Clinical trial NCT02789657
Conditions: Breast Cancer
Keywords: neoadjuvant breast cancer stage I-III breast cancer HER 2 positive breast cancer
Sponsor: Brown University
Start date: 2016-11-21; Completion date: 2020-03-27
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Neoadjuvant therapy is given to breast cancer patients whose cancers are relatively large or have spread to lymph nodes or both. The primary goal of this treatment is to prevent the cancer from coming back (recurring) elsewhere in the body, but if it makes the cancer in the breast and lymph nodes shrink it might be easier to remove. This could allow a patient to have a lumpectomy instead of a mastectomy and reduce the number of lymph nodes that the surgeon has to remove. In some cases, the neoadjuvant therapy works so well that it kills all of the cancer in the breast and lymph nodes. This is referred to as a pathologic complete response (pCR). Patients who achieve a pCR have a much lower risk of the cancer recurring elsewhere in their bodies.

Investigators aren't sure which chemotherapy drugs work best with the HER2-targeted drugs, and what combination of these drugs causes the fewest side effects.Thus, this study has two main goals:

1. To find out if treatment with wPCbTP, weekly paclitaxel and carboplatin given with trastuzumab and pertuzumab every 3 weeks, leads to as many pCRs as TCHP in patients with HER2-positive breast cancer, but has fewer side effects.
2. To find out if HER2-positive patients whose cancers are not responding well after 12 weeks of wPCbTP get a better response when they are switched to a doxorubicin-containing regimen called AC for 4 cycles (8-12 weeks).

Detailed description:
See summary above

Arms: arm 1: 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab. Post treatment, patients will undergo surgery. arm 2: 12 weeks (4 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab. Post 12 weeks, initiation of doxorubicin and cyclophosphamide for 4 cycles (6 weeks), followed by surgery. arm 3: Less than 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab, followed by initiation of doxorubicin and cyclophosphamide. Post treatment, patients will undergo surgery. arm 4: 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab. Post treatment, patients will undergo surgery.
Interventions: intervention 1: paclitaxel intervention 2: Trastuzumab intervention 3: Pertuzumab intervention 4: carboplatin intervention 5: Breast surgery intervention 6: AC
Intervention descriptions: intervention 1: 80 mg/m2 (or nab-paclitaxel 80-100 mg/m2) weekly intervention 2: Either every 3 weeks (8 mg/kg cycle 1 then 6 mg/kg cycles 2-4) or weekly (4 mg/kg week 1 then 2 mg/kg weeks 2-12) intervention 3: every 3 weeks (840 mg cycle 1 then 420 mg cycles 2-4) or weeks 1 and 2 cycle 1 (420 mg each dose) during the first 3-6 weeks of treatment, then 420 mg day 1 of cycles 2-4. intervention 4: AUC 2 administered weekly with no planned treatment breaks intervention 5: breast conserving or mastectomy intervention 6: doxorubicin and cyclophosphamide (AC) every 2 or 3 weeks for 4 cycles

Dose-dense AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV day 1 every 2 weeks x 4 cycles

Standard AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV day 1 r every 3 weeks x 4 cycles

Protocol documents:
Prot_SAP_000.pdf: 
BrUOG BR-308  
                                           1 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Efficacy of Weekly Carboplatin and Paclitaxel with Trastuzumab and Pertuzumab 
(wPCbTP) and Switching to an Anthracycline-based Regimen (AC) in                  
Non-responding Patients as Neoadjuvant Therapy in Clinical Stage I-III          
HER2-positive Breast Cancer: BrUOG BR-308  
 
Study Chairs 
William M. Sikov, MD, FACP - Women and Infants Hospital of Rhode Island  
Mary L. Lopresti, DO – Rhode Island Hospital/Miriam Hospital 
   
Co-Investigators: 
Mary Anne Fenton, MD 
Maria Constantinou, MD  
Rhode Island Hospital 
Rochelle S. Strenger, MD 
Miriam Hospital 
Robert D. Legare, MD 
Bachir J. Sakr, MD 
Tina Rizack, MD  
Women and Infants Hospital of Rhode Island  
Brown University Oncology Research Group (BrUOG)  
                                                       
Kayla Rosati, EdM, CCRP 
Director, BrUOG 
233 Richmond G002 
Providence RI 02903 
401-863-3000 
401-863-3820 (fax) 
CONFIDENTIALITY STATEMENT 
The information in this document is considered privileged or confidential and may not be disclosed unless 
federal law or regulations require such disclosure. In any, event persons to whom this information is disclosed 
must be informed that the information is privileged or confidential and may not be disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you, which is indicated as 
privileged or confidential.  
 
 
 
 
 
 
 
 


BrUOG BR-308  
                                           2 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
TABLE OF CONTENTS 
Section 
 
 
 
 
 
 
 
 
 
Page 
I. 
Introduction 
 
 
 
 
 
 
 
 
  3 
II. 
Objectives 
 
 
 
 
 
 
 
 
  3 
III. 
Protocol synopsis 
 
 
 
 
 
 
 
  5 
IV. 
Eligibility 
 
 
 
 
 
 
 
 
  6 
 
V. 
Treatment 
 
 
 
 
 
 
 
 
  8 
 
VI. 
Dose modifications 
 
 
 
 
 
 
 
  9 
 
VII. 
Required data  
 
 
 
 
 
 
 
11 
VIII. 
Pathologic analysis 
 
 
 
 
 
 
 
11 
IX. 
Recording surgical options  
 
 
 
 
 
 
12 
X. 
Pharmacy 
 
 
 
 
 
 
 
 
12 
XI. 
Record Retention 
 
 
 
 
 
 
 
12 
XII. 
DSMB  
 
 
 
 
 
 
 
 
12 
 
XIII. 
Statistics 
 
 
 
 
 
 
 
 
13 
XIV. 
References 
 
 
 
 
 
 
 
 
13 
Appendix I: Adverse Event Reporting  
 
 
 
 
 
15  
Appendix II: Pharmaceutical Information  
 
 
 
 
 
20 
Appendix III: Required On-Study Data Submissions   
 
 
 
29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BrUOG BR-308  
                                           3 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
I. Introduction 
 
          Administration of neoadjuvant chemotherapy and HER2-targeted therapy results in 
high clinical and pathologic response rates in patients with stage II-III HER2-positive 
breast cancer, and achievement of a pathologic complete response (pCR), usually defined 
as the absence of residual invasive disease in the breast and axillary nodes (ypT0/is N0), 
in these patients is associated with excellent long-term outcomes (1,2). However, the 
optimal chemotherapy regimen, in terms of efficacy and toxicity, is not clear. In the 
adjuvant setting, patients exposed to both an anthracycline and trastuzumab have 
significantly higher rates of cardiac toxicity and leukemogenesis than patients treated 
with a non-anthracycline-containing regimen and trastuzumab (such as docetaxel, 
carboplatin and trastuzumab, TCH), while long-term breast cancer-free outcomes are not 
significantly different (3). In the neoadjuvant setting, the addition of pertuzumab to the 
combination of chemotherapy and trastuzumab appears to substantially increase the 
percentage of patients who achieve a pCR, though the impact of this enhanced 
locoregional response on long-term outcomes is not yet known (4,5). On the randomized 
phase II TRYPHAENA neoadjuvant trial, patients who received a non-anthracycline-
containing regimen consisting of TCH plus pertuzumab (TCHP) administered every 3 
weeks for 6 cycles had a pCR rate of 64% compared to 55% for patients who received 
sequential therapy with an anthracycline-based regimen, with or without concurrent 
trastuzumab and pertuzumab, followed by docetaxel with trastuzumab and pertuzumab 
(FEC+/-HP→THP) (5). While these results support the efficacy of the non-anthracycline-
containing TCHP regimen, they do not rule out the existence of a subset of HER2-
positive patients who would benefit from treatment with an anthracycline. TCH is 
associated with such severe and prolonged neutropenia that many patients require the 
administration of a myeloid growth factor such as pegfilgrastim to reduce the risk of 
infections, and the addition of pertuzumab to this regimen increases the risk of severe and 
occasionally life-threatening toxicities, especially neutropenia and diarrhea (5). In 
HER2+ metastatic breast cancer, the combination of weekly paclitaxel with trastuzumab 
and pertuzumab has similar antitumor efficacy as docetaxel with trastuzumab and 
pertuzumab and a much more favorable toxicity profile (6). In the neoadjuvant setting, 
administration of the combination of weekly paclitaxel and carboplatin with trastuzumab 
has been shown to induce a high pCR rate (7-9). This pilot study is designed to test the 
addition of pertuzumab to this well-tolerated combination in patients with stage I (clinical 
T=2.0 cm)-III HER2-positive breast cancer, and to assess whether patients with a 
suboptimal response to 12 weeks of the weekly paclitaxel and carboplatin with 
trastuzumab and pertuzumab (wPCbTP) regimen benefit from switching to an 
anthracycline-based regimen, specifically doxorubicin and cyclophosphamide (AC).   
 
