Pilot Study of 18F-FLT-PET Imaging of the Brain in Patients With Metastatic Breast Cancer to the Brain Treated With Whole Brain Radiation Therapy With or Without Sorafenib: Comparison With MR Imaging of the Brain
Phase: NA
Conditions: Metastatic Breast Cancer to the Brain
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Page 1 of 30 
 
 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
Pilot Study of 18F-FLT-PET Imaging of the Brain in Pati 
Breast Cancer to the Brain Treated with Whole Brain 
Comparison with MR Imaging of the Br 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTO 
Principal Investigator/Department: 
Andrew Seidman, MD 
ents with Metastatic 
Radiation Therapy: 
ain 
COL 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Heiko Schoder, MD 
Radiology 
Investigator(s)/Department: 
Shanu Modi, MD 
Sarat Chandarlapaty, MD, PhD 
Mark Robson, MD 
Larry Norton, MD 
Victoria Blinder, MD, MSc 
Tiffany Traina, MD 
Monica Fornier, MD 
Teresa Gilewski, MD 
Nancy Sklarin, MD 
Gabriella D‟Andrea, MD 
Jacqueline Bromberg, MD, PhD 
Mary Ellen Moynahan, MD 
Shari Goldfarb, MD 
Elizabeth Comen, MD 
Devika Gajria, MD, MPH 
Ayca Gucalp, MD 
Neil Iyengar, MD 
Ting Bao, MD 
Chau Dang, MD 
Diana Lake, MD 
Komal Jhaveri, MD 
Rachel Sanford, MD 
Pedram Razavi, MD, PhD 
Christopher Klebanoff, MD 
Linda Vahdat, MD 
Tomas Lyons, MD 
Mila Gorsky, MD 
Louise Ligresti, MD 
Audrey Hamilton, MD 
Neha Korde, MD Karen 
Dougherty, APN 
Leticia Smith, APN 
Janet Cogswell, CRN 
Jennifer Howgate-Klingaman, RN 
Lisa Sarmasti, CRN 
Wanqing Iris Zhi, MD, PhD 
Steven Sugarman, MD 
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Page 2 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
Sarah Schweber, MD 
Stuart Lichtman, MD 
Roseann Caruso, NP 
Irene Kelly, CRN 
Pamela Drullinsky, MD 
Tiffany Troso-Sandoval, MD 
Arlyn Apollo, MD 
Kenneth Ng, MD 
Zoe Goldberg, MD 
Oscar Lahoud, MD 
Jasmeet Singh, MD 
Rachel Grisham, MD 
Chrisann Kyi, MD Karen 
Budrock, NP         
Gloria Wasilewski, CRN 
Sherie Mar-Chaim, RN 
Maureen Kennedy, RN 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Marina Shcherba, DO 
Raylene Langish, RN 
Doris Pindilli, APN 
Nicole Heinz, RN 
John Humm, PhD 
Kyung Peck, PhD 
Andrei Holodny, MD 
Sujata Patil, PhD 
Kathryn Beal, MD 
Timothy Chan, MD 
Yoshiya Yamada, MD 
Daphna Gelblum, MD 
Richard Gewanter, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Karen Schupak, MD 
Pinaki Dutta, MD 
John Cuaron, MD 
Annmarie Shepherd, MD 
Marsha Reyngold, MD, PhD 
Jillian Tsai, MD, PhD 
Beryl McCormick, MD 
Lior Braunstein, MD 
Atif Khan, MD 
Jonathan Yang, MD 
Daniel Gorovets, MD 
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Page 3 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
Justin Mann, MD 
Jung Kang, MD, PhD 
Daniel Shasha, MD 
Narek Shaverdian, MD 
Christopher Barker, MD 
Michael Bernstein, MD 
Nancy Lee, MD 
Erin Gillespie, MD 
Yao Yu, MD 
Samuel Bakhoum, MD, PhD 
Janice Terlizzi, APN 
Carol Ann Milazzo, NP 
Eileen Jackson, NP 
Lauren Wood, RN 
Tina Alano, RN 
Aimee Rogado, RN 
Esthefanie Giordano, RN 
Maureen Cannon, NP 
Karen Drucker, NP 
Odessa Williams, NP 
Danielle Alleva, NP 
Nicole Jimenez, NP 
Renee Wisniewski, NP 
Veronica Fitzpatrick, NP 
Melissa Emerzian, NP 
Mikel Ross, NP 
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Consenting  Professional(s)/Department: Andrew Seidman, MD 
Shanu Modi, MD 
Sarat Chandarlapaty, MD, PhD 
Mark Robson, MD 
Larry Norton, MD 
Victoria Blinder, MD, Msc 
Tiffany Traina, MD 
Monica Fornier, MD 
Teresa Gilewski, MD 
Nancy Sklarin, MD 
Gabriella D‟Andrea, MD 
Jacqueline Bromberg, MD, PhD 
Mary Ellen Moynahan, MD 
Shari Goldfarb, MD 
Elizabeth Comen, MD 
Devika Gajria, MD, MPH 
Ayca Gucalp, MD 
Neil Iyengar, MD 
Ting Bao, MD 
Chau Dang, MD 
Diana Lake, MD 
Komal Jhaveri, MD 
Rachel Sanford, MD 
Pedram Razavi, MD, PhD 
Christopher Klebanoff, MD 
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Page 4 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
Linda Vahdat, MD 
Tomas Lyons, MD 
Mila Gorsky, MD 
Louise Ligresti, MD 
Audrey Hamilton, MD 
Neha Korde, MD 
Wanqing Iris Zhi, MD, PhD 
Steven Sugarman, MD 
Sarah Schweber, MD Stuart 
Lichtman, MD Pamela 
Drullinsky, MD           
Tiffany Troso-Sandoval, MD 
Arlyn Apollo, MD 
Kenneth Ng, MD 
Zoe Goldberg, MD 
Oscar Lahoud, MD 
Jasmeet Singh, MD 
Rachel Grisham, MD 
Chrisann Kyi, MD 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Marina Shcherba, DO 
Kathryn Beal, MD 
Timothy Chan, MD 
Yoshiya Yamada, MD 
Daphna Gelblum, MD 
Richard Gewanter, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Karen Schupak, MD 
Pinaki Dutta, MD 
John Cuaron, MD 
Annmarie Shepherd, MD 
Marsha Reyngold, MD, PhD 
Jillian Tsai, MD, PhD 
Beryl McCormick, MD 
Lior Braunstein, MD 
Atif Khan, MD 
Jonathan Yang, MD 
Daniel Gorovets, MD 
Justin Mann, MD 
Jung Kang, MD, PhD 
Daniel Shasha, MD 
Narek Shaverdian, MD 
Christopher Barker, MD 
Michael Bernstein, MD 
Nancy Lee, MD 
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Page 5 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
Erin Gillespie, MD 
Yao Yu, MD 
Samuel Bakhoum, MD, PhD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Commack 
Rock ville Center 
Westchester 
Monmouth 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Page 6 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 7 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 8 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 12 
4.1 
Design .............................................................................................................................. 12 
4.2 
Intervention ........................................................................................................................... 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 12 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 13 
6.1 
Subject Inclusion Criteria .................................................................................................. 13 
6.2 
Subject Exclusion Criteria ................................................................................................ 13 
7.0 
RECRUITMENT PLAN ................................................................................................................... 14 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 14 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 15 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 16 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 18 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 19 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 22 
14.0 
BIOSTATISTICS ............................................................................................................... 22 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES23 
15.1 Research Participant Registration ......................................................................................... 23 
15.2 
Randomization ................................................................................................................... 24 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 24 
16.1 
Quality Assurance ............................................................................................................ 24 
16.2 
Data and Safety Monitoring .................................................................................................. 24 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 25 
17.1 
Privacy ............................................................................................................................. 25 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................. 25 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 27 
19.0 
REFERENCES ...................................................................................................................... 27 
20.0 
APPENDICES ................................................................................................................... 29 

