Conditions: Breast Cancer
Keywords: Implantable Microdevice In Vivo Drug Sensitivity Testing HER2-Positive Triple Negative 15-127
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the safety and feasibility of placing and removing a small device that contains anti-cancer drugs in a breast tumor of patients who plan on having breast surgery without treatment prior or patients who plan on receiving standard preoperative chemotherapy prior to their breast surgery. This device may be able to predict what types of treatment work best against an individual's breast cancer. With this device, the investigators hope to be able to personalize treatment choices based on an individual's type of breast cancer.

Detailed description:

Arms:
arm 1: Patients will have the microdevice implanted prior to breast surgery, in the absence of neoadjuvant chemotherapy arm 2: Patients will have the device placed and retrieved on a core biopsy the following day, then receive neoadjuvant chemotherapy prior to definitive breast surgery.

Interventions: intervention 1: KIBUR MICRODEVICE intervention 2: anthracycline and taxane based chemotherapy
Intervention descriptions: intervention 1: This device contains 16 reservoirs, each with a unique single agent or drug combination in microdose amounts of less than one millionth of a systemic patient dose. The device is implanted directly into the tumor during a biopsy procedure, and remains in situ for \~24 hours. intervention 2: Conventional, standard of care neoadjuvant chemotherapy delivered irrespective of device readout

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 1 of 31 
 
 
 
Pilot Trial of an Implantable Microdevice for in vivo Drug Sensitivity Testing in 
Patients with Early Stage, Triple Negative Breast Cancer 
 
 
PROTOCOL FACE PAGE FOR 
MSK NON THERAPEUTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Tiffany A. Traina, MD 
Medicine: Breast 
Co-Principal 
Investigator(s)/Department: 
George Plitas, MD 
Surgery: Breast 
Investigator(s)/Department: 
Jorge Reis-Filho, MD, PhD 
Hannah Wen, MD, PhD 
Fresia Pareja, MD, PhD 
Felipe Geyer, MD 
Sujata Patil, PhD 
José Baselga, MD, PhD 
Maura Dickler, MD 
Ting Bao, MD 
Victoria Blinder, MD 
Sarat Chandarlapaty, MD, PhD 
Gabriella D‟Andrea, MD 
Monica Fornier, MD 
Jacqueline Bromberg, MD, PhD 
Teresa Gilewski, MD 
Shari Goldfarb, MD 
Ayca Gucalp, MD 
Mary Ellen Moynahan, MD 
Larry Norton, MD 
Mark Robson, MD 
Rachel Sanford, MD 
Andrew Seidman, MD 
Nancy Sklarin, MD 
Devika Gajria, MD, MPH 
Elizabeth A. Comen, MD 
Shanu Modi, MD 
Neil Iyengar, MD 
Chau Dang, MD 
Diana Lake, MD 
Komal Jhaveri, MD 
Pedram Razavi, MD, PhD 
Lillian Smyth, MD 
Christofer Klebanoff, MD 
Linda Vahdat, MD 
Mila Gorsky, MD 
Louise Ligresti, MD 
Neha Korde, MD 
Pathology 
Pathology 
Pathology 
Pathology 
Epidemiology/Biostatistics 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast/GYN 
Medicine: Breast/GYN 
Medicine: Myeloma 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 2 of 31 
 
 
 
Audrey Hamilton, MD 
Paul Hamlin, MD 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Jasmeet Singh, MD 
Sarah Schweber, MD 
Wanqing Iris Zhi, M.D., Ph.D 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Tiffany Troso-Sandoval, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Rachel Grisham, MD 
Monica Morrow, MD 
Hiram Cody III, MD 
Mahmoud El-Tamer, MD 
Virgilio Sacchini, MD 
Kimberly Van Zee, MD 
Andrea Barrio, MD 
Mary Gemignani, MD 
Alexandra Heerdt, MD 
Melissa Pilewskie, MD 
Deborah Capko, MD 
Lisa Sclafani, MD 
Laurie Kirstein, MD 
Debra Mangino, MD 
Mary Hughes, MD 
Janice Sung, MD 
Elizabeth Morris, MD 
Yolanda Bryce, MD 
Jill Gluskin, MD 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Marina Scherba, DO 
Colette Owens, MD 
Loren Michel, MD 
Virginia Klimek, MD 
Roseann Caruso, NP 
Karin Budrock, NP 
Karen Dougherty, APN 
Karen Drucker, NP 
Carrie Mancini, NP 
Maureen Cannon, NP 
Cathy Lombardo, NP 
Courtney Hennelly, APN 
Medicine: Hematology 
Medicine: Lymphoma 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast/GYN 
Medicine: Thoracic, Head & Neck 
Medicine: GU 
Medicine: Breast/ 
Medicine: Hematology 
Medicine: GI 
Medicine: GYN 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Radiology 
Radiology 
Radiology 
Radiology 
Radiology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 3 of 31 
 
 
 
Valentina Sterlin, RN 
Lauren Wood, RN 
Tina Alano, RN 
Odessa Williams, RN 
Danielle Alleva, RN 
Nora Messinger, NP 
Aimee Rogado, RN 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting 
Professional(s)/Department: 
Tiffany Traina, MD 
José Baselga, MD, PhD 
Maura Dickler, MD 
Ting Bao, MD 
Victoria Blinder, MD 
Sarat Chandarlapaty, MD, PhD 
Gabriella D‟Andrea, MD 
Monica Fornier, MD 
Jacqueline Bromberg, MD, PhD 
Teresa Gilewski, MD 
Shari Goldfarb, MD 
Ayca Gucalp, MD 
Mary Ellen Moynahan, MD 
Larry Norton, MD 
Mark Robson, MD 
Rachel Sanford, MD 
Andrew Seidman, MD 
Nancy Sklarin, MD 
Devika Gajria, MD, MPH 
Elizabeth A. Comen, MD 
Shanu Modi, MD 
Neil Iyengar, MD 
Chau Dang, MD 
Diana Lake, MD 
Komal Jhaveri, MD 
Lillian Smyth, MD 
Christofer Klebanoff, MD 
Pedram Razavi, MD, PhD 
Linda Vahdat, MD 
Mila Gorsky, MD 
Louise Ligresti, MD 
Neha Korde, MD 
Audrey Hamilton, MD 
Paul Hamlin, MD 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Jasmeet Singh, MD 
Sarah Schweber, MD 
Wanqing Iris Zhi, M.D., Ph.D 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast/GYN 
Medicine: Breast/GYN 
Medicine: Myeloma 
Medicine: Hematology 
Medicine: Lymphoma 
Medicine: Breast 
Medicine: GYN 
Medicine: Breast 
Medicine: Breast 
Medicine: Breast/GYN 
Medicine: Thoracic, Head & Neck 
Medicine: GU 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 4 of 31 
 
 
 
