring 
should occur approximately every 6 months and may occur more frequently if there are 
significant findings or discrepancies.  On-site and virtual monitoring will be performed by the 
Coordinating Center’s Clinical Research Specialist (CRS).  The data will be reviewed for 
completeness, quality, and adherence to the protocol requirements.  Sites will be asked to provide 
source documentation via fax, email, or mail as specified by the Clinical Research Specialist for 
all virtual monitoring visits.  A virtual site initiation visit (SIV) will be conducted with each 
participating site prior to study activation.  Participating sites many not begin enrolling until the 
SIV has occurred. 
 
All data submitted to the DF/HCC ODQ will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. The Coordinating Center or designee and if 
applicable ODQ Data Analysts assigned to the Protocol will perform the ongoing protocol data 
compliance monitoring with the support of the Participating Institution’s Coordinators, the Principal 
Investigators, and the Protocol Chair.  

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9. 0 Evaluation of Participating Institution Performance 
 
9.1.1 Eligibility Checklist:  
 
Eligibility criteria are checked on a protocol-specific eligibility checklist and faxed to the 
DF/HCC ODQ prior to registration on protocol.  The checklist and informed consent document 
are reviewed by a DF/HCC ODQ Protocol Registrar before the participant can be registered on 
a protocol.  The DF/HCC ODQ cannot make exceptions to the eligibility requirements. 
 
9.2.2 Accrual of Eligible Participants:  
 
 Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.A total of 170 subjects will be enrolled among all 
participating sites during a three year period. Participating Institutions are expected to enroll 3 patients 
annually.   
 
 
 
10.0 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. The main focus in auditing is to measure if the standards and 
procedures set are being followed. Auditing is the systematic and independent examination of all trial 
related activities and documents.  Audits determine if evaluated activities were appropriately conducted 
and the data were generated, recorded and analyzed, and accurately reported per the protocol, Standard 
Operating Procedures (SOPs) and the Code of Federal Regulations. 
 
10.1 DF/HCC Sponsored Trials 
 
On-site audits will be conducted by ODQ at participating sites as needed (as determined by the 
Protocol chair).  An audit may be triggered if deficiencies are noted related to consent practices, 
eligibility, missing, incomplete, or questionable data submission, or any other issue the protocol 
chair deems appropriate for audit.  If a participating site is selected for audit, approximately 3-4 
subjects would be audited at the site over a 2 day period.  If violations which impact subject 
safety or the integrity of the study are found, more subject records may be audited.   
 
10.2 Participating Institution 
It is the Participating Institution’s responsibility to notify the DF/HCC Lead Institution of all 
scheduled audit dates (internal or external) and re-audit dates (if applicable), which involve the 
DF/HCC Multi-Center Protocol. All institutions will forward a copy of final audit and/or re-audit 
reports and corrective action plans (if applicable) to the DF/HCC Lead Institution or designee 
within 12 weeks after the audit date.  

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10.3 Coordinating Center (Lead Institution or designee)  
The Protocol Chair will review all DF/HCC Multi-Center Protocol Final Audit reports and 
corrective action plans if applicable. The Lead Institution or designee must forward these reports 
to the DF/HCC ODQ per DF/HCC policy for review by the DF/HCC Audit Committee. Based 
upon the audit assessments the DF/HCC Audit Committee could accept or conditionally accept 
the audit rating and final report. Conditional approval could require the Protocol Chair to 
implement recommendations or require further follow-up.  For unacceptable audits, the Audit 
Committee would forward the final audit report and corrective action plan to the DFCI IRB as 
applicable. 
 
10.4 Sub-Standard Performance 
 
The Protocol Chair, DFCI IRB and the NCI for CTEP trials, is charged with considering the 
totality of an institution’s performance in considering institutional participation in the DF/HCC 
Multi-Center Protocol. 
 
10.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely accurate data, adherence to protocol requirements, and compliance with state and 
federal will be recommended for a six- month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered 
by the Protocol Chair for revocation of participation. 

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Appendix G:  12-258 SPECIMEN REQUISITION (Diagnostic and Surgery Blocks/Slides) 
 
Complete this form and include with the specimen shipment.  Label ALL materials with participant initials, DFCI participant study ID, and the date 
the specimen was obtained. Include a pathology report with any archival tissue specimens being submitted.  
 