Page 7 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
We will perform a pilot study of serial [18F] 3'-deoxy-3'-fluorothymidine (FLT) PET imaging of 
the brain at baseline (less than 4 weeks of initiation of WBRT), up to 7-10 days post- 
treatment and 10-12 weeks after treatment in patients with metastatic breast cancer to the 
brain (N=20) treated with standard whole brain radiotherapy (WBRT) with or without 
sorafenib to evaluate the radiographic response to WBRT and sorafenib. We will examine if 
FLT- PET imaging can be used to determine early treatment response to sorafenib. Lastly, 
we will also assess whether FLT can distinguish residual viable tumor from inflammation or 
radionecrosis. This exploratory study will include two cohorts with 10 patients each. Cohort 1 
will include the first ten patients treated with WBRT concomitantly with sorafenib (The first 10 
patients on Dr. Seidman‟s Phase I “Whole Brain Radiotherapy (WBRT) with Sorafenib for 
Breast Cancer Brain Metastases (BCBM): A Phase I Study” will also be enrolled concurrently 
on this trial). Cohort 2 will include patients treated with standard WBRT alone. Patients in 
both cohorts will also be assessed with standard non-invasive MRI imaging of the brain in 
addition to [18F] FLT PET at baseline and then 10-12 weeks after completion of WBRT. MR 
imaging will include T1 perfusion sequence (DCE- Dynamic Contrast enhanced Perfusion 
MR) images. Patients will later be followed with MR imaging of the brain every 3 months (+/- 
7 days) during the first year, every 6 months (+/- 7 days) thereafter until CNS progression or 
death.  FLT PET is considered investigational, and thus these scans will be performed under 
an FDA-approved Investigational New Drug (IND) application. The results of the FLT scans 
will have no impact on patient management. On 3/26/2009 an IND (#104742) was approved 
for the fluorothymidine (FLT). We will cross file this IND for the use of FLT in this protocol. 
 