Tiffany Troso-Sandoval, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Rachel Grisham, MD 
George Plitas, MD 
Monica Morrow, MD 
Hiram Cody III, MD 
Mahmoud El-Tamer, MD 
Virgilio Sacchini, MD 
Kimberly Van Zee, MD 
Andrea Barrio, MD 
Mary Gemignani, MD 
Alexandra Heerdt, MD 
Melissa Pilewskie, MD 
Deborah Capko, MD 
Lisa Sclafani, MD 
Laurie Kirstein, MD 
Debra Mangino, MD 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Marina Scherba, DO 
Colette Owens, MD 
Loren Michel, MD 
Virginia Klimek, MD 
Medicine: Breast 
Medicine: Hematology 
Medicine: GI 
Medicine: Breast/GYN 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Surgery: Breast 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK Sites 
Westchester 
Basking Ridge 
Commack 
Rockville 
Manhattan 
Monmouth 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 5 of 31 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................6 
Figure 1. Protocol schema ............................................................................................................. 7 
Cohort 1: Upfront Breast Surgery .................................................................................................. 7 
Cohort 2 ........................................................................................................................................ 7 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ...............................................................................8 
• 
To preliminarily assess ............................................................................................................8 
• 
To evaluate the reproducibility of data from replicate drug/drug combinations in each device 
and across devices in the case where more than one device is retrieved .......................................8 
• 
To define the inter-observer variability between pathologists for the assessment of 
phenotypic response in native tumor tissue ....................................................................................8 
• 
To determine the accuracy by which tissue responses can be co-localized with the specific 
drug regimens on the microdevice both in the setting of extracting the device surgically with the 
entire tumor as well as extracting the device percutaneously ..........................................................8 
3.0 
BACKGROUND AND RATIONALE ....................................................................................8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 13 
4.1 
Design ........................................................................................................................... 13 
4.2 
Intervention .................................................................................................................... 15 
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 19 
5.1 
Subject Inclusion Criteria ................................................................................................ 19 
5.2 
Subject Exclusion Criteria .............................................................................................. 19 
6.0 
RECRUITMENT PLAN ...................................................................................................... 20 
7.0 
ASSESSMENT/EVALUATION PLAN ............................................................................... 21 
8.0 
TOXICITIES/SIDE EFFECTS ............................................................................................ 22 
9.0 
PRIMARY OUTCOMES..................................................................................................... 22 
10.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 23 
11.0 
BIOSTATISTICS ............................................................................................................... 23 
12.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
24 
12.1 
Research Participant Registration .................................................................................. 24 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility ........... 25 
12.2 
Randomization ............................................................................................................... 25 
13.0 
DAT A M ANAGEMENT ISSUES ....................................................................................... 25 
13.1 
Quality Assurance .......................................................................................................... 25 
13.2 
Data and Safety Monitoring ............................................................................................ 25 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 6 of 31 
 
 
14.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 26 
14.1 
Privacy ........................................................................................................................... 26 
14.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 26 
14.2.1 
 28 
15.0 
INFORMED CONSENT PROCEDURES ........................................................................... 28 
16.0 
REFERENCES .................................................................................................................. 29 
17.0 
APPENDICES ................................................................................................................... 30 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This pilot trial seeks to evaluate the feasibility of implanting and retrieving at least 1 implantable 
microdevice in patients with early stage Triple Negative Breast Cancer (TNBC) who are 
candidates for neoadjuvant therapy or upfront surgery. The overarching development plan, if 
proven feasible in this pilot, would be to test whether in vivo chemotherapy sensitivity assessed 
by an implantable microdevice (the “device”) correlates with response to standard of care, 
neoadjuvant chemotherapy for the treatment of patients with early stage TNBC. The study has 
been amended to include 2 cohorts. In Cohort 1, patients will have the microdevice placed prior 
to breast surgery and in the absence of neoadjuvant chemotherapy. Removal of the device with 
the entire tumor will be used to confirm our ability to pathologically correlate in vivo tumor 
response to the individual drug regimens included on the microdevice. In Cohort 2, patients will 
have the device placed, retrieved 1 day later by core biopsy and proceed on to standard of care 
neoadjuvant chemotherapy. In exploratory objectives, in vivo chemotherapy sensitivity to 
doxorubicin and cyclophosphamide (AC) as defined by a panel of prespecified biomarkers 
related to apoptosis, DNA damage and proliferation will be analyzed for correlation with 
pathologic complete response as defined by residual cancer burden (RCB 0/1) following a 
standard of care, neoadjuvant, AC-based chemotherapy regimen for patients in Cohort 2. 
Exploratory endpoints include the subanalyses to evaluate the device‟s ability to correlate 
response from taxane/platinum therapy, to investigate the intervariability of the measurements by 
device and within a device and to evaluate pathologist interobserver variability. We will also 
evaluate the safety of implanting and retrieving the device. The protocol schema is shown in 
Figure 1. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 7 of 31 
 
 
*Paclitaxel (T) + Carboplatin (C) 
 
dose dense 
AC 
Figure 1. Protocol schema 
Cohort 1: Upfront Breast Surgery 
 
 
 
Cohort 2: Neoadjuvant Therapy 
 
 
 
 
 
 
Research 
Biopsy 
 
• Eligible patients 
with T>2cm TNBC BC 
who are candidates 
for neoadjuvant 
therapy 
• Implant up to 3 
devices 
• Devices explanted 1 
day later by core 
biopsy 
• Device efficacy 
readout is performed 
Residual 
cancer 
burden 
determined 
Correlation 
of clinical 
response 
with in vivo, 
device- 
predicted 
readout 
S 
u 
r 
g 
e 
r 
y 
Conventional, standard of care neoadjuvant chemotherapy 
delivered irrespective of device readout. 
* Study participation is permitted if patient will not receive 
paclitaxel or carboplatin following AC in the judgment of the 
treating physician 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 8 of 31 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective: 
• 
To determine the feasibility of implanting and retrieving at least 1 device in patients with 
early stage triple-negative breast cancer who are candidates for neoadjuvant 
chemotherapy or upfront surgery. Three devices will be implanted in the patient unless 
otherwise limited by tumor size, where fewer may be placed. 
Secondary Objectives: 
• 
To describe the safety and possible toxicity of implanting and retrieving at least 1 device 
in patients with early stage breast cancer who are candidates for neoadjuvant 
chemotherapy or upfront surgery. 
• 
To preliminarily assess in vivo chemotherapy sensitivity to AC as predicted by the device 
correlates with residual cancer burden (RCB) 0/1 following standard of care, AC-based 
neoadjuvant chemotherapy regimen for patients with early stage TNBC who receive 
neoadjuvant therapy (Cohort 2). 
• 
To evaluate whether in vivo chemotherapy sensitivity to paclitaxel and carboplatin as 
predicted by the device correlates with RCB 0/1 for patients with early stage TNBC 
receiving standard of care neoadjuvant chemotherapy with AC followed by paclitaxel + 
carboplatin (Cohort 2). 
• 
To evaluate whether in vivo chemotherapy sensitivity to AC combination at baseline 
correlates with biomarkers of response in vivo following systemic administration of AC for 
those patients receiving neoadjuvant therapy. 
• 
To evaluate the reproducibility of data from replicate drug/drug combinations in each 
device and across devices in the case where more than one device is retrieved. 
• 
To define the inter-observer variability between pathologists for the assessment of 
phenotypic response in native tumor tissue 
• 
To determine the accuracy by which tissue responses can be co-localized with the 
specific drug regimens on the microdevice, both in the setting of extracting the device 
surgically with the entire tumor, as well as extracting the device percutaneously. 
 
3.0 
BACKGROUND AND RATIONALE 
Efforts to personalize treatment by in vitro tumor assays to predict chemotherapy sensitivity have 
been ongoing across solid tumors for many years. However, these methods have been limited in 
their usefulness to date. In fact, the American Society of Clinical Oncology issued a statement in 
2011 which recommended against the use of chemotherapy sensitivity and resistance assays 
(CSRA) to select chemotherapeutic agents for individual patients outside of the clinical trial 
setting. [1]This practice guideline is based on the lack of evidence that any available CSRA 
demonstrated improved outcomes (i.e., overall survival, response to therapy, disease free 
survival, progression free survival, local tumor control or treatment toxicity) when used to make 
chemotherapy decisions rather than empiric choice based upon clinical trial literature. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 9 of 31 
 