Ship specimen(s) to: Beth Israel Deaconess Medical Center, Attn: 
 
Specimen Information 
Participant Initials (FML): __________     DFCI Participant Study ID Number: _____________    Date specimen(s) shipped: __________________ 
Site of Lesion: 
 Right breast  
 Left breast             Pathology reports included (Mark all that apply):  
 Pre-chemo     
Post-chemo                                 
 
Responsible contact: _______________________________          Mailing address 
(to return 
slides): 
__________________________________________  
__________________________________________ 
__________________________________________ 
__________________________________________ 
Email: ___________________________________________ 
Phone number: ____________________________________ 
Site: _____________________________________________ 
 
 
Specimen Type  
(indicate inclusion in shipment by checking box) 
Pathology Number(s) or Serial Coding 
Quantity 
submitted 
Date specimen 
obtained 
 Representative H&E slide from each block from Diagnostic biopsy 
 
 
 
 Block / 
 Unstained slides from Diagnostic biopsy 
 
 
 
 All H&E slides from Definitive surgery (post chemotherapy)  
 
 
 
 All H&E slides from Axillary Lymph Nodes 
 
 
 
 Block / 
 Unstained slides from Definitive surgery (post 
chemotherapy) 
 
 
 
 Block / 
 Unstained slides from Normal breast tissue, skin or 
uninvolved lymph nodes 
 
 
 
 Other, specify: 
 
 
 

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Appendix I: INFORM/TBCRC031 Questionnaire for Annual Follow-Up after Breast Surgery 
This questionnaire should be utilized by the study team if contacting a participant, their designee, or local 
provider directly for follow up information.  
 
For the first annual follow up, please complete Questions 1-11. For the second and third annual follow up, only 
Questions 6-11 need to be completed.  
 
Patient Name: ________________________________ 
 
Date of Birth: ________________________________ 
 
Date Questionnaire Completed: ________________________________ 
 
1) Please provide all the ways in which we may contact you: 
• Phone #s: ___________________________ 
  
home: ___________________________ 
  
cell: ____________________________ 
• Email:  ___________________________ 
 
2) What are the names and contact information of any members of your health care team who have treated 
you for your breast cancer or followed you since completing surgery on the INFORM trial:  
 
• Surgeon: __________________________________ 
 
name: __________________________________ 
 
phone #/email:  ___________________________ 
 
• Radiation Therapist: ___________________________ 
 
name: ____________________________________ 
 
phone #/email: _____________________________ 
 
• Medical Oncologist: ___________________________ 
 
name: ____________________________________ 
 
phone/email: _______________________________ 
 
• Primary Care physician: __________________________ 
 
 
name: ______________________________________ 
 
 
phone/email: _________________________________ 
 
3) Did you have any additional breast surgeries after your first breast surgery to remove your breast cancer 
on the INFORM trial (Yes/No)? _____________ 
• If yes, what kind (unilateral mastectomy, bilateral mastectomy, conserving surgery, other)? 
__________________________ 
i. If unilateral or conserving surgery, which breast? _____________ 
ii. Date of surgery: ____/_____/____ 

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4) Did you receive chemotherapy after the breast surgery (Yes/No)? _____________ 
• If yes, which chemotherapy agent(s)? _____________ 
• If you were not assigned to Cisplatin as part of the INFORM trial, did you receive platinum 
chemotherapy at any time to treat the breast cancer (Yes/No)? _____________ 
i. If yes: was platinum given right after your breast surgery or to treat recurrent breast cancer? 
_______________________________________ 
 
5) Did you receive any other systemic therapy after surgery (including, but not limited to, immune therapy 
and PARP inhibitors) (Yes/No)? _____________ 
• If yes, which agents? _________________ 
 
6) Did you receive radiation as part of your care (Yes/No)? _____________ 
• If yes, what was the start date of the radiation? ____/_____/____ 
 
7) Have you had your ovaries and fallopian tubes removed (Yes/No)? _____________ 
• If yes, what was the date of the procedure? ____/_____/____ 
 