II. Objectives 
     A. Primary  
 
1. Measure the percent of patients who achieve a pCR (ypT0/isN0) in the 
following populations: 
 
     a. The overall study population 
 
     b. Patients with an optimal clinical response (>50% reduction in the sum of 
their breast tumor’s two-dimensional measurements) to wPCbTP at 12 weeks  


BrUOG BR-308  
                                           4 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
 
 
i. who complete 18 weeks of the wPCbTP regimen  
 
 
ii. who complete less than 18 weeks of the wPCbTP regimen but do not 
receive any additional chemotherapy 
 
 
iii. who switch to AC in the neoadjuvant setting for any reason 
 
     c. Patients with a suboptimal clinical response (<50% reduction in the sum of 
their breast tumor’s two-dimensional measurements) to wPCbTP at 12 weeks 
 
 
i. who switch to AC in the neoadjuvant setting 
 
 
ii. who complete 18 weeks of the wPCbTP regimen (did not switch despite 
the suboptimal response at 12 weeks)   
 
 
iii. who complete less than 18 weeks of the wPCbTP regimen but did not 
receive any additional chemotherapy 
          2. Measure the percent of patients who achieve pCR or RCB I in the same patient 
populations 
          3. Measure the percentage of patients with optimal and suboptimal response to 
wPCbTP at 12 weeks 
          4. Measure the percentage of patients who develop major toxicities (defined below) 
during their neoadjuvant therapy (wPCbTP or AC)  
               a. Neutropenia (grade>2)   
   b. Febrile neutropenia (grade 3-4)  
 
   c. Thrombocytopenia (grade >2)  
 
   d. Anemia (grade >2) 
 
   e. Diarrhea (any grade, grade >3)   
 
   f. Neuropathy (any grade, grade 2, grade >3) 
 
   g. Vomiting (any grade, grade >3)  
 
   h. Other grade >3 toxicities 
          5. Measure delivery of treatment with the wPCbTP regimen over 12 weeks and 
(where appropriate) 18 weeks 
 
   a. Frequency of and reasons for treatment delays and dose modifications    
 
     B. Secondary objectives 
          1. Measure the percentage of patients who were clinically node-positive at study 
entry who become pathologically node-negative at surgery 
          2. Measure the impact of neoadjuvant therapy on surgical options 
 
   a. The percentage of patients who were not candidates for breast-conserving 
surgery (BCS) at baseline who become candidates for BCS after treatment (whether or 
not the patient opts for BCS or mastectomy)  
 
   b. The percentage of patients who would have required a full axillary lymph 
node dissection (ALND) at study entry who become candidates for sentinel node 
sampling (SLN) after treatment 
   c. Assess the impact of splitting the loading dose of pertuzumab between weeks 
1 and 2 of cycle 1 and the percentage of these patients in whom the week 2 dose is held 
for early onset diarrhea versus administering the standard loading dose (840 mg) on week 
1 on the incidence and severity of diarrhea and other toxicities experienced during cycles 
1 and 2 of wPCbTP.   
 
    


BrUOG BR-308  
                                           5 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
III. Protocol synopsis 
A. Prior to enrollment on study, patients will have had diagnostic biopsies of their breast 
cancer and, when indicated, sampling (FNA or needle biopsy) of a suspicious ipsilateral 
axillary node, ultrasound and/or MRI of the breast for tumor measurement, baseline 
blood tests, including a pregnancy test when appropriate, cardiac evaluation 
(echocardiogram or MUGA scan), and staging studies to rule out overt metastatic disease 
(strongly recommended for stage III or if clinical suspicion).  
B. Once the patient agrees to participate in the study, her treating doctors will record their 
assessment as to whether, prior to treatment, the patient would have required a 
mastectomy, and if so why, or if the patient would have been a candidate for BCS, and 
whether the patient would require an ALND or would be a candidate for SLN sampling.     
C. The patient will then initiate neoadjuvant therapy with paclitaxel 80 mg/m2 (or nab-
paclitaxel 80-100 mg/m2) and carboplatin AUC 2 administered weekly with no planned 
treatment breaks (3 weeks = 1 cycle). Trastuzumab can be administered either every 3 
weeks (8 mg/kg cycle 1 then 6 mg/kg cycles 2-4) or weekly (4 mg/kg week 1 then 2 
mg/kg weeks 2-12). Pertuzumab will be administered every 3 weeks, with either a 
loading dose (840 mg) week 1 of cycle 1, or two doses (420 mg each) weeks 1 and 2 of 
cycle 1, with the week 2 dose held if the patient is already experiencing grade >1 diarrhea  
to see if this modified dosing schedule reduces the frequency and severity of toxicities, 
especially diarrhea, during the first 3-6 weeks of treatment. The choice of dosing 
schedule for pertuzumab is left to the discretion of the treating oncologist.    
D. While dose modifications will be left to the discretion of the treating oncologist, our 
recommendation is that chemotherapy be delayed or modified only for moderately severe 
neutropenia (<800/mm3) or thrombocytopenia (<50,000/mm3) or persistent grade >2 non-
hematologic toxicities (neuropathy, diarrhea, etc.) on the day of treatment, or for a 
serious or life-threatening toxicity, such as an episode of febrile neutropenia or a bleed 
requiring an urgent platelet transfusion, during the previous cycle. If chemotherapy is 
delayed, the HER2-targeted therapies should continue.  
E. Patients should be assessed clinically every q3 weeks and as indicated for any 
significant new symptoms or findings; patients with disease progression on the wPCbTP 
regimen should be switched to doxorubicin and cyclophosphamide (AC) every 2 or 3 
weeks for 4 cycles followed by surgery, taken immediately to surgery or removed from 
the study (in which case they will be considered a non-pCR).  
F. At the end of 4 cycles of wPCbTP, patients will undergo repeat breast US or MRI to 
assess their response to treatment. Patients with >50% reduction in the sum of the 2 
greatest dimensions of their breast tumor (or axillary node, if the breast tumor is occult) 
will be labelled optimal responders and should continue the wPCbTP regimen for another 
2 cycles. Patients with <50% reduction in the sum of the 2 greatest dimensions of their 
breast tumor will be considered suboptimal responders and should be switched to AC for 
4 cycles. While this is the recommended treatment plan based on response to the first 4 
cycles of wPCbTP, each patient’s treatment is left to the discretion of the treating 
oncologist based on response evaluation and toxicity concerns.  
G. In patients switched to AC, a repeat cardiac evaluation to rule out a significant fall in 


BrUOG BR-308  
                                           6 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
their LVEF prior to starting that treatment is recommended. Patients who receive AC 
every 2 weeks (dose-dense AC) should receive growth factor support, either 
pegfilgrastim or filgrastim.  
H. If there is uncertainty regarding a patient’s response to treatment after 4 cycles of 
wPCbTP based on imaging studies, a repeat tumor biopsy can be performed; a complete 
or near-complete pathologic response in this biopsy sample would justify continuing 
wPCbTP as opposed to switching to AC.  
I. After the completion of neoadjuvant therapy, the patient’s eligibility for breast 
conserving surgery vs. mastectomy and ALND vs. SLN sampling will be reassessed, and 
the surgical plan recorded.  
J. After surgery, the patient’s actual surgical management will be recorded. Her 
pathologic response to treatment will be scored by the institutional pathologist according 
to TN staging and RCB criteria (if residual invasive disease is present).  
K. Post-op, patients may receive additional chemotherapy, endocrine therapy (if ER or 
PR positive) and radiation treatments at physician discretion, as well as completing a year 
of trastuzumab. Adjuvant pertuzumab may be added if the results of the APHINITY trial 
demonstrate a benefit to this treatment. Post-op treatments and any residual or delayed 
toxicities attributed to the patient’s neoadjuvant therapy will be collected at a follow-up 
visit approximately 3 months after surgery. Sexually active premenopausal patients will 
be advised to continue contraception for at least 2 months after completion of protocol 
chemotherapy (longer if they receive post-op chemotherapy).    
L. Patients will be asked to give permission to collect residual tumor tissue from their 
diagnostic biopsies, any other biopsies that were performed (such as after week 12) and 
their surgical specimens (if present) to be used for future correlative studies.   
M. Our assumption is that pCR (ypT0/isN0) will be achieved in at least 70% of patients 
with wPCbTP +/- AC and this response assessment/switching strategy.   
 