 
However, it has been recognized that an in vitro strategy could have potential clinical importance 
and further development of models to individualize chemotherapy choice are a priority. 
Unfortunately, in vitro models are unable to recapitulate the exact microenvironment in which a 
tumor exists. Development of cell line and xenograft models take time that makes real-time 
decision making based upon results less practical. In addition, limited resources may result in 
difficulty bringing patient-derived xenograft models to practice on a larger scale. 
There is an unmet need for an in vivo, chemosensitivity assay that could simply and quickly 
predict benefit from a particular treatment for patients with solid tumor malignancy. Kibur has 
invented an implantable microdevice which may serve as a rapid screen for multiple single agent 
or combination therapy regimens in vivo, reflecting the native tumor and patient 
microenvironment. 
In this pilot first-in-human trial, we propose studying whether this device may be placed within a 
breast primary tumor, successfully retrieved (either through radiology-guided retrieval process 
prior to neoadjuvant chemotherapy or at the time of definitive breast surgery) and yield evaluable 
tumor tissue for readout of drug sensitivity. Secondary exploratory endpoints will evaluate whether 
the device has the ability to predict RCB 0/1 for patients receiving standard of care, neoadjuvant 
chemotherapy for early stage breast cancer in Cohort 2. 
Neoadjuvant chemotherapy 
The goal of systemic chemotherapy for the treatment of early stage breast cancer is to eradicate 
micrometastases and improve overall survival. In addition to this objective, the primary aim of 
neoadjuvant chemotherapy for nonmetastatic invasive breast cancer is to improve surgical 
outcomes in patients for whom a primary surgical approach is not feasible or for those patients 
who desire breast conservation. The standard, highly effective chemotherapy regimens typically 
used in the adjuvant, post-operative setting are instead administered preoperatively to facilitate 
surgery. To date, survival outcomes for chemotherapy given in the pre- or post-op setting have 
been comparable. 
There is a trend towards increased usage of neoadjuvant therapy for patients with triple negative 
(TNBC) breast cancers, in part because these cancers are most likely to show good locoregional 
responses. 
Triple Negative Breast Cancer 
Two recent randomized phase 2 studies have demonstrated higher pCR rates with the addition of 
carboplatin to an anthracycline- and taxane-containing regimen for the neoadjuvant treatment of 
patients with early stage triple negative breast cancer. The GeparSixto study randomized a cohort 
of 315 patients with TNBC to weekly liposomal doxorubicin + paclitaxel with bevacizumab, with or 
without weekly carboplatin.[4] The addition of carboplatin was associated with a significantly 
higher pCR rate (57% vs. 43%, OR 1.94, 95% CI 1.24-3.04). These results were later confirmed 
by CALGB 40603, a randomized phase 2 trial which utilized a more conventional backbone 
chemotherapy regimen (weekly paclitaxel followed by dose dense AC) and randomized 443 
women with TNBC to the addition of carboplatin AUC 6 every 3 weeks concurrently with 
paclitaxel.[5] Despite the slight variations in backbone chemotherapy, the addition of carboplatin 
was also associated with a higher pCR rate (54% vs. 41%, OR 1.71). Recently, the GeparSixto 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 10 of 31 
 
 
trial reported that the addition of carboplatin improved disease free survival as compared to the 
non-platinum containing control arm (85.8% vs. 76.1%; HR 0.56 p=0.035) (von Minckwitz et al, 
Abstract S2-04 SABCS 2015). These results are supportive of the antitumor activity associated 
with platinum agents for the treatment of TNBC and the addition of carboplatin to weekly 
paclitaxel as part of a neoadjuvant regimen is a reasonable option for patients with stage II-III 
TNBC. However, platinum-based chemotherapy regimens have not replaced acceptable 
anthracycline- and taxane-based regimens for the treatment of early stage breast cancer, nor has 
neoadjuvant administration of chemotherapy become a standard for all triple-negative breast 
cancers. The incorporation of platinum to ddAC-T presents one additional reasonable option for 
treatment of early stage TNBC. 
Neoadjuvant treatment allows for an early evaluation of the effectiveness of systemic therapy 
from clinical observation, radiographic findings and ultimately pathologic response evaluations at 
the time of definitive breast surgery (i.e., pathologic complete response). Additionally, in the HER2 
and TNBC subtypes of breast cancer, pathologic complete response has been shown to correlate 
with survival outcomes. [6]These features make the neoadjuvant space an appealing setting for 
the conduct of clinical trials in which tissue acquisition is required to identify tumor- or patient- 
specific biomarkers. 
An implantable microdevice to predict in vivo chemotherapy sensitivity 
 
Kibur Medical has developed a rapid parallel in vivo assay that consists of an implantable 
microscale device that is placed inside the native tumor microenvironment. This device 
contains 16 reservoirs, each with a unique single agent or drug combination in microdose 
amounts of less than one millionth of a systemic patient dose. The device is implanted directly 
into the tumor during a biopsy procedure, and remains in situ for ~24 hours (Figure 2). Drugs 
from each reservoir are released during this time into distinct regions of tumor tissue, 
effectively creating in vivo micro-reactors for the interaction of tumor with a specific drug. 
Crosstalk between drugs from different reservoirs is eliminated by appropriate spatial 
separation of reservoirs and by drug formulation and other techniques. The microdevice is of 
cylindrical shape measuring 820µm in diameter, and is delivered through an 18 gauge biopsy 
needle. 
 
 
Figure 2: Concept for in-vivo drug sensitivity assay: Device is implanted directly into tissue. During implantation, drugs diffuse into 
confined regions of tumor. Each such region can be assayed independently to assess the tumor-specific response of a given drug. 
Follow ing incubation, a second biopsy procedure is administered in which a coring needle selectively retrieves a small column of 
tissue that immediately surrounds the device. This tissue contains the regions of drug diffusion and is sufficient for determination of 
efficacy of drugs. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 11 of 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Removal of drug-exposed 
tumor region by a coring needle. 
The device and the region of drug 
distribution w as removed by a 13- 
gauge coring needle after 20-24 h for 
pure and formulated drug contents. 
More than 99% of drug was removed, 
as measured by autofluorescence of 
pure doxorubicin. 
The device with surrounding tissue is excised using a larger 
coring biopsy needle (~7-12 gauge) which is inserted into 
the tumor and positioned concentric to the device using 
ultrasound imaging. The coring needle then protrudes over 
and beyond the device, capturing the device itself and a 
cylindrical column of tissue of 1.6mm thickness and 4-5mm 
length, including ~400µm thickness radially outward from 
the device along its entire length. This represents virtually 
the entire region of drug distribution over the incubation 
period of 1 day and is thus sufficient for examining drug 
effect. The drug amounts that were released from reservoirs 
into tissue are removed almost entirely during the retrieval 
procedure, along with the tumor tissue that was exposed to 
these compounds. In this manner, Kibur investigators were 
capable of gathering in vivo phenotypic data on the action of 
a large number of anti-cancer single agents or combinations 
within 1 day inside the tumor microenvironment, all without 
systemic or residual exposure to the drugs tested. 
The local concentration of drug released into distinct regions of tumor tissue can be measured 
by drug autofluorescence (A-D) or mass spectrometry tissue imaging (E, F), and can be 
observed at different time points (J) as shown in Figure 4. 
Figure 4: A-I: Anti-cancer drugs are delivered into confined regions of tumor. Detection by fluorescence: (A) Doxorubicin (B) 
Sunitinib (C) Lapatinib. (D) Cetuximab conjugated w ith Alexa488. Detection by MALDI mass spectrometry: (E) Gemcitabine and 
(F) Docetaxel. (J): Image compares the release of a microdose of sunitinib at 3 time points, demonstrating expanded but confined 
region of tissue distribution even at longer time points. Scale bar = 300 μm. 
 
A small region of tissue is removed from the tumor and analyzed by multi-parameter 
immunohistochemistry (IHC) to determine anti-neoplastic effect for each treatment being 
evaluated on the device at the end of the device implantation period. Multiple biomarkers can 
be used to understand the specific effect of drug on tumor tissue. 
 