 
Schema: 
 
 
 
 
 
* MRI will be done within one week before FLT PET scan 
MRI and 
FLT-PET 
10-12 wks 
post- 
WBRT 
FLT-PET 7- 
10 days 
post-WBRT 
(for early 
response) 
Cohort 1: First ten 
patients treated with 
Sorafenib (S) + WBRT 
on a separately 
submitted phase I trial 
(N= 10) 
MRI and 
FLT-PET at 
baseline (< 
4 wks* prior 
to WBRT) 
Cohort  2: Patients 
treated with WBRT off 
protocol (N = 10) 

Page 8 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: The primary objectives of this study are as follows: 
 
1) To examine the radiographic response to WBRT by FLT-PET and MRI for each cohort of 10 
patients separately. 
2) To examine and quantify changes in response as assessed by serial FLT PET images taken 
over the course of treatment for each cohort of 10 patients separately. 
 
Secondary Objectives: The secondary objectives of this study are as follows: 
 
1)   To correlate treatment response as measured by FLT-PET with response assessment based 
on MRI of the brain in all patients and assess duration of response (i.e., CNS progression- 
free survival) during follow-up with MR imaging. 
Exploratory Objective: The exploratory objectives of this study are as follows: 
 
1) 
To correlate the ability of FLT-PET and MRI of the brain imaging to differentiate viable tumor, 
inflammation and necrosis with surgical resection specimens (if available) obtained in  
patients with a medical indication for craniotomy. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Brain metastasis from breast cancer 
 
Brain metastasis affects 10-30% of women with metastatic breast cancer depending on 
subtype of breast cancer. The incidence of brain metastases appears to be rising as a result 
of superior imaging modalities, earlier detection, and more effective treatment of systemic 
disease. Survival remains poor despite treatment modalities like surgical resection and whole 
brain radiotherapy (WBRT). Prognosis depends largely on brain metastases recursive 
partitioning analysis (RPA) of Radiation Therapy Oncology Group  prognostic class I to III 
(Table 1) [1,2] and biologic subtypes (Table 2) [3-5]. Effective treatment of brain metastases 
in these patients remains an unmet medical need. 
Table 1: Recursive Partitioning Analysis (RPA) for patients with breast cancer brain 
metastases 
 
 

Page 9 of 30 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
Table 2. Prognosis by histologic subtypes 
 
Subtype 
PFS 
OS 
ER + [3,4] 
4-6 
6-7 
HER-2 + [3,4] 
12 
10-22 
Triple Negative (ER, PR and HER-2 negative) [3-5] 
3.7 
5 
 
 
3.2 Treatment of brain metastases 
 
Therapeutic approaches to brain metastases include surgery, WBRT, stereotactic 
radiosurgery, chemotherapy and more recently novel molecularly targeted therapy. Sorafenib 
is an oral anti vascular endothelial growth factor (VEGF) and multi- tyrosine kinase inhibitor 
with demonstrated safety and activity in various tumor types including breast cancer [6]. 
VEGF TKI have the potential for increased CNS penetration compared to VEGF monoclonal 
antibodies and recently, long lasting successful cerebral response of sorafenib has been 
reported in brain metastases [7]. 
3.3 Sorafenib and cranial radiation in the treatment of brain metastases 
 
In preclinical models, radiation treatment followed sequentially by sorafenib was found to be 
associated with delay in tumor growth [8]. Sorafenib has been given safely with concurrent 
cranial radiation for brain metastases [9]. Ongoing studies are further evaluating the 
feasibility and activity of tyrosine kinase inhibitors in combination with cranial radiotherapy. 
We are currently conducting an open label phase I, standard 3+3 design, trial of sorafenib 
given concurrently with WBRT for patients with metastatic breast cancer to the brain. The 
first ten patients from this trial will have to agree and be enrolled on this study in addition to 
patients who receive standard WBRT for treatment of brain metastases from breast cancer. 
3.4 [
18F] FLT PET imaging 
3'-deoxy-3'-[
18F] fluorothymidine ([
18F] FLT) is a new PET radiotracer that can be used to 
assess tumor cell proliferation [10].  FLT is a thymidine analog that tracks the salvage 
pathway of DNA synthesis, becoming phosphorylated by thymidine kinase 1 (TK1).  FLT 
differs from thymidine in that it does not become incorporated into DNA; however 
phosphorylation by TK1 traps in the cell.  TK-1 activity is up-regulated in cells entering the S- 
phase, whereas the protein is nearly undetectable in growth arrested cells. Thus, the uptake 
of FLT correlates with thymidine uptake, thymidine kinase activity, and the percentage of 
cells in S-phase. It can therefore be used to image and measure tumor proliferation in cells 
that predominantly use the salvage pathway. 
Shields et al [11] published the first human studies using FLT-PET in a patient with non– 
small cell lung cancer, demonstrating the high image quality and low background afforded by 
FLT. Good images were obtained from injection of 5 mCi or less of FLT, and imaging stable 

Page 10 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
uptake was noted at around 45 to 60 minutes after injection. Recently, dosimetry date for  
FLT have been published [12], showing that patient imaging is feasible with clinically 
acceptable radiation exposure for the subject. This is a critical issue for FLT because it is 
likely to be used in clinical applications