IV. Inclusion and Exclusion Criteria       
A. Inclusion Criteria 
1 Histologically confirmed adenocarcinoma of the breast, with sufficient tissue 
available from needle or incisional biopsy (excisional biopsy not permitted) for 
ER, PR and HER2 testing. The diagnostic biopsy pathology report, including 
hormone receptor and HER2 analysis, will be submitted to BrUOG.   
2. Resectable - clinical stage I (only with T=2.0 cm), IIA-IIIA – T2 N0-T3N0 or 
T1-3 N1-N2a - or unresectable – clinical stage IIIB-C - T4 or N2b-3 - disease. No 
evidence of M1 disease. Pretreatment clinical stage will be recorded by the 
treating physician.  
3. Breast tumor measuring at least 1 cm in greatest dimension by ultrasound or 
MRI; patients without measurable disease in the breast (TX) by imaging studies 
are eligible if they have measurable disease (a node measuring at least 1 cm along 
its short axis, and histologically confirmed to contain metastatic disease) in the 


BrUOG BR-308  
                                           7 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
axilla. The report from the imaging study to be used for the baseline tumor 
measurements will be submitted to BrUOG.  
4. HER2+, defined by either IHC 3+ or amplification of the HER2 gene by FISH 
analysis (ratio >2.0 or >6 HER2 targets per cell; patients with equivocal HER2 
testing, 2+ by IHC with a FISH ratio of <2.0 and 4-6 HER2 signals per nucleus, 
are not eligible).  
5. Patients with multiple foci of invasive cancer in the same breast are eligible if 
any single lesion meets the above size criteria and all sampled lesions > 1 cm in 
maximum dimension are histologically similar and HER2+. Patients are also 
eligible if there is a focus of HER2- invasive cancer that is <1 cm in maximum 
dimension in a different quadrant of the breast from the HER2+ cancer, such that 
its presence will not interfere with clinical or pathologic assessment of response of 
the HER2+ cancer; whether radiographically detected lesions adjacent to but 
separate from the target lesion - ‘satellite’ lesions - are sampled for histologic 
evaluation and marker analysis is left to the discretion of the treating physicians. 
The presence of DCIS or LCIS in either breast will not render a patient ineligible. 
Patients with a small focus of invasive cancer detected in the contralateral breast 
(clinical T1a/bN0) are eligible, whether the contralateral tumor is HER2+ or 
HER2-, while patients with a more advanced invasive cancer in the contralateral 
breast are not eligible; in patients with a small focus of invasive cancer in the 
contralateral breast or a small focus of HER2- cancer in the same breast only the 
histologic response in the HER2+ target lesion will be considered in determining 
the patient's pathologic response.  
6 It is recommended that patients have a pretreatment echocardiogram or MUGA 
scan with an LVEF above the institutional lower limit of normal. If performed, site 
should submit confirmation that results were above institutional lower limit. 
7. Female, age >18, Zubrod PS 0-1.  
8. It is recommended that patients have adequate bone marrow, renal and hepatic 
function. Examples of this include: ANC > 1000/ul, platelet count >100,000/ul, 
HGB> 9.0 g/dl, serum creatinine <1.5 mg/dl or measured creatinine clearance of 
>30 ml/min and AST <5 x ULN. Site must submit confirmation from treating 
physician that patient’s labs were deemed adequate, but is not required to submit 
results as values are only recommended.  
9. Signed informed consent. Per GCP guidelines, if patient signs consent more 
than 30 days prior to starting treatment patient is to be re-consented. The signed 
consent will be sent to BrUOG. 
 
B. Exclusion criteria  
1. Prior chemotherapy or radiation therapy for this cancer; hormonal therapies, 
including LHRH analogs, contraceptives, and antitumor endocrine therapies, are 
permitted prior to and during protocol therapy at the discretion of the treating 
physician.  
2. Patients with congestive heart failure, unstable angina pectoris, uncontrolled 
clinically significant arrhythmia or grade II or greater peripheral vascular disease 
are not eligible. Patients with BP >180 (systolic) or >100 (diastolic) are excluded; 
patients with BP 160-180/90-100 are eligible with assurance from the treating 


BrUOG BR-308  
                                           8 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
physician that this is being addressed and that the physician is comfortable 
initiating study treatment despite the elevated value(s),  
3. Patients with myocardial infarction, stroke or arterial thrombotic event within 
the past 12 months are not eligible.  
4. Pregnant women are not eligible. Lactating women are eligible only if they are 
not breast-feeding. All patients of reproductive potential should have a negative 
pregnancy test at baseline and be advised to use an effective barrier method of 
contraception as per institutional standard of care. Sites will be asked to confirm 
the patient’s menopausal status at study entry and that premenopausal women had 
a negative pregnancy test performed within 7 days of starting treatment, but will 
not be required to submit test results.   
5. Active (defined as symptomatic, currently requiring treatment or likely to 
require treatment within the 6 months following study enrollment, or likely to 
affect the efficacy or tolerability of the study treatment) non-breast malignancy.   
6. Baseline grade >2 peripheral neuropathy 
 
V. Treatment plan  
A. Neoadjuvant therapy  
 
1. wPCbTP 
Paclitaxel 80 mg/m2 IV or nab-paclitaxel (Abraxane) 80-100 mg/m2 IV weekly x 12 (18 
if indicated)  
Carboplatin AUC 2 IV (for calculation of dose, GFR capped at 125 ml/min) weekly x 12 
(18 if indicated)  
Trastuzumab IV 8 mg/kg day 1 cycle 1 then 6 mg/kg day 1 cycles 2-4 (weeks 4, 7, and 
10) and cycles 5-6 (weeks 13 and 16) if indicated or 4 mg/kg week 1 then 2 mg/kg weeks 
2-12 and weeks 13-18 if indicated      
Pertuzumab IV 840 mg cycle 1 then 420 mg cycles 2-4 (weeks 4, 7, and 10) and cycles 5-
6 (weeks 13 and 16) if indicated or 420 mg weeks 1 and 2 then 420 mg cycles 2-4 (weeks 
4, 7, and 10) and cycles 5-6 (weeks 13 and 16) if indicated. Patients whose treating 
physician selects the 420 mg cycle 1 weeks 1 and 2 dosing schedule for pertuzumab must 
be assessed prior to administration of the week 2 dose; this dose will be omitted for grade 
>1 diarrhea.     
  
2. AC   
            Dose-dense AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV 
day 1 every 2 weeks x 4 cycles with pegfilgrastim 6 mg SC day 2 or Neulasta on-body 
injector OBI applied day 1 for injection on day 2 or filgrastim 5 mcg/kg (typically 
rounded to 300 mcg or 480 mcg) SC daily starting day 2-3 and continued for a minimum 
of 7 days until recovery of ANC from nadir  
 
          Standard AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV day 1 r 
every 3 weeks x 4 cycles (administration of pegfilgrastim or filgrastim at the discretion of 
the treating oncologist)  
 
 


BrUOG BR-308  
                                           9 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
B. Adjuvant therapy 
1. Additional chemotherapy at the discretion of the treating oncologist  
2. It is recommended that patients resume trastuzumab 6 mg/kg IV every 3 weeks 
x 11 cycles (if received 6 cycles of wPCbTP preop) or 13 cycles (if received 4 
cycles of wPCbTP preop) after surgery or completion of any adjuvant 
chemotherapy. Pertuzumab 420 mg IV every 3 weeks x 11-13 cycles can be 
added if indicated based on results of the APHINITY trial, when available.  
3. Adjuvant endocrine therapy (in ER+/HER2+ patients) and radiation per 
treating physicians 
 