Figure 5: Device/tissue cross -sections stained for multiple IHC biomarkers, showing time and concentration 
dependent effects on proliferation and apoptosis of drug -exposed cells. Scale = 200µm. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 12 of 31 
 
 
Preclinically, Kibur Medical has validated the ability to use the local microdose effect as a 
predictor of drug efficacy across multiple drugs and tumor models. (Figure 6) 
 
 
Figure 6: (A) Differential response of three tumor models to doxorubicin. TOP: 
Representative tumor sections IHC-stained for CC3: PC3 (left), BT474 (middle) 
and A375 (right). BOTTOM: Left: Automated counting of sections for CC3- 
positive cells. Right: Averages for each tumor model response are calculated 
from at least 18 unique reservoirs from 12 tumors. Scale = 250μm. (B) 
Apoptosis induction following systemic administration of doxorubicin in A375 
and PC3 tumors. Representative sections of PC3 (top) and A375 (bottom) are 
shown at 8 mg/kg (left) and control (right). CC3-stained regions (brown) 
indicate induction of apoptosis in affected cells. Averages are calculated from 
12 spatially separated sections from 3 distinct tumors. (C-E) Comparison of 
differential apoptotic response for vemurafenib, gemcitabine and topotecan, as 
assessed by CC3 expression after 24h in 12 spatially distinct tumor regions 
from at least 4 tumors each. Scale = 200μm. (F-G) Enhancement of apoptotic 
response by addition of targeted agents to doxorubicin in device reservoir. 
Lapatinib leads to an enhancement of CC3 expression in MDA-MB231, and a 
very significant apoptosis increase in BT474. Averages are calculated from 10 
distinct reservoirs from 4 tumors. All sections taken at 20-24h post implantation. 
(H) Control sections for tumor models used, representing empty device 
reservoirs with no local drug treatment. Scale = 400μm. All error bars represent 
one standard deviation. 
 
Modified Device: 
 
We have studied our methodology and outcomes of first patient accruals on study and have noted 
that the microdevice, although successfully retrieved, would often become dislodged from 
surrounding tumor tissue during retrieval process. In response to this, in collaboration with Kibur, 
we have developed a modified microdevice that seeks to address the difficulties with tissue 
retention and biopsy retrieval incurred with the previous device design (Figure 7). There are 3 
modifications featured on the new microdevice design: 
• 
The back of the microdevice features a barb which restricts axial movement and keeps the 
device locked onto tissue more tightly. 
• 
The diameter of the cylindrical section bearing the reservoirs is reduced from 820 µm to 720 
µm. 
• 
The tip of the microdevice is conical, allowing for better penetration into tissue and lower 
associated tissue damage. This also provides a tighter encapsulation of the device with tissue. 
 
All methods of device insertion and specimen analysis remain unchanged and have been 
successfully piloted preclinically (Figure 8). Radiology has modified retrieval methodology to 
minimize disruption to device/tumor relationship as a result of the biopsy procedure and pathology 
has optimized specimen handling techniques. These modifications are not thought to alter the risk 
level of the protocol. While the design of the microdevice has been changed, it is composed from 
the same inert polymer that the original device was made. 


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Rationale 
This first in human pilot study will preliminarily assess the feasibility of implanting and retrieving at 
least 1 device from the breast in patients with early stage breast cancer and to assess whether 
the Kibur device and the in vivo measurements it produces correlate with pathologic response to 
chemotherapy. Pathologic response will be measured by residual cancer burden. The patient 
population includes patients with breast cancer receiving standard of care, neoadjuvant 
anthracycline- and taxane-based chemotherapy for T2 N any, triple negative breast cancer. The 
Kibur device measurements linked to the AC wells will be used to test our primary hypotheses. To 
date, there are no available methods for predicting an individual patient‟s or tumor‟s response to 
therapy which recapitulates the in vivo complexities of both the tumor and its microenvironment. 
Individual patient derived xenograft or cell line models are costly, time consuming and difficult to 
scale into clinical practice. 
If the readout obtained from the Kibur device is shown to be feasible and correlated with 
chemotherapy sensitivity in vivo, this pilot trial will lead to a larger study to validate findings and 
investigate the use of the device in making individual treatment decisions. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This study will assess the feasibility of implanting and retrieving at least 1 device in patients with 
early stage breast cancer who are candidates for neoadjuvant chemotherapy or upfront surgery. 
We will also obtain preliminary data regarding the ability of the Kibur device, an in vivo indicator of 
chemotherapy sensitivity, to predict response to neoadjuvant AC in patients with early stage 
breast cancer receiving systemic, standard of care, pre-operative anthracycline- and taxane- 
based chemotherapy as defined by residual cancer burden (RCB) 0/1. RCB is an accepted 
measure of response to neoadjuvant chemotherapy which correlates with survival ( Appendix 
B).[7] Twelve patients with early stage triple negative breast cancer, who are candidates for 
upfront surgery (Cohort 1) or neoadjuvant therapy (Cohort 2) will be accrued. 
Figure 7. New microdevice 
design. 
Figure 8. Retrieved specimens, using new 
microdevices and standard coring biopsy 
needle. 


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Patients with early stage TNBC with primary tumors greater than or equal to 1 cm in size are 
candidates for this protocol. Patients may be accrued to one of two Cohorts. Appropriateness for 
one cohort over the other will depend on whether patient will pursue a neoadjuvant chemotherapy 
approach (Cohort 2) or elect to proceed directly to surgery and defer chemotherapy to the post- 
operative setting (Cohort 1). This decision will be made in a multidisciplinary way with input from 
Breast Surgery and Breast Medical Oncology, taking into account patient preference as well. The 
infrastructure for this multidisciplinary approach is already in place within the Breast Disease 
Management Team. 
 
 
Cohort 1: Upfront Surgery 
In this cohort, patients will undergo placement of 3 devices within the tumor unless limited by 
tumor size, where fewer may be placed. In patients undergoing a lumpectomy the devices may be 
placed at the time of wire or seed localization. Each device has several wells loaded with single 
agent and combination therapy. The devices will be retrieved 1 day later at the time of definitive 
breast surgery (breast conservation or mastectomy per standard of care). The sample will be sent 
to pathology fresh and if a device is encountered intra-operatively, the device will be separately 
delivered to pathology. Study team will coordinate scheduling such that Dr. Elizabeth Morris is 
available for placing the device and Dr. Hannah Wen is available in the Pathology Department to 
help in tissue handling appropriately. Specimen radiograph to confirm removal of devices will be 
performed in pathology. Devices and a small amount of surrounding tumor will be sent to Reis- 
Filho‟s laboratory where tumor analyses will be performed to evaluate an apoptotic index defined 
by cleaved caspase 3, Ki67 labeling index, phospho-H2AX score, and RAD51 score to estimate 
response to therapy. The patient will then proceed on to adjuvant therapy at the discretion of the 
treating medical oncologist. 
Cohort 2: Neoadjuvant Therapy 
In this cohort, patients will undergo placement of 3 devices prior to systemic therapy, unless 
limited by tumor size, where fewer may be placed. Each device has several wells loaded with 
single agent and combination therapy. The devices will be retrieved 1 day later by core needle 
biopsy. The sample will be sent to pathology fresh and if a device is encountered intra- 
operatively, the device will be separately delivered to pathology. Study team will coordinate 
scheduling such that Dr. Elizabeth Morris is available for placing the device and Dr. Hannah Wen 
is available in the Pathology Department to help in tissue handling appropriately. Specimen 
radiograph to confirm removal of devices will be performed in pathology. Devices and a small 
amount of surrounding tumor will be sent to Reis-Filho‟s laboratory. 
Tumor analyses will be performed to evaluate an apoptotic index defined by cleaved caspase 3, 
Ki67 labeling index, phospho-H2AX score, and RAD51 score to estimate response to therapy. 
Patients will go on to receive standard of care neoadjuvant therapy. A research biopsy will be 
performed following AC treatment. RCB will be determined by the study pathologist at the time of 
definitive surgery following neoadjuvant chemotherapy. 
All analyses will be primarily descriptive and graphical in nature. The primary endpoint will be to 
evaluate the feasibility of the device. We have defined feasibility as the ability to implant and 