8) Have you had your breast cancer return (recurrence) anywhere in the body (please complete all 
applicable from the list below) (Yes/No)? _____________ 
• Breast (Yes/No) _____________ 
i. If yes, what date? ____/_____/____ 
ii. If yes, was it the same breast as the initial cancer? _____________ 
• Regional lymph nodes (Yes/No)  _____________ 
i. If yes, what date? ____/_____/____ 
• Skin (Yes/No) _____________ 
i. If yes, what date? ____/_____/____ 
• Distant (Yes/No)  _____________ 
i. If yes, what date? ____/_____/____ 
ii. If yes, what location(s)? _____________ 
 
9)  Have any of your treatments including a PARP inhibitor (e.g. Olaparib, Talazoparib, Nirapirib)? 
• If yes, what was the name of the PARP inhibitor? _____________ 
• If yes, what date(s)? ____/_____/____ 
• If yes, what was your response (e.g. shrinkage vs stable disease vs. immediate progression)? 
_______________________________________ 
• If yes, what was the duration of your treatment on the PARP inhibitor? _____________ 
 
10)  Have you developed any new cancers since completing surgery on the INFORM trial? _____________ 
 
If contacting designee or local provider: 
11)  Is the patient to whom we are referring currently living? _____________ 
• If no, when did she pass away (date of death)? ____/_____/____ 
• If no, was the cause of death breast cancer? _____________ 
 

 
Potential Participant Information Sheet 
 
What is the INFORM trial? 
It is a study evaluating whether a chemotherapy drug, cisplatin is better than currently 
used standard chemotherapy drugs (Cyclophosphamide/Doxorubicin) for treating patients 
with newly diagnosed breast cancer due to an inherited abnormality (mutation) in one of 
the breast cancer genes, BRCA1 or BRCA2. 
 
 
How do I know if I have breast cancer due to BRCA1 or BRCA2? 
Genetic testing is performed on a blood sample after genetic counseling; results usually 
return in about 10 days. Breast cancer patients who fit one of the criteria below are 
appropriate candidates for genetic testing. The cost of the test would be covered by 
insurance or the INFORM study.  
 
 
What is involved in being in the INFORM trial? 
If you are found to have a BRCA1 or BRCA2 abnormality (mutation), you are potentially 
eligible to be in the study if your cancer is the kind that would otherwise be treated with 
chemotherapy. If you choose to be in the study, you would receive chemotherapy before 
your breast cancer is removed surgically. As part of the study you would either receive 
conventional chemotherapy, or cisplatin, the study drug.  
 
 
Why is this study being done? 
There are some data to show that cisplatin is an effective drug for treating breast cancers 
in women with BRCA1 and BRCA2 mutations, possibly more effective than currently 
used chemotherapy.  However, this has not been proved in a randomized clinical trial like 
the INFORM study.  Therefore, you would not receive cisplatin to treat your breast 
cancer outside of a study. 
 
 
Thank you for considering this study. Undergoing genetic testing does not obligate you 
to participate in the study but does allow us to determine if you are eligible. If you 
would consider participating in the study, please ask your doctor for a consult with a 
genetic counselor, possibly even today, so you can hear more about genetic testing. If 
you feel that you would prefer to have your tumor removed before any systemic 
treatment, then this study is not for you.  You may still choose to have genetic 
testing, but there is no rush to do so.  It is important that the genetic test be 
performed before your tumor is removed, because in the study, chemotherapy would 
be given before your breast surgery. 
 
 

 
Provider Information Sheet 
 
INFORM: BRCA1/2 trial is a randomized neoadjuvant trial for women with newly 
diagnosed breast cancer and BRCA1/2 mutations comparing 4 cycles of 
Cisplatin to standard “AC” (Adriamycin/Cytoxan) followed by surgery  
(lumpectomy or mastectomy). There are data suggesting that cisplatin is an 
extremely effective drug for BRCA+ breast cancers. 
 
Eligibility 
 Newly diagnosed breast cancer > 1.5 cm, triple negative or high grade ER+ 
(Grade 2 or 3 or recurrence score  > 31). 
 BRCA1 or BRCA2 germline mutation. 
 No prior chemotherapy   
 
Genetic Testing Availability 
All patients who meet criteria listed below are eligible for genetic testing. The cost 
of testing will be covered by insurance or the trial: expedited results within 10 
days.  Patients who would consider the trial should be referred for genetic 
counseling and testing expeditiously.  Please contact  <Insert Site Information 
here >  to facilitate an appointment.  .   
 