VI. Suggested dose modifications for chemotherapy 
 
While decisions regarding treatment delays or modifications will be left to the treating 
oncologist, and their occurrence and rationale collected, the following are guidelines and 
not requirements: 
A. Hematologic toxicities:  
1. Neutropenia – OK to proceed with paclitaxel/nab-paclitaxel and carboplatin 
with ANC >800. If treatment is held for neutropenia this should be a treatment 
delay; skipping doses should be avoided. If treatment is held 2 consecutive 
weeks for neutropenia, when treatment is resumed the dose of paclitaxel/nab-
paclitaxel should be reduced by 25% to paclitaxel 60 mg/m2 or nab-paclitaxel 
60-75 mg/m2. Filgrastim 5 mcg/kg SC daily x 3-5 days per week (between 
days 2 and 6) may be added to try to avoid further dose modification. If 
neutropenia requiring a second hold of 2 consecutive weeks recurs at the lower 
dose, when treatment is resumed the treating oncologist has the option of 
reducing the paclitaxel/nab-paclitaxel dose by another 25% and the carboplatin 
dose by 25% or adding filgrastim (if not added previously) 5 mcg/kg SC daily 
x 3-5 days per week (between days 2 and 6) to try to avoid further reduction of 
the chemotherapy doses.  
2. Febrile neutropenia – Should reduce paclitaxel/nab-paclitaxel by 25%. 
Filgrastim 5 mcg/kg SC daily x 3-5 days per week (between days 2 and 6) may 
be added to try to avoid further episodes or dose modification.  
3. Thrombocytopenia – OK to proceed with paclitaxel/nab-paclitaxel and 
carboplatin with platelet count >50,000. If treatment is held for 
thrombocytopenia even once, when treatment is resumed the dose of 
carboplatin should be reduced by 25% (to AUC 1.5). If treatment has to be 
held for thrombocytopenia on AUC 1.5, should reduce carboplatin to AUC 1.0. 
If treatment has to be held for thrombocytopenia on AUC 1.0, should 
discontinue carboplatin. 
4. Anemia – No recommended dose modifications. Transfuse as indicated.  
 
B. Non-hematologic toxicities  
1. Neuropathy – Should reduce paclitaxel/nab-paclitaxel by 25% for grade 2 
peripheral neuropathy. Should hold treatment for grade 3 neuropathy, resume 
with 25% reduction of paclitaxel/nab-paclitaxel when improves to grade < 2. If 
does not improve to grade <2 within 3 weeks, or if progresses from grade 2 to 


BrUOG BR-308  
                                           10 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
grade 3 despite the 25% reduction in dose of paclitaxel/nab-paclitaxel, should 
discontinue wPCbTP regimen and either switch to AC, take to surgery or 
remove from study.  
2. Diarrhea – A) Patients receiving pertuzumab 420 mg cycle 1 weeks 1 and 2 
must be assessed for diarrhea prior to administration of the week 2 dose, and 
the dose omitted for grade >1 diarrhea.  B) At all other times during study 
treatment, all treatment (including trastuzumab and pertuzumab) should be 
held for grade > 2 when due to resume treatment. If treatment is held for >2 
weeks for grade 2 diarrhea or patient develops grade 3 diarrhea, when 
treatment resumes should temporarily discontinue pertuzumab; resumption of 
pertuzumab following improvement in or control of diarrhea on medication is 
at the discretion of the treating oncologist. If grade >2 diarrhea recurs despite 
discontinuation of pertuzumab and administration of antidiarrheal medications, 
discontinue the wPCbTP regimen and either switch to AC, take to surgery or 
remove from study.  
3. Vomiting – Should hold treatment for grade >2 vomiting on day of treatment. 
Intensify antiemetic regimen as indicated for post-chemotherapy nausea or 
vomiting that resolves by next scheduled treatment. 
4. Allergic reactions –  
a. Paclitaxel - Patients who experience a significant (grade >2) 
hypersensitivity reaction to paclitaxel may, at the discretion of the 
treating oncologist, be re-challenged with additional premedications 
and/or changes in the rate of administration of the drug or switched to 
nab-paclitaxel. 
b. Carboplatin – Patients who experience a significant (grade>2) 
hypersensitivity reaction to carboplatin may, at the discretion of the 
treating oncologist, be re-challenged with additional premedications 
and/or changes in the rate of administration of the drug or undergo 
desensitization with the goal of continuing this part of their treatment, 
or treatment with carboplatin may be permanently discontinued. If this 
occurs prior to the week 12 reassessment, the patient should continue 
on treatment with paclitaxel/nab-paclitaxel, trastuzumab and 
pertuzumab (wPTP) until week 12. It is left to the discretion of the 
treating oncologist as to whether this would influence his/her decision 
to continue wPTP or switch to AC at any time after week 12.        
5. Other grade >2 toxicities. Physician discretion as to whether toxicity warrants 
treatment delay, dose modification or discontinuation of wPCbTP regimen. 
 
C. If paclitaxel/nab-paclitaxel and carboplatin chemotherapy is delayed due to 
hematologic or non-hematologic toxicity, the patient should continue trastuzumab 
(every 3 weeks or weekly) and pertuzumab (every 3 weeks). 
  
D. Dose modifications during AC are left to the discretion of the treating oncologist.       
 
E. Adverse event reporting -See Appendix I  
 


BrUOG BR-308  
                                           11 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
 
VII. Required data 
To reduce the burden of data collection, and because treatment modifications are 
primarily left up to the treating investigator, lab results will not be collected. Submission 
of data sheets collecting pertinent data is required at the following time points:  
 
A. On-study data sheet: Baseline tumor stage, measurements (US or MRI), histologic 
confirmation of malignancy with ER, PR and HER2 status (pathology report), 
clinical/histologic status of ipsilateral axilla PS, pretreatment assessment of 
operability (mastectomy vs. lumpectomy, ALND vs.SLN only).  On study 
information required for BrUOG review before registration. 
B. s/p 2 cycles wPCbTP: Treatment and toxicity data  
C. s/p 4 cycles wPCbTP: Treatment and toxicity data, results of reassessment (US or 
MRI), treatment plan going forward  
D. Pre-op (s/p 6 cycles of wPCbTP or 4 cycles of AC): Treatment and toxicity data, 
pre-op assessment of operability (including US or MRI, if done)  
E. Post-op: Surgical outcomes, pathology results, RCB number and class if not pCR 
F. 3 months post-op: Post-op treatment received and planned, delayed or persistent 
toxicities  
 
VIII. Pathologic analysis 
 
A. Definition of pCR: A patient will be considered to have achieved a pCR if there is 
no residual invasive cancer in the submitted breast tissue (the presence of DCIS or 
microinvasion (T1mic) will not disqualify a patient from being defined a pCR) or 
in any sampled axillary nodes (the presence of isolated tumor cells – N0i+ - will 
not disqualify a patient from being defined a pCR).  
B. Residual Cancer Burden: In patients who do not meet the definition of pCR, the 
pathologist will be asked to quantify the residual cancer burden (RCB), as defined 
by Symmans et al. The RCB value can be calculated using an online calculator 
that can be accessed at the site below, and the necessary data to calculate the value 
is listed below:      
 
http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3 
 
(1) Primary Tumor Bed 
Primary Tumor Bed Area: 
(mm) X 
(mm) 
Overall Cancer Cellularity (as percentage of 
area): 
(%) 
Percentage of Cancer That Is in situ Disease: 
(%) 
(2) Lymph Nodes 
Number of Positive Lymph Nodes: 
Diameter of Largest Metastasis: 
(mm) 


BrUOG BR-308  
                                           12 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
IX. Recording Surgical options: Surgical data will not be collected on patients who come 
off study prior to the week 12 assessment, but response and surgical data (including 
pathology report results) will be collected on all patients who come off study any time 
after the 12 week assessment. 
A. Eligibility for BCS: At baseline and again after completion of neoadjuvant 
therapy, the patient’s physicians (ideally her surgeon) will be asked to assess 
whether she is a candidate for BCS – whether or not the patient is interested in 
BCS – and, if not, why (tumor size or location, multicentric invasive disease, 
DCIS or other imaging or histologic findings elsewhere in the breast, poor 
candidate for radiation, etc.) This will be recorded on the pre- and post-treatment 
surgical assessment form.  
B. Axillary management: At baseline and again after completion of neoadjuvant 
therapy, the patient’s physicians (again, ideally her surgeon) will be asked to 
assess the clinical status of her axilla and whether she requires an ALND or, if 
clinically N0, is a candidate for SLN sampling only. This is also recorded on the 
surgical assessment form.  
C. At the patient post-op visit, the surgery performed (breast and axilla) should be 
recorded, and whether this was different from her pre-op surgical plan and if so 
why.  
X. Pharmaceutical information – See Appendix II 
 
XI. Record Retention 
 
The investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s).   
 