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retrieve at least one device. Numerous secondary and exploratory analyses are planned. We will 
evaluate the safety and toxicity of implanting and removing the device as well as our ability to 
determine tissue response to the agents incorporated in the device, both by core biopsy or at time 
of definitive surgery. We will explore whether in vivo chemotherapy sensitivity to AC as predicted 
by the device correlates with residual cancer burden (RCB) 0/1 following standard of care. In this 
patient population, we estimate that standard neoadjuvant regimens will achieve RCB 0/1 in 50% 
of patients. Similar analyses to evaluate the sensitivity of subtype-specific regimens will be done 
in the TNBC subsets. In addition, we will evaluate whether AC chemotherapy sensitivity in vivo at 
baseline (measured by apoptotic index defined by cleaved caspase 3, Ki67 labeling index, 
phospho-H2AX score and RAD51 score in the area closest to the AC wells of the device) is 
correlated with the same measures obtained from tumor biopsy after AC therapy. Exploratory 
endpoints will evaluate the reproducibility of each device and across devices, as well as 
interobserver variability. 
4.2 
Intervention 
Patients will be offered participation in this trial by their Breast Surgeon or Breast Medical 
Oncologist once a determination of neoadjuvant or upfront surgery has been made. Eligible 
patients who give informed consent will be referred to Breast Radiology for implantation of 3 
devices within the primary tumor unless limited by tumor size, where fewer may be placed. Each 
device has 16 wells; the 8 drug regimens shown below will be loaded in duplicate on each device. 
 
Kibur Drug Wells 
1. Doxorubicin and cyclophosphamide (AC) 
2. Doxorubicin (A) 
3. Paclitaxel (T) 
4. Paclitaxel (T) and carboplatin (Pl) 
5. Carboplatin (Pl) 
6.  AC + paclitaxel + carboplatin (AC-TPl) 
7. Gemcitabine (G) 
8. Eribulin (E) 
 
The 3 devices will be implanted into the primary tumor by a Breast Radiologist trained in this 
method on Monday through Thursdays. Women accrued to the trial will be scheduled for 
appointments on two consecutive days; Cohort 1 will have device placement followed by definitive 
surgery the next day. Cohort 2 will have device insertion one day, followed by a removal the next 
day. Three devices will be implanted into each tumor. The technique involved with device 
insertion is equivalent to placement of a radioactive seed using ultrasound guidance or placement 
of a localizing clip after ultrasound guided biopsy, which is standard practice. On the day of 
implantation, the biopsy proven cancer will first be localized with real time sonography. The skin 
will be cleansed with Betadine and 8 cc of 1% lidocaine will be used for superficial and deep 
anesthesia. A skin nick may be made. There will be one insertion site for local anesthesia and 
efforts will be made to place all devices through the same needle insertion. The 18 gauge spinal 
needle will then be inserted through the skin and directed into the cancer where the device will be 
deployed. Each device will be loaded into an 18 gauge spinal needle. Three separate 18 gauge 
spinal needles will be used; each will insert one device into the tumor. 


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Cohort 1 
 
Patients on Cohort 1 will proceed to surgery as previously scheduled, the day after device 
placement. The type of surgery, either a lumpectomy or mastectomy will be at the surgeon‟s 
discretion. In the setting of a lumpectomy, non-palpable tumor will be localized with a radioactive 
seed the day prior to surgery at which point the devices will be placed. The surgery will proceed 
as routine except that the tumor will be sent to pathology freshly. A specimen radiograph of 
lumpectomies will be performed at the discretion of the surgeon to confirm retrieval of the 
radioactive seed or biopsy marker. If on this radiograph the devices are not evident, the additional 
shave margins that are taken as per routine will also be radio graphed in pathology to determine if 
the devices are present. If the devices are not accounted for, no additional tissue will be excised 
from the patient and a post excision mammogram will performed postoperatively when tolerable 
to the patient to confirm a retained device. In patients undergoing a mastectomy, the breast will 
be delivered to pathology where it will undergo X-ray to determine device presence. If a device is 
encountered intraoperatively it will be placed in a container and sent to pathology. 
 
Cohort 2 
 
Patients on Cohort 2 will return to Breast Radiology to have the devices retrieved 1 day following 
implantation. The device with surrounding tissue will be excised using a ~7-12 gauge core biopsy 
needle, which will be inserted into the tumor and positioned concentric to the device using 
stereotactic or ultrasound guidance. Study radiologists have undergone dedicated training for 
device removal under ultrasound guidance. Devices with empty reservoirs have been placed in a 
chicken breast to simulate the breast tissue. Each radiologist has successfully removed three 
devices from these models using a 7-12 vacuum needle on several occasions. Device removal 
under stereotactic guidance models standard practices for breast tumor biopsies. The decision 
about the method for device retrieval will be based on the visibility of the device within the tumor. 
Based on phantom studies, it is expected that ultrasound will be feasible in the majority of cases. 
Ultrasound has the advantage of real time visualization and the ability to line up the device with 
the opening of the biopsy needle. However in the event that the device is not able to be seen on 
ultrasound, stereotactic biopsy will be performed for device retrieval. All devices have markers 
that will be easily seen with x-ray and therefore can undergo stereotactic biopsy. It is expected 
that all devices can be removed with either of these methods. 
For ultrasound guided device removal, the target will first be localized sonographically. The breast 
will be cleansed with Betadine, and 3 cc of 1% lidocaine and 10 cc of 1% lidocaine with 
epinephrine (unless contraindicated) will be used for deep anesthesia. A skin nick will be made 
with a scalpel. A vacuum assisted needle will be inserted and its accurate position confirmed with 
sonographic images. Multiple samples will be taken at each site in order to attempt removal of all 
three devices. A maximum of three insertions will be performed with procedure time not 
exceeding 30 minutes. The specimens will be delivered for analysis. 
 
For device removal under stereotactic guidance, a preliminary grid localizing film will be obtained 
to localize and the skin marked. The patient will then be positioned on the stereotactic table or 
chair and the target localized with digital images. The breast will be cleansed with Betadine, and 3 
cc of 1% lidocaine will be used for superficial anesthesia and 10 cc of 1% lidocaine (with 
epinephrine) will be used for deep anesthesia. A skin nick will be made with a scalpel. A 7-12 


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gauge probe will be inserted and its accurate position confirmed with images. Multiple samples 
will be taken in order to attempt removal of all three devices. If possible, the same incision will be 
used to retrieve all three devices. However, depending on the distance between three devices, 
separate skin incisions and biopsy devices may be required. The procedure time will not exceed 
30 minutes. 
 
Following the ultrasound or stereotactic guided procedure, pressure will be held on the site(s) until 
bleeding ceases. The area(s) will be cleansed and Steri-Strips applied. Post biopsy instructions 
will be given verbally and in writing. 
Informed consent will be obtained prior to both device implantation and removal. Risks of either 
procedure include bleeding and infection. 
In the event that a device cannot be retrieved, we do not expect side effects from prolonged 
incubation. The device consists of a polyaryletherketone (PEEK) polymer which has 
demonstrated long-term safety and biocompatibility in multiple biomedical applications, such as 
trauma, orthopedic and spinal implants.[8] A close comparable for the Kibur device is the “Cassi 
Beacon” tissue marker, an FDA-approved fiducial marker used for long-term localization of breast 
tumors (http://scionmedtech.com/products/breast-biopsy/cassi-beacon/). The Cassi Beacon is 
structurally very similar to the Kibur device (composed of PEKK) though it is more than 4 times 
larger by volume (cylindrical shape, 1.5mm in diameter and 5mm long). If devices cannot be 
retrieved 1 day following implantation, they will be removed from the patient along with the 
remainder of the tumor during surgical tumor resection which is maximally 6 months after 
implantation. In the rare circumstance where a patient did not have device retrieved on Day 2 and 
has unresectable disease at the time of completion of preoperative neoadjuvant chemotherapy, 
the study surgeon will discuss alternative options for device removal with the patient. It is possible 
that additional neoadjuvant therapy may be given to facilitate curative resection which may extend 
the time the device is in place to >6 months. It is also possible that the device is intentionally and 
knowingly left in situ if the risks of surgery were to outweigh the benefit. 
Following device retrieval, or definitive surgery, the tumor-device specimens will be sent to the 
research laboratory of Dr. Reis-Filho. Specimens will be fixed in buffered formalin for 16 hours 
and subsequently processed and embedded in paraffin for histochemical and 
immunohistochemical analysis. Tissue sectioning will be performed essentially as described by 
Jonas et al., to ensure that at least 5 sections centered on each reservoir are cut. One section will 
be stained with hematoxylin-and-eosin and the remaining sections will be subjected to IHC or 
immunofluorescence using antibodies against cleaved caspase 3, Ki67, RAD51, γH2AX, and 
Geminin as previously described. (Jonas O et al, Sci Transl Med 2014)[9] 
 