Genetic Testing Criteria (For breast cancer patients) 
• Has a blood relative with a BRCA1 or BRCA2 mutation 
• Age 45 or younger 
• Ashkenazi Jewish (ancestors from Europe) 
• Age 50 or younger and has a blood relative with breast cancer who 
was diagnosed at age 50 or younger 
• Age 60 or younger and has triple negative breast cancer (i.e., ER-, 
PR-, HER2-)  
• Bilateral breast cancer (cancer in both breasts) and is younger than 
age 50 
• Had a blood relative with male breast cancer 
• Had a blood relative with ovarian cancer 
• Has 2 blood relatives (on the same side of the family) who have 
also had breast cancer 
• This is a second breast cancer, the first diagnosed before age 50 
(however, prior chemotherapy renders a patient ineligible) 
• Also had prior ovarian cancer (however, prior chemotherapy 
renders a patient ineligible) 
• Is a male 
 

Version date: 7/29/2013 
Dear Patient, 
We are writing to you because you have previously been seen in [INSERT CLINIC NAME HERE] 
due to a personal or family history of cancer and have been found to have a BRCA1 or BRCA2 
mutation.   
As  you  are  likely  aware,  the  medical  management  recommendations  for  individuals  with  a 
hereditary predisposition to develop cancer are constantly evolving as we learn new information 
about  cancer  risks  in  families,  as  new  technology  is  developed,  and  as  new  genetic  testing 
becomes  available.  We  strongly  encourage  all  of  our  patients  to  follow  up  with  our  genetics 
team on a regular basis to ensure we keep you up to date regarding the latest information about 
screening and prevention.  If you have not been seen in our program for greater than one year 
(and you aren’t otherwise followed regularly by your oncologist or other cancer specialist), we 
encourage you to take the time to make a follow up visit with our program.  
At [INSERT CLINIC NAME HERE] we are continually striving to provide our patients with the latest 
and most advanced information on the treatment of hereditary cancers that may be relevant to 
you, your family or a community of BRCA carriers with whom you have connected. 
 [INSERT THIS SECTION FOR DF/HCC AND DF/PCC SITES; DELETE THIS SECTION FOR EXTERNAL 
SITES]Towards this end, we want to let you know about an important study for BRCA carriers 
newly diagnosed with breast cancer, the INFORM BRCA1/2 trial. This study investigates whether 
a particular chemotherapy agent, cisplatin is superior to conventional chemotherapy for BRCA 
carriers with breast cancer. This study will accrue patients at many centers across the country, 
and is open at several hospitals in Boston including [INSERT HOSPITAL NAME HERE]. Please feel 
free to share the information about this study with your family members or other individuals 
you know who are at increased risk for cancer due to an inherited BRCA mutation. Included is a 
brochure  about  this  trial  and  contact  information  for  any  potentially  eligible  and  interested 
patients. 
[INSERT  THIS SECTION FOR EXTERNAL  SITES; DELETE THIS SECTION FOR DF/HCC AND DF/PCC 
SITES] Towards this end, we want to let you know about an important study for BRCA carriers 
newly diagnosed with breast cancer, the INFORM BRCA1/2 trial. This study investigates whether 
a particular chemotherapy agent, cisplatin is superior to conventional chemotherapy for BRCA 
carriers with breast cancer. This study will accrue patients at many centers across the country 
including [INSERT HOSPITAL NAME HERE]. Please feel free to share the information about this 
study with your family members or other individuals you know who are at increased risk for 
cancer due to an inherited BRCA mutation.  
There are also many other cancer trials for BRCA carriers available at [INSERT HOSPITAL NAME 
HERE]. For questions regarding these studies, please contact [INSERT CONTACT INFORMATION 
HERE]  (research nurse) at [INSERT PHONE # HERE},  or me, [INSERT DOCTOR NAME HERE]  at 
[INSERT PHONE # HERE]. 
If you have any questions about the information provided with this letter, or if you would like to 
discuss making a follow up appointment with our program, please call us directly at [INSERT 
PHONE # HERE].  
 

Version date: 7/29/2013 
Sincerely, 
 
 
[INSERT PHYSICIAN NAME HERE] 
[INSERT TITLE HERE]