The Brown University Oncology Research Group, as coordinator of this study, is 
responsible for ensuring proper conduct of the study with regard to protocol adherence 
and the validity of the data recorded on the case report forms. The Principal Investigators 
(William Sikov, M.D. and Mary Lopresti, D.O.) and Brown University Oncology 
Research Group Director of Operations (Kayla Rosati) will monitor this study. The case 
report forms will be monitored against the submitted documents for accuracy, 
completeness, adherence to the protocol and regulatory compliance.  
 
All records and documents pertaining to the conduct of this study and the distribution of 
drug, including CRFs, consents forms, laboratory test results and medication inventory 
records, must be retained by the Principal Investigator for 2 years after the investigation 
is discontinued, study is published and once BrUOG confirms records can be destroyed 
or moved. 
 
XII. Data Safety and Monitoring Board  
 
All trials initiated by the Brown University Oncology Research Group (BrUOG) are 
subject to oversight by the Data Safety Monitoring Board (DSMB).  This board meets 
two times per year with any additional meetings scheduled when needed.  The 
responsibilities are as follows: 


BrUOG BR-308  
                                           13 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
• Familiarize themselves with the research protocol (s)  
• The DSMB reviews trial performance information such as accrual information.   
• Review interim analyses of outcome data and cumulative toxicity data summaries 
to determine whether the trial should continue as originally designed, should be 
changed, or should be terminated based on these data.   
• The DSMB also determines whether and to whom outcome results should be 
released prior to the reporting of study results. 
• All adverse events are reviewed by the committee, with assurances that these have 
been in fact sent for review to all pertinent IRBs. 
• Review of reports of related studies to determine whether the monitored study 
needs to be changed or terminated. 
• Review major proposed modifications to the study prior to their implementation 
(e.g., termination, dropping an arm based on toxicity results or other reported trial 
outcomes, increasing target sample size). 
• Following each DSMB meeting, provide the study leadership with written 
information concerning findings for the trial as a whole related to cumulative 
toxicities observed and any relevant recommendations related to continuing, 
changing, or terminating the trial.  
 
The study leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s. 
 
 
XIII. Statistical design 
 
The study will continue until at least 30 evaluable patients are enrolled and treated. The 
pCR and pCR + RCB I rates for the overall study population and the subpopulations 
listed in Section II. A. 1-2 will be calculated with 95% confidence intervals. If we 
achieve an overall pCR rate of 70% in 30 patients, the 95% confidence interval for the 
pCR rate (50-85%) will essentially exclude an actual pCR with these regimens and this 
‘switching’ strategy of less than 50%, with an alpha 0.07 and power of 77%, according to 
both the Fleming design and exact binomial tests.     
  
XIV. References      
 
1. Cortazar P, Zhang L, Untch M, et al. Pathologic complete response and long-term 
clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 
384(9938): 164-172.  
2. Broglio KR, Quintana M, Foster M, et al. Association of pathologic complete 
response to neoadjuvant therapy in HER2-positive breast cancer with long-term 
outcomes: a meta-analysis. JAMA Oncol 2016 Feb 25; EPub Ahead of Print.  
3. Slamon DJ, Eiermann W, Robert NJ, et al. Ten-year follow-up of BCIRG-006 
comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) 
with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab 
(AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early 
breast cancer. 38th Annual San Antonio Breast Cancer Symposium, San Antonio, 
Texas, December 8-12, 2015, Abstract S5-04.  


BrUOG BR-308  
                                           14 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
4. Gianni L, Pienkowski T, Im Y, et al. Efficacy and safety of neoadjuvant 
pertuzumab and trastuzumab in women with locally advanced, inflammatory, or 
early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-
label, phase 2 trial. Lancet Oncol 2012; 13 (1): 25-32.  
5. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in 
combination with standard neoadjuvant anthracycline-containing and 
anthracycline-free chemotherapy regimens in patients with HER2-positive early 
breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann 
Oncol 2013; 24: 2278–2284.  
6. Dang C, Iyengar M, Datko F, et al. Phase II Study of paclitaxel given once per 
week along with trastuzumab and pertuzumab in patients with human epidermal 
growth factor receptor 2–positive metastatic breast cancer. J Clin Oncol 2015; 
33(5), 442-447.  
7. Sikov WM, Dizon DS, Strenger R, et al. Frequent pathologic complete responses in 
aggressive stages II to III breast cancers with every-4-week carboplatin and weekly 
paclitaxel with or without trastuzumab: a Brown University Oncology Group Study. 
J Clin Oncol 2009; 27:4693-4699.  
8. Sinclair NF, Sakr BJ, Abu-Khalaf MM, et al. Multicenter phase II trial of 
neoadjuvant carboplatin, weekly nab-paclitaxel, and trastuzumab in stage II-III 
HER2+ breast cancer: A BrUOG study. J Clin Oncol 2013; 31 (suppl; abstr 619) 
9. Yu KD, Liu GY, Chen CM, et al. Weekly paclitaxel/carboplatin/trastuzumab 
therapy improves pathologic complete remission in aggressive HER2-positive 
breast cancers, especially in luminal-B subtype, compared with a once-every-3-
weeks schedule. Oncologist 2013; 18(5):511-7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BrUOG BR-308  
                                           15 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Appendix I: Adverse Event Reporting 
 
The only Adverse events that will be captured by participating sites during this clinical 
trial will be the pre-determined hematological and non-hematological toxicities noted in 
section II. A. 4, which are: 
a. Neutropenia (grade>2)   
   b. Febrile neutropenia (grade 3-4)  
 
   c. Thrombocytopenia (grade >2)  
 
   d. Anemia (grade >2) 
 
   e. Diarrhea (any grade, grade >3)   
 
   f. Neuropathy (any grade, grade 2, grade >3) 
 
   g. Vomiting (any grade, grade >3)  
 
   h. Other grade >3 toxicities 
 
No other adverse events are required to be documented, captured, or reported to BrUOG 
and therefore, BrUOG will not be reporting on any adverse events other than the pre-
determined toxicities noted above. All adverse events and special reporting situations, 
related or unrelated, will be reported from the time a signed and dated ICF is obtained 
until 3 months post-operative, or until the subject withdraws consent from study 
participation (declines participation) or at the time patient becomes a screen failure, 
whichever occurs first. If a patient comes off study early, prior to completion of all 
treatment, the SAE review period will be 30 days from the last treatment.  
Regarding SAEs: All SAEs, whether related or unrelated, will be reported from the time 
a signed and dated ICF is obtained until 3 months post-operative, or until the subject 
withdraws consent from study participation (declines participation) or at the time patient 
becomes a screen failure, whichever occurs first. If a patient comes off study early, prior 
to completion of all treatment, the SAE review period will be 30 days from the last 
treatment. 
This includes the period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g. treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication).  
This study will utilize the descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 for grading all adverse 
events. 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).  
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and that does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use treatment regimen whether or not 
considered related. This includes any newly occurring event or previous condition that 
has increased in severity or frequency since the administration of drug. 


BrUOG BR-308  
                                           16 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
During clinical trials, adverse events can be spontaneously reported or elicited during 
open-ended questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific occurrence of one 
or more adverse events.) 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial medication. All 
AEs considered related to trial medication will be followed until resolution even if this 
occurs post-trial. 
Definitions 
An adverse event is any new, undesirable medical experience or change of an existing 
condition that occurs during or after treatment, whether or not considered product-related. 
Serious adverse event (SAE) 
An adverse event occurring at any dose that results in any of the following outcomes 
(CFR 312.32): 
• death 
• is life-threatening  
• inpatient hospitalization or prolongation of existing hospitalization excluding those 
for study drug administration, transfusion support, disease staging/re-staging 
procedures, concomitant radiotherapy, thoracentesis / paracentesis, or placement of an 
indwelling catheter, unless associated with other serious events. 
• persistent or significant disability or incapacity, 
• congenital anomaly / birth defect.  
The definition of serious adverse event (experience) also includes important medical 
event. Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious.  Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. A new diagnosis of cancer during the 
course of treatment should be considered an important medical event. 
The definition of “related” being that there is a reasonable possibility that the drug caused 
the adverse experience. 
Unexpected adverse event 
An adverse event that is not mentioned in the package insert or informed consent or the 
specificity or severity of which is not consistent with the investigator's brochure or 
package insert. 
 