Quantification of the IHC and immunofluorescence results will be performed by two trained 
pathologists with experience and expertise in breast cancer. The regions in tissue directly 
perpendicular to the reservoirs will be quantified for the presence of morphologically unequivocal 
neoplastic cells expressing Caspase 3, Ki67, phospho-H2AX foci, RAD51 foci and Geminin. 
To determine the impact of each therapeutic agent or drug combination on apoptosis, caspase 3 
expression will be analyzed. Only cytoplasmic and/ or nuclear expression will be considered 
specific. The apoptotic index (AI) will be calculated as the number of Caspase 3-positive 
morphologically unequivocal cells/ 1000 morphologically unequivocal neoplastic cells (Jonas O et 
al, Sci Transl Med 2014). To define the impact of each therapeutic agent or drug combination on 
proliferation, the Ki67 labeling index in tumor tissue around each reservoir will be calculated, 


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through the analysis of at least 1000 morphologically unequivocal cells, as previously described. 
[10-12]To determine the DNA damage induced by each therapeutic agent or drug combination, 
sections will be subjected to immunofluorescence with antibodies against phospho-H2AX as 
previously described [9]. We will capture representative images from tissue adjacent to each 
reservoir on a confocal microscope, and nuclei from 500 morphologically unequivocal cells will be 
analyzed per reservoir. A cell will be considered positive if at least one 1 discrete phospho-H2AX 
focus is identified. The phospho-H2AX index will be calculated as the number of phospho-H2AX- 
positive morphologically unequivocal neoplastic cells/ total number of morphologically 
unequivocal neoplastic cells analyzed. To determine whether each therapeutic agent or drug 
combination induce DNA damage that is corrected by homologous recombination DNA repair, 
RAD51 and Geminin expression will be analyzed by double-immunofluorescence, as previously 
described. For this, immunofluorescence images will be captured on a confocal microscope, and 
nuclei from 500 morphologically unequivocal cells will be analyzed per reservoir. A cell will be 
counted as being RAD51 positive if there is at least 1 distinct focus per nucleus as previously 
described. Given that homologous recombination DNA repair preferentially happens during S/ G2 
phases of the cell cycle, the RAD51 score will be assessed as the percentage of Geminin-positive 
cells that are also positive for RAD51. Samples where the device reservoir was located within a 
highly necrotic tumor region (i.e. >50% of the tissue adjacent to the reservoir is necrotic) or a 
stroma-rich area (i.e. >50% of the cells in the tissue adjacent to the reservoir are stromal cells) will 
be considered not informative. For each reservoir, the AI, Ki67 labeling index, phospho-H2AX foci 
score and RAD51 score will be recorded. 
 
These results will not be used to determine patient treatment and are for research purposes only. 
The patient may undergo any necessary preparatory procedures or tests in anticipation of 
beginning standard of care neoadjuvant chemotherapy during this protocol period. 
Adverse event data will be collected with respect to relatedness to the device implantation, 
incubation and retrieval. 
Following retrieval, patients on Cohort 1 will proceed to receive standard of care adjuvant therapy 
at the discretion of their treating medical oncologist. 
If treated on Cohort 2, patients will proceed to receive a standard of care, neoadjuvant 
anthracycline- based chemotherapy regimen as appropriate for their specific tumor histology, co- 
morbidities and pre-existing conditions. Pre-operative chemotherapy may be administered at local 
physician practices outside of MSK. 
 
 
Options for neoadjuvant regimens include the following: 
1) Dose dense AC (doxorubicin + cyclophosphamide) IV q2 weeks x4 followed by weekly 
paclitaxel x12 + carboplatin IV every 3 weeks x4.[5] Growth factor support will be used for 
dose dense AC per standard of care. 


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2) Dose dense AC (doxorubicin + cyclophosphamide) IV q2 weeks x4 followed by weekly 
paclitaxel x12 + carboplatin weekly x12. Growth factor support will be used for dose dense 
AC per standard of care. 
3) Dose dense AC (doxorubicin + cyclophosphamide) IV q2 weeks x4 (for those patients 
unable to receive taxanes or platinums). Growth factor support will be used for dose dense 
AC per standard of care. 
Dose adjustments and modifications will be guided by standard clinical practice. If a patient will 
not receive taxane or platinum in the judgment of the treating physician, they may have the 
opportunity to participate on this trial following discussion with and at the discretion of the study 
PI. In the case of allergy, substitution or discontinuation is permitted. 
For patients on Cohort 2, a research core biopsy will be performed following AC chemotherapy 
and prior to beginning taxane-based treatment. This biopsy will be performed in the time period 
immediately following the final AC infusion and up to 2 days later. 
Patients will proceed to definitive surgery at MSK within 4 weeks of their last neoadjuvant 
chemotherapy dose. The choice for breast conservation or mastectomy will be decided upon by 
the patient and her breast surgeon based upon clinical and radiographic findings and personal 
preference. 
At the time of breast surgery, pathologic complete response will be determined by standard Dept 
of Pathology methods and a residual cancer burden score will be assigned by a study pathologist. 
Correlations between AC and residual cancer burden 0/ 1 will be evaluated for all evaluable 
patients. 
Additional adjuvant chemotherapy, radiation therapy or endocrine therapy may be given at the 
discretion of the treating oncologist. 
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
5.1 
Subject Inclusion Criteria 
• 
Patients with histologically confirmed invasive breast cancer that is: Triple 
negative (ER<10%, PR<10%, and HER2 0/1+ or 2+/FISH not amplified) 
• 
Tumor size 1cm or greater; N any; M0 (Cohort 1) 
• 
Tumor size 2cm or greater; N any; M0 (Cohort 2) 
• 
Candidate for curative breast cancer surgery (Cohort 1 or 2) 
• 
Candidate for neoadjuvant chemotherapy with a standard of care, anthracycline- 
based regimen (Cohort 2 preferred over Cohort 1) 
• 
Age >18 years of age 
• 
ECOG performance status of ≤2 
• 
Serum or urine pregnancy test negative within 2 weeks for women of childbearing 
potential. 
• 
Willing and able to provide informed consent 
5.2 
Subject Exclusion Criteria 


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• 
Prior treatment including surgery, chemotherapy or radiation therapy for the 
current primary breast cancer. 
• 
Severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational 
device administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate for entry 
into this 
 
6.0 
RECRUITMENT PLAN 
Women of all races and ethnic groups are eligible for this trial. Patients will be recruited for 
enrollment on this trial primarily through referrals from their primary oncologists and surgeons. 
The clinical trial will be listed on the clinicaltrials.gov website as well as on the MSKCC website. 
Patients will not be paid for participation in this study. Prior to enrollment on the study, the 
physician will discuss the study protocol in detail with the patient, including possible toxicities. An 
informed consent will be reviewed by the physician with the patient. 
Potential research subjects will be identified by a member of the patient‟s treatment team, the 
protocol investigator, or research team at Memorial Sloan Kettering Cancer Center (MSKCC). If 
the investigator is a member of the treatment team, s/he will screen their patient‟s medical records 
for suitable research study participants and discuss the study and their potential for enrolling in 
the research study. Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study. 
The principal investigator may also screen the medical records of patients with whom they do not 
have a treatment relationship for the limited purpose of identifying patients who would be eligible 
to enroll in the study and to record appropriate contact information in order to approach these 
patients regarding the possibility of enrolling in the study. 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical 
records at MSKCC in order to further assess eligibility. They will use the information provided by 
the patient and/or medical record to confirm that the patient is eligible and to contact the patient 
regarding study enrollment. If the patient turns out to be ineligible for the research study, the 
research staff will destroy all information collected on the patient during the initial conversation 
and medical records review, except for any information that must be maintained for screening log 
purposes. 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment team. 
The recruitment process outlined presents no more than minimal risk to the privacy of the patients 
who are screened and minimal PHI will be maintained as part of a screening log. For these 
reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) reviewing 
medical records to identify potential research subjects and obtain information relevant to the 
enrollment process; (2) conversing with patients regarding possible enrollment; (3) handling of 


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PHI contained within those records and provided by the potential subjects; and (4) maintaining 
information in a screening log of patients approached (if applicable). 
 
 
7.0 
ASSESSMENT/EVALUATION PLAN 
Screening: 
The following must be completed within 28 days of study start: 
• 
Signed protocol informed consent 
• 
Medical history 
• 
Medication list review 
• 
Physical exam with a clinical tumor measurement 
• 
ECOG performance status 
• 
Pathology confirmed at MSKCC. Local assessment of hormone receptor and HER2 
status acceptable for study participation. 
 
The following must be completed within 14 days of study start: 
• 
Serum or urine pregnancy test negative for women of childbearing potential. 
Baseline: 
• 
Physical exam with a clinical tumor measurement 
• 
Medication list review 
• 
Toxicity review 
 
Please note: Screening assessments may be used for baseline assessments. 
 
Cohort 1: 
Day 1 (must be completed Mondays through Thursdays): 
• 
Placement of up to 3 devices by study Breast Radiologist. 
• 
Toxicity review 
 
Day 2: 
• 
Standard of Care breast surgery at which time device(s) will be removed with 
resection. 
• 
Toxicity review 
 
Post- Operative Surgery visit: 
• 
Toxicity review 
 
Cohort 2: 
Day 1 (must be completed Mondays through Thursdays): 
• 
Placement of up to 3 devices by study Breast Radiologist. 
• 
Toxicity review 
 
Day 2: 
• 
Removal of device(s) by concentric core needle biopsy using core needle. 
• 
Toxicity review 
Day 2 to 30: 


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• 
Begin standard of care, neoadjuvant chemotherapy. Patients may begin neoadjuvant 
chemotherapy on same day as device removal and no later than Day 30. 
 
Cycle #4 of AC: 
• 
Research biopsy of tumor following final AC and prior to receiving first dose of taxane- 
based therapy. This biopsy will occur in the time period ranging from immediately 
following infusion of final AC to 2 days following final infusion. Radiology will provide a 
clinical estimate of tumor size at time of biopsy. 
After all planned neoadjuvant chemotherapy: 
Proceed to definitive surgery within 4 weeks of last dose of chemotherapy. 
Post- Operative Surgery visit: 
• 
Toxicity review 
8.0 
TOXICITIES/SIDE EFFECTS 
 
Anticipated adverse events are those that may be expected from tissue biopsy. This m Kiay 
include pain, bleeding, bruising, and infection or wound healing complications. We do not expect 
side effects from the device or from prolonged incubation in the event that it is not successfully 
retrieved the day following implantation. The device consists of a polyaryletherketone (PEEK) 
polymer which has demonstrated long-term safety and biocompatibility in multiple biomedical 
applications, such as trauma, orthopedic and spinal implants.[8] A close comparable for the Kibur 
device is the “Cassi Beacon” tissue marker, an FDA-approved fiducial marker used for long-term 
localization of breast tumors. (http://scionmedtech.com/products/breast-biopsy/cassi-beacon/) 
The Cassi Beacon is structurally very similar to the Kibur device (composed of PEKK) though it is 
more than 4 times larger by volume (cylindrical shape, 1.5mm in diameter and 5mm long). If 
devices cannot be retrieved, they will be removed from patient along with the remainder of the 
tumor during surgical tumor resection which is maximally 6 months after implantation. The device 
is not expected to interfere with neoadjuvant systemic chemotherapy. 
9.0 
PRIMARY OUTCOMES 
 
Screening1 
Baseline 
Day 1 
Day 2 
Day 2-30 
Post-AC 
After all 
planned 
chemo 
Signed informed consent 
X 
Medical history 
X 
X 
Medication Review 
X 
X 
ECOG PS 
X 
Physical examination with tumor measurement 
X 
X 
Pathology confirmed at MSK 
X 
Placement of 3 devices unless limited by tumor size 
X 
Tumor analysis for apoptotic index5 
X 
Toxicity review6 
X 
X 
X 
COHORT 1 Specific: 
Standard of Care Breast Surgery 
X 


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COHORT 2 Specific: 
Removal of device(s) 
X 
Begin standard of care neoadjuvant chemotherapy 2 
X 
Research breast tumor biopsy3 
X 
Definitive breast cancer surgery4 
X 
1 Screening assessments may be used for baseline. 
2 Neoadjuvant chemotherapy is to begin between Days 2 and 30. 
3 A research core biopsy of breast tumor will be performed in the time period between completion of final 
AC infusion and up to 2 days after final infusion. Tumor measurement will be documented at this time. 
4 Proceed to definitive breast cancer surgery within 4 weeks of last dose of chemotherapy if cancer is 
resectable. 
5 Tumor analysis of apoptotic index from tissue collected on Day 2 and Post -AC will not necessarily occur in 
real time. Data derived from the device will not be used for treatment decision-making. RCB will be 
determined by the study pathologist at the time of definitive cancer surgery following neoadjuvant 
chemotherapy. 
6 Toxicity review will be completed at post operative surgery visit. 
 
10.0 
CRITERIA FOR REMOVAL FROM STUDY 
The following events may result in the removal of patients from the study: 
• 
Inability to comply with protocol requirements 
• 
Patients whose health would be jeopardized by continued participation 
• 
Withdrawal of informed consent (subject‟s decision to withdraw for any reason) 
• 
Discretion of the Investigator 
 
If a patient is removed based on the criteria above, we will replace the patient. 
 
11.0 
BIOSTATISTICS 
 
This is a pilot study in 12 patients with early stage triple negative breast cancer to examine the 
feasibility of using the Kibur device that aims to test for in vivo drug sensitivity. With results from 
this study, we plan to open a larger trial in order to examine whether data obtained from the Kibur 
device is correlated with clinical outcome as defined by pathologic complete response measured 
by residual cancer burden (RCB 0/1). 
Patients in this trial will be a mix of TNBC patients who 1) will have the microdevice implanted 
prior to breast surgery, in the absence of neoadjuvant chemotherapy and patients who 2) will 
have the device placed and retrieved on a core biopsy the following day, then receive 
neoadjuvant chemotherapy prior to definitive breast surgery. For the first type of patient, the 
device will be retrieved from the surgical tumor specimen. For the second type of patient, the 
device will be retrieved via core biopsy. To date, we have recruited 4 patients where the device 
has been retrieved by core. The sample size for each type of patient is not explicitly delineated. 
Rather, recruitment will continue until we have 12 patients of any of the two types. Analyses on 
feasibility will be done on all 12 patients together. 
Our decision to deem this pilot study feasible will be based on the ability to implant, retrieve at 
least one device, and collect evaluable tumor tissue for readout on drug sensitivity. If we are able 
to collect data from at least 6 out of the 12 patients, we will deem this study feasible to conduct in 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 24 of 31 
 
 
a larger cohort of patients. There is a .62 probability that we will be able to collect data from at 
least 6 patients assuming a .50 binomial probability. The below table shows the probability of 
having a successful trial under higher assumed probabilities of .60, .70, and .80. 
True underlying rate of success 
Probability of observing 6 or more successes 
.60 
.84 
.70 
.96 
.80 
~1.0 
 