BrUOG BR-308  
                                           17 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred.  It does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
BRUOG ADVERSE EVENT REPORTING REQUIREMENTS  
Investigators are required by Federal Regulation to report adverse drug reactions. 
Questions regarding drugs as used in this study should be directed to the Brown 
University Oncology Research Group (BrUOG) Central Office, Phone: (401) 863-3000 
Fax (401) 863-3820, which will in turn notify the Principal Investigator. 
Intensity for each adverse event will be scored using CTCAE Version 4.0.  A copy of the 
CTCAE Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  All appropriate treatment areas have access to a copy of the 
CTCAE Version 4.0.  All adverse clinical experiences, whether observed by the 
investigator or reported by the patient, must be recorded, with details about the duration 
and intensity of each episode, the action taken with respect to the test drug, and the 
patient’s outcome.  The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness. 
Pregnancies 
Pregnancies occurring while the subject is on study drug or within 4 weeks after the 
subject’s last treatment are considered expedited reportable events.  If the subject is 
receiving treatment, the drugs are to be discontinued immediately.  The pregnancy must 
be reported by the Brown University Oncology Research Group within 24 hours and 
BrUOG will in turn report to FDA within 24 hours of the Investigator’s knowledge of the 
pregnancy by phone and/or facsimile using the 3500A MedWatch form. Pregnancies and 
suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female subject occurring while the subject is on treatment (drug), or within 4 
weeks (30 days) of the subject’s last treatment, are considered immediately reportable 
events. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
to BrUOG via the Medwatch3500A form. 
The Investigator will follow the subject until completion of the pregnancy, and must 
notify BrUOG of the outcome as specified below.  The Investigator will provide this 
information as a follow-up to the initial report. If the outcome of the pregnancy meets the 
criteria for immediate classification as a SAE (i.e., spontaneous abortion [any congenital 
anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting SAEs 
(i.e., report the event to BrUOG who will then report to the FDA). 
Any suspected fetal exposure must be reported to BrUOG within 24 hours who will then 
report to the FDA within 1 working day of being made aware of the event.  The patient 
should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for 
further evaluation and counseling. 


BrUOG BR-308  
                                           18 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 30 days that the Investigator 
suspects to be related to the in utero exposure to the study drug should also be reported.  
Types of Report: For sites: 
Telephone report:  For SAE’s contact BrUOG Central Office (401) 863-3000 (or via 
email), immediately upon learning of the event (within 24 hours). 
Written report: Send the copy of the MedWatch 3500A form within 5 business days of 
the event (24 hours if pregnancy or related death) to the BrUOG Central Office by email, 
scan or Fax: 
Brown University Oncology Research Group 
Phone: (401) 863-3000, Fax: (401) 863-3820 
Emails: Kayla_rosati@brown.edu and Kristen_Mitchell@brown.edu 
All SAEs and deaths during treatment or within 3 months post-operative must be reported 
within 5 business days or as soon as the investigator is made aware of the event. If the 
death is thought to be related to the study drug, deaths must be reported within 24 hours 
of the investigator being made aware of the event. If a patient comes off study early, prior 
to completion of all treatment, the SAE review period will be 30 days from the last 
treatment. 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each product 
and suspect medication  
• SAE must be typed 
• **It is required that you put the following numbers on the MedWatch form 
for tracking: 
o BrUOG 308 
A final report to document resolution of the SAE (such as discharge from hospital) 
is required. 
Follow-up information:   
Additional Info may be added to a previously submitted report by any of the following 
methods. 


BrUOG BR-308  
                                           19 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form  
Summarize new information and fax it with a cover letter including subject identifiers 
(i.e. D.O.B. initial, subject number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up 
information is being submitted.  (The subject identifiers are important so that the new 
information is added to the correct initial report). 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy.   
BrUOG Responsibility Regarding Reporting:  
The BrUOG Central Office will notify by phone and/or fax all drug reaction reports to 
the FDA, the Principal Investigator, and the participating sites (who will in turn notify 
their local IRBs) as soon as possible but no later than 7 calendar days after initial receipt 
of the information. SAEs will be reported as an amendment to the IND (if applicable) 
within 15 days of sponsor notification. They will all receive a simultaneous copy via 
facsimile or email of all adverse events filed with the FDA (which will be sent to the 
MedWatch fax line for IND exemption or to the division fax if there is an IND). A copy 
of the form will be kept by the BrUOG Central Office.   
 
 
Fax: 1-800-FDA-0178 (1-800-332-0178) For IND exempt study or for IND study the 
SAE will be sent to Center Drug Evaluation Division fax line that has responsibility 
for review of IND) 
Mail: For IND studies BrUOG will send the SAE as an amendment to the IND as 
well 
 
 
 
 
 
 
 
 
 
 
 
 
 


BrUOG BR-308  
                                           20 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Appendix II: Pharmaceutical information 
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. For full 
instructions and guidelines, please always refer to the package inserts for the drugs being 
used in this trial, below is just a summary of basic information for each drug.  
 
1. Paclitaxel (Taxol) 
Formulation: Commercially available for injection 6 mg/mL (5 mL, 16.7 mL, 25 mL, and 
50 mL) (contains alcohol and purified Cremophor EL {polyoxyethylated castor oil}).  
Preparation, Storage and Stability:  
Unopened vials of TAXOL (paclitaxel) Injection are stable until the date indicated on the 
package when stored between 20°–25° C (68°–77° F), in the original package. Neither 
freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, 
components in the TAXOL vial may precipitate, but will redissolve upon reaching room 
temperature with little or no agitation. There is no impact on product quality under these 
circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial 
should be discarded. Solutions for infusion prepared as recommended are stable at ambient 
temperature (approximately 25° C) and lighting conditions for up to 27 hours. 
Procedures for proper handling and disposal of anticancer drugs should be considered. 
TAXOL (paclitaxel) Injection must be diluted prior to infusion. TAXOL should be diluted 
in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 
0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for 
up to 27 hours at ambient temperature (approximately 25° C) and room lighting conditions. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. 
Upon preparation, solutions may show haziness, which is attributed to the formulation 
vehicle. No significant losses in potency have been noted following simulated delivery of 
the solution through IV tubing containing an in-line (0.22 micron) filter. 
Administration: Administer under the supervision of a health care provider experienced in 
the use of cancer chemotherapeutic agents. Appropriate management of complications is 
possible only when adequate diagnostic and treatment facilities are readily available. 
TAXOL should be administered through an in-line filter with a microporous membrane not 
greater than 0.22 microns. 
Administer dose per the protocol. 
Drug Interactions:  
The metabolism of TAXOL is catalyzed by cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4. Caution should be exercised when TAXOL is concomitantly administered with 
known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, 
simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, 


BrUOG BR-308  
                                           21 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
itraconazole, 
ketoconazole, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 
and 
telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4.  
Caution should also be exercised when TAXOL is concomitantly administered with known 
substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers 
(eg, rifampin) of CYP2C8.  
Adverse Events Consult the package insert for the most current and complete information. 
Percentages reported with single-agent therapy.  
TAXOL is contraindicated in patients who have a history of hypersensitivity reactions to 
TAXOL or other drugs formulated in Cremophor
® 
EL (polyoxyethylated castor oil).  
 
Toxicities 
U.S. Boxed Warning: Bone marrow suppression is the dose-limiting toxicity; do not 
administer if baseline absolute neutrophil count (ANC) is <1500 cells/mm3 (1000 
cells/mm3 for patients with AIDS-related KS); reduce future doses by 20% for severe 
neutropenia. U.S. Boxed Warning: Severe hypersensitivity reactions have been reported. 
Common known potential toxicities, > 10%:  
Cardiovascular: Flushing, ECG abnormal, edema, hypotension. Dermatologic: 
Alopecia, rash. Gastrointestinal: Nausea/vomiting, diarrhea, mucositis, stomatitis, 
abdominal pain (with intraperitoneal paclitaxel) Hematologic: Neutropenia, 
leukopenia, anemia, thrombocytopenia, bleeding. Hepatic: Alkaline phosphatase 
increased, AST increased. Local: Injection site reaction (Erythema, tenderness, skin 
discoloration, swelling). Neuromuscular & skeletal: Peripheral neuropathy, arthralgia, 
myalgia, weakness. Renal: Creatinine increased. Miscellaneous: Hypersensitivity 
reaction, infection 
Less common known potential toxicities, 1% - 10%: Cardiovascular: Bradycardia, 
tachycardia, hypertension, rhythm abnormalities, syncope, venous thrombosis. 
Dermatologic: Nail changes. Hematologic: Febrile neutropenia. Hepatic: Bilirubin 
increased. Respiratory: Dyspnea 
Rare known potential toxicities, <1% (limited to important or life-threatening): 
Anaphylaxis, ataxia, atrial fibrillation, AV block, back pain, cardiac conduction 
abnormalities, cellulitis, CHF, chills, conjunctivitis, dehydration, enterocolitis, 
extravasation recall, hepatic encephalopathy, hepatic necrosis, induration, intestinal 
obstruction, intestinal perforation, interstitial pneumonia, ischemic colitis, lacrimation 
increased, maculopapular rash, malaise, MI, necrotic changes and ulceration following 
extravasation, leukoencephalopathy, neutropenic enterocolitis, ototoxicity, pancreatitis, 
paralytic ileus, phlebitis, pruritus, pulmonary embolism, pulmonary fibrosis, radiation 
recall, radiation pneumonitis, pruritus, renal insufficiency, seizure, skin exfoliation, 
skin fibrosis, skin necrosis, Stevens-Johnson syndrome, supraventricular tachycardia, 
toxic 
epidermal 
necrolysis, 
ventricular 
tachycardia 
(asymptomatic), 
visual 
disturbances. 
 
 


BrUOG BR-308  
                                           22 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Nursing Guidelines: 
Premedicate with steroids, antihistamines, and H2 blockers as per institutional guidelines. 
Mix the infusion bag well. Thorough admixture of this drug often prevents a 
hypersensitivity reaction.  
Assess the patient frequently for the first 30 minutes. Taxol® hypersensitivity reactions, 
which may include chest pain, back pain, flushing, diaphoresis, dyspnea, pruritus, 
hypotension, hypertension, bronchospasm and/or urticaria, usually occur early in the 
infusion. Have the anaphylaxis tray available. If a reaction occurs, stop the infusion 
immediately. Epinephrine, IV fluids, diphenhydramine, and methylprednisolone may be 
used as per physician’s order. 
Approximately 60% of patients experience peripheral sensory neuropathy (numbness, 
tingling, burning pain, fine motor skills impairment, paresthesias, distal sensory loss). 
Nonsteroidal anti-inflammatory agents and opiates have not been effective in treating 
neuropathic pain.  
Monitor CBC closely. Neutropenia is most severe in patients who have had previous 
chemotherapy. Instruct patient to report signs or symptoms of infection, unusual bruising 
or bleeding to the health care team.  
Monitor IV site closely and establish patency before administration. Paclitaxel is an irritant, 
however rarely rash, radiation recall, and ulceration have occurred with infiltration of drug.  
Monitor liver function tests  
Inform patient about total alopecia.  
If given on the same day as a platinum agent, paclitaxel should be administered first to 
limit myelosuppression and enhance efficacy of agent. 
Availability: Commercial product will be utilized.  
2. Nab-Paclitaxel   
Packaging, Labeling, and Storage  
Each single-use 50 ml vial will contain paclitaxel (100 mg) and approximately 900 mg 
human albumin (HA) as a stabilizer.  Unreconstituted Abraxane should be stored at 
controlled room temperature (20° to 25°C or 68° to 77°F) in its carton.  Reconstituted 
Abraxane should be used immediately.  If not used immediately, the vial of reconstituted 
Abraxane must be placed in its carton and be placed in a refrigerator at 2° to 8°C (36° to 
46°F) for a maximum of 8 hours.  Both forms should be stored in an area free of 
environmental extremes and must be accessible only to study personnel.  
     
Administration 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line filters 
during the administration of Abraxane. In any event, filters of pore-size less than 15 
micrometers must not be used. 
Abraxane will be reconstituted by appropriate study personnel and administered to the 
patient in the study site.  The investigator will calculate the body surface area (BSA) of the 
patient in order to determine the total amount of paclitaxel to be administered. 
 


BrUOG BR-308  
                                           23 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Administer dose per the protocol. 
 
Reconstitution and use of Abraxane: 
• Calculate the patient’s body surface area at the beginning of the study and if the 
weight changes by > 10% by using the formula provided in the study manual. 
• Calculate the total dose (in mg) to be administered = BSA x 100 mg/m2 (unless 
dose is modified by criteria listed above). 
• Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
100 (mg/vial) 
Round up the number of vials to be reconstituted to the next higher whole 
number when a fractional number of vials is obtained by the above formula 
(e.g., if the total number of vials = 4.05 or 4.5, then 5 vials would be 
reconstituted).  
Using sterile technique, prepare the vials for reconstitution. 
Swab the rubber stoppers with alcohol. 
Reconstitute each Abraxane vial by injecting 20 mL of 0.9% Sodium Chloride 
Injection, USP or equivalent into each vial over a period of not less than 1 
minute.  
• Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a 
minimum of 1 minute, using the sterile syringe directing the solution flow onto 
the inside wall of the vial. 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly onto the 
lyophilized cake as this will result in foaming. 
• Once the injection is complete, allow the vial to sit for a minimum of 5 (five) 
minutes to ensure proper wetting of the lyophilized cake/powder.   
• Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs.  Rapid agitation or shaking will result 
in foaming. 
• If foaming or clumping occurs, stand solution for at least 15 minutes until foam 
subsides. 
• Each ml of reconstituted product will contain 5 mg of paclitaxel. 
• Calculate the exact total dosing volume of 5 mg/ml suspension required for the 
patient: 
Dosing volume (ml) = Total dose (mg) / 5 (mg/ml) 
• The reconstituted sample should be milky and homogeneous without visible 
particulates.  If unsuspended powder is visible, the vial should be gently 
inverted again to ensure complete resuspension, prior to use. 


BrUOG BR-308  
                                           24 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
• Once the exact volume of reconstituted Abraxane has been withdrawn from the 
vials, discard any excess solution left over in accordance with standard 
operating procedures. 
• Further dilution is not necessary. Inject the calculated dosing volume of 
reconstituted Abraxane suspension into an empty sterile, standard PVC IV bag 
using an injection port.  Inject perpendicularly into the center of the injection 
port to avoid dislodging plastic material into the IV bag.   
• Administer the calculated dosing volume of reconstituted Abraxane suspension 
by IV infusion over 30 minutes.  The use of in-line filters is not necessary.  If 
used, in-line filters with pore sizes of < 15µ should not be used. 
• Use within 8 hours of reconstitution.  If not used immediately, store 
reconstituted Abraxane in a refrigerator for no longer than 8 hours. 
Availability: Commercial supply will be utilized.  
 
3. Carboplatin 
Availability 
Carboplatin Injection is supplied as a sterile, aqueous solution available in 50 mg/5 mL, 
150 mg/15 mL, 450 mg/45 mL or 600 mg/60 mL multi-dose vials containing 10 mg/mL of 
carboplatin for administration by intravenous infusion. Each mL contains 10 mg 
carboplatin and Water for Injection, USP. Refer to the package insert for further 
information. 
Commercial supply will be utilized. 
 
Preparation 
Carboplatin Injection is a premixed aqueous solution of 10mg/mL carboplatin.  
Carboplatin Injection can be further diluted to concentrations as low as 0.5mg/mL with 5% 
Dextrose in Water or 0.9% sodium chloride injection, USP. When prepared as directed 
carboplatin solutions are stable for eight hours at room temperature.  Since no antibacterial 
preservative is contained in the formulation it is recommended that carboplatin solutions 
be discarded eight hours after dilution. 
Carboplatin Injection is supplied as follows: 
 
 
 
Vial Strength 
Diluent Volume 
 
 
 
     50 mg 
        5 ml 
 
 
 
    150 mg 
      15 ml 
 
 
  
    450 mg 
      45 ml 
 
 
 
    600 mg 
      60 ml 
These dilutions all produce a carboplatin concentration of 10 mg/ml.   
Note:  Aluminum reacts with carboplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that may come in contact 
with the drug must not be used for the preparation or administration of carboplatin. 


BrUOG BR-308  
                                           25 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
 
Storage and Stability 
Unopened vials of carboplatin are stable for the life indicated on the package. Store 
unopened vials of Carboplatin Injection at 30º to 25ºC (68º to 77ºF); excursions permitted 
between 15º and 30ºC (59º to 86ºF).  Protect from light. 
Administration 
Infuse over at least 15 minutes; usually infused over 15 to 60 minutes. 
 
Hazardous agent; use appropriate precautions for handling and disposal. 
 
Administer dose per the protocol. 
 
Toxicities 
Bone marrow suppression: Bone marrow suppression is dose related and may be 
severe, resulting in infection or bleeding. Anemia may be cumulative and may require 
transfusion support. 
Vomiting: Vomiting is a frequent drug-related side effect. 
Hypersensitivity reactions: Anaphylactic-like reactions to carboplatin have been 
reported and may occur within minutes of carboplatin administration. Epinephrine, 
corticosteroids, and antihistamines have been employed to alleviate symptoms. 
 
4. Trastuzumab 
Availability and Supply 
Trastuzumab (Herceptin™) will be obtained from commercial sources for this study.      
 
Supply  
Herceptin is supplied in a multi-use vial containing 440 mg trastuzumab as a lyophilized 
sterile powder, under vacuum. Each carton contains one vial Herceptin and one vial (20 
mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol 
as a preservative. 
 
Preparation and Administration: 
Reconstitution 
Reconstitute each 440 mg vial of Herceptin with 20 mL of Bacteriostatic Water for 
Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a 
multi-dose solution containing 21 mg/mL trastuzumab. In patients with known 
hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection 
(SWFI) without preservative to yield a single use solution. 
Use appropriate aseptic technique when performing the following reconstitution steps: 
• Using a sterile syringe, slowly inject the 20 mL of diluent into the vial 
containing the lyophilized cake of Herceptin. The stream of diluent should be 
directed into the lyophilized cake. 
• Swirl the vial gently to aid reconstitution. DO NOT SHAKE. 
• Slight foaming of the product may be present upon reconstitution. Allow the vial 
to stand undisturbed for approximately 5 minutes. 


BrUOG BR-308  
                                           26 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
• Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
Inspect visually for particulates and discoloration. The solution should be free of 
visible particulates, clear to slightly opalescent and colorless to pale yellow. 
• Store reconstituted Herceptin at 2-8○C; discard unused Herceptin after 28 days. 
If Herceptin is reconstituted with SWFI without preservative, use immediately 
and discard any unused portion. 
 
Dilution 
• Determine the dose (mg) of Herceptin. Calculate the volume of the 21 mg/mL  
reconstituted Herceptin solution needed, withdraw this amount from the vial and 
add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, 
USP. DO NOT USE DEXTROSE (5%) SOLUTION. 
• Gently invert the bag to mix the solution. 
 
Administer per the protocol. 
 
Storage and Stability 
Vials of Herceptin are stable at 2-8°C (36-46°F) prior to reconstitution. Do not use 
beyond the expiration date stamped on the vial. A vial of Herceptin reconstituted with 
BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated at 2-
8°C (36-46°F). Discard any remaining multi-dose reconstituted solution after 28 days. A 
vial of Herceptin reconstituted with unpreserved SWFI (not supplied) should be used 
immediately and any unused portion discarded. 
Do not freeze Herceptin following reconstitution or dilution. 
The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags 
containing 0.9% Sodium Chloride Injection, USP, should be stored at 2-8°C (36-46°F) 
for no more than 24 hours prior to use. 
 
Administration 
Administer dose per the protocol. For intravenous (IV) infusion only. Do not administer 
as an IV push or Bolus.  
 
Toxicities 
The following adverse reactions are discussed in greater detail in other sections of the 
label: 
• Cardiomyopathy [see package insert for details]. US Boxed Warning: Trastuzumab is 
associated with symptomatic and asymptomatic reductions in left ventricular ejection 
fraction (LVEF) and heart failure (HF); the incidence is highest in patients receiving 
trastuzumab with an anthracycline-containing chemotherapy regimen. Evaluate LVEF in 
all patients prior to and during treatment; discontinue for cardiomyopathy. Extreme 
caution should be used in patients with pre-existing cardiac disease or dysfunction.  
• Infusion Reactions [see package insert for details] US Boxed Warning: Infusion 
reactions (including fatalities) have been associated with use; discontinue for anaphylaxis 
or angioedema. Most reactions occur during or within 24 hours of the first infusion; 
interrupt infusion for dyspnea or significant hypotension; monitor until symptoms 


BrUOG BR-308  
                                           27 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
resolve. Infusion reactions may consist of fever and chills, and may also include nausea, 
vomiting, pain, headache, dizziness, dyspnea, hypotension, rash, and weakness. Re-
treatment of patients who experienced severe hypersensitivity reactions has been 
attempted (with premedication). Some patients tolerated re-treatment, while others 
experienced a second severe reaction. 
• Embryo-Fetal Toxicity [see package insert for details] 
• Pulmonary Toxicity [see package insert for details] US Boxed Warning: May cause 
serious pulmonary toxicity (dyspnea, hypoxia, interstitial pneumonitis, pulmonary 
infiltrates, pleural effusion, noncardiogenic pulmonary edema, pulmonary insufficiency, 
acute respiratory distress syndrome [ARDS], and/or pulmonary fibrosis); discontinue for 
ARDS or interstitial pneumonitis. Use caution in patients with pre-existing pulmonary 
disease or patients with extensive pulmonary tumor involvement; these patient 
populations may have more severe toxicity. Pulmonary events may occur during or 
within 24 hours of administration; delayed reactions have occurred. 
• Exacerbation of Chemotherapy-induced Neutropenia [see package insert for details] 
• Renal toxicity: Rare cases of nephrotic syndrome with evidence of glomerulopathy have 
been reported, with an onset of 4-18 months from trastuzumab initiation; complications 
may include volume overload and HF. 
 
Please refer to the Herceptin package insert for a detailed description of the safety profile 
of Herceptin.   
 
5. Pertuzumab 
 
Availability:  
Commercially available drug will be utilized.  
 
Supplied: 
PERJETA is supplied as a 420 mg/14 mL (30 mg/mL) single-use vial containing 
preservative- free solution.  
 
Preparation and administration: 
Prepare the solution for infusion, using aseptic technique, as follows:  
• Parenteral drug products should be inspected visually for particulates and discoloration 
prior to administration.  
• Withdraw the appropriate volume of PERJETA solution from the vial(s).  
• Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.  
• Mix diluted solution by gentle inversion. Do not shake.  
• Administer immediately once prepared.  
• If the diluted infusion solution is not used immediately, it can be stored at 2oC to 8oC 
for up to 24 hours.  
• Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.  
 
Administer as an intravenous infusion only. Do not administer as an intravenous push or 
bolus.  Do not mix PERJETA with other drugs.   


BrUOG BR-308  
                                           28 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Administer dose per protocol. 
 
Storage: 
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use.  
Keep vial in the outer carton in order to protect from light.  
DO NOT FREEZE. DO NOT SHAKE. 
 
 
ADVERSE REACTIONS  
 
 The following adverse reactions as well as other precautions are discussed in greater 
detail in the package insert.  
• Left Ventricular Dysfunction: Monitor LVEF and withhold dosing as appropriate  
• Embryo-Fetal Toxicity  
• Infusion-Related Reactions: Monitor for signs and symptoms. If a significant infusion-
associated reaction occurs, slow or interrupt the infusion and administer appropriate 
medical therapies  
• Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and symptoms. If a severe 
hypersensitivity reaction/anaphylaxis occurs, discontinue the infusion immediately and 
administer appropriate medical therapies.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BrUOG BR-308  
                                           29 of 29                               Study Version 5/18/2016, Amendment #3 
5/7/18 
 
Appendix III: Required On-Study Data Submissions 
 
Required for registration: 
• 
On study form 
• 
ICF first, page patient chooses tissue storage, and last page (de-identified)  
• 
Pathology report with HER2, ER, PR statuses 
o All pathology reports for diagnosis 
o If multiple foci and histologic evaluation not done on other detected lesions,  note 
this (otherwise send those path reports) 
• 
Imaging reports (source) with tumor measurements 
o If patient had imaging studies to rule out overt metastatic disease (at physician 
discretion), ask physician to comment on results in clinic note or addendum  
• 
Treating Physician H&P 
o This should include mention of patient’s PS, clinical stage, whether patient is 
considered resectable or unresectable at baseline, whether patient is a 
candidate for breast conservation or not and for SLN sampling or would 
require ALND at baseline.   
o Ask treating physician to comment that he or she has reviewed the study’s 
inclusion and exclusion criteria (Sections IV. A. and B.), including baseline 
labs and cardiac evaluation (if performed) and that he or she certifies that 
the patient is eligible for the study; this can be done in a clinic note or 
addendum or in an email forwarded to BrUOG.