The sample size for this pilot is limited due to practical and budgetary constraints. As such, our 
analyses will be primarily descriptive and graphical in nature. All primary and secondary analyses 
will be based on the TNBC patients enrolled (n=12), unless other noted below. 
We will summarize the safety and toxicity of implanting and retrieving the device(s). 
In the second group of patients (candidates for neoadjuvant therapy) AC chemotherapy sensitivity 
in vivo (measured by apoptotic index defined by cleaved caspase 3, Ki67 labeling index, 
phospho-H2AX score and RAD51 score in the area closest to the AC wells of the device) is 
correlated with RCB 0/1 using graphical methods, such as boxplots. In this second group of 
patients, we will also evaluate the correlation between AC chemotherapy sensitivity (as measured 
by the apoptosis index, Ki67 labeling index, phospho-H2AX score and RAD51 score) assessed 
prior to treatment (in vivo) and assessed following AC treatment (the same 4 measures assessed 
in the research biopsy specimen). This also will be done graphically. 
There is likely to be more than one set of values obtained for each patient. This is because each 
well is in duplicate and there can be up to 3 devices retrieved per patient, thereby creating up to 6 
data points per biomarker per patient. In addition, two pathologists will review the readout from 
each device, bringing the maximum number of replicates possible up to 12 per biomarker per 
patient. For the main analyses, we will use the average value. However, we will also investigate 
the intervariability of the measurements by device and within a device. We will also evaluate 
pathologist interobserver variability. This will be done graphically and if warranted, by calculating 
the concordance correlation coefficient. These studies of variability will be especially valuable 
when designing a larger trial. In addition to our exploratory studies on intervariability, we will 
assess the quality of data in terms of the ability to successfully obtain the four measurements of 
interest. 
There are several exploratory hypotheses. We will correlate device readouts at the paclitaxel and 
carboplatin wells with RCB 0/1 in TNBC patients who receive AC followed by paclitaxel and 
carboplatin. We will evaluate this graphically and if warranted, using a Wilcoxon rank sum test. 
We expect to complete accrual of 12 patients in the next 12 months. 
Note: In this amendment (September 2016) we are opening recruitment to include TNBC patients 
who will have the microdevice implanted prior to breast surgery. The biostatistics text above has 
been edited to reflect this change. 
12.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
12.1 
Research Participant Registration 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 25 of 31 
 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System. 
12.2 
Randomization 
Not applicable 
13.0 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. 
 
The data collected for this study will be entered into the CRDB, a secure database. Source 
documentation will be available to support the computerized patient record. 
13.1 
Quality Assurance 
 
Regular registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated. 
13.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled ―Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials‖ which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. 
The 
DSM 
Plans 
at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.html. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 26 of 31 
 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs. The committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the Center„s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
 
 
14.0 
PROTECTION OF HUMAN SUBJECTS 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will 
be reviewed with the participant, including a discussion of the possible side effects. 
Alternative options will be reviewed, including standard therapy outside of a clinical trial, 
as appropriate. Financial costs and burdens of the trial will be reviewed, including a 
detailed discussion of the tests that will be the financial responsibility of the study, and the 
tests which will be the financial responsibility of the patient. 
14.1 
Privacy 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure 
of protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
14.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 27 of 31 
 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or intervention. 
Any events that occur after the 30-day period and that are at least possibly related to 
protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of 
Serious Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of 
the event. The IRB requires a Clinical Research Database (CRDB) SAE report is 
submitted electronically to the SAE Office as follows: 
 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All other 
reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI‟s signature and the date it was signed are required on the completed report. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 28 of 31 
 
 
14.2.1  
 
Not applicable 
15.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 29 of 31 
 
 
16.0 
REFERENCES 
 
1. 
Burstein, H.J., et al., American Society of Clinical Oncology clinical practice guideline 
update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol, 2011. 
29(24): p. 3328-30. 
2. 
Gianni, L., 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): p. 25-32. 
3. 
Schneeweiss, A., 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(9): p. 2278-84. 
4. 
von Minckwitz, G., et al., Neoadjuvant carboplatin in patients with triple-negative and 
HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. 
Lancet Oncol, 2014. 15(7): p. 747-56. 
5. 
Sikov, W.M., et al., Impact of the Addition of Carboplatin and/or Bevacizumab to 
Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and 
Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple- 
Negative Breast Cancer: CALGB 40603 (Alliance). J Clin Oncol, 2015. 33(1): p. 13-21. 
6. 
Cortazar, P., et al., Pathological complete response and long-term clinical benefit in breast 
cancer: the CTNeoBC pooled analysis. Lancet, 2014. 384(9938): p. 164-72. 
7. 
Symmans, W.F., et al., Measurement of residual breast cancer burden to predict survival 
after neoadjuvant chemotherapy. J Clin Oncol, 2007. 25(28): p. 4414-22. 
8. 
Kurtz, S.M. and J.N. Devine, PEEK biomaterials in trauma, orthopedic, and spinal 
implants. Biomaterials, 2007. 28(32): p. 4845-69. 
9. 
Graeser, M., et al., A marker of homologous recombination predicts pathologic complete 
response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res, 2010. 
16(24): p. 6159-68. 
10. 
Polley, M.Y., et al., An international Ki67 reproducibility study. J Natl Cancer Inst, 2013. 
105(24): p. 1897-906. 
11. 
Dowsett, M., et al., Assessment of Ki67 in breast cancer: recommendations from the 
International Ki67 in Breast Cancer working group. J Natl Cancer Inst, 2011. 103(22): p. 
1656-64. 
12. 
Dowsett, M., et al., Prognostic value of Ki67 expression after short-term presurgical 
endocrine therapy for primary breast cancer. J Natl Cancer Inst, 2007. 99(2): p. 167-70. 
13. 
Dang, C., 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, 2014. 
14. 
Ivanova, A., B.F. Qaqish, and M.J. Schell, Continuous toxicity monitoring in phase II trials 
in oncology. Biometrics, 2005. 61(2): p. 540-5.15. (CPPB) in adult respiratory disease 
syndrome. 1990 J Thoracic Cardiovasc Surg 57:31-41 


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IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 30 of 31 
 
 
17.0 
APPENDICES 
Appendix A: Biospecimen Processing and Handling 
 
Cohort 1: 
Upfront Breast 
Surgery group 
Device retrieval at time of Surgery 
 
Tissue will be sent fresh to Pathology. If a device is found intra-operatively, 
it will be delivered separately to Pathology. Specimen radiograph will be 
performed in Pathology to confirm removal of devices. 
 
 
Tissue transferred to Pathology for clinical testing 
Device and surrounding tissue is sent to Reis Lab 
Schwartz S-916 
 
Tissue sample bar-coded and logged into a password controlled database 
Tissue sample fixed for 16 hours 
Routine tissue processing (paraffin-embedding) in the Histopathology Core 
Tissue sectioning in Reis Lab 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-127 A(6) 
Approval date: 22-Nov-2017 
Page 31 of 31 
 
 
 
Cohort 2 
(Neoadjuvant 
group) 
Stereotactic/ ultra-sound guided biopsy with device retrieval 
Breast Imaging, 5th floor BAIC 
 
 
Tissue and device collected by RSA at BAIC and placed in a container with 
buffered formalin (10x the volume of the sample) 
 
Tissue transferred to Reis Lab 
Schwartz S-916 
Tissue sample bar-coded and logged into a password controlled database 
Tissue sample fixed for 16 hours 
Routine tissue processing (paraffin-embedding) in the Histopathology Core 
Tissue sectioning in Reis Lab 
 
 
Appendix B: Residual Cancer Burden Determination 
 
Symmans WF et al. Measurement of residual breast cancer burden to predict survival after 
neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22 
 
http://jco.ascopubs.org/content/25/28/4414.full.pdf+html 
 
 
Appendix C: Manuscript Regarding Kibur Microdevice 
 
 
1.  Jonas O et al, Sci Transl Med. 2015 Apr 22;7(284):284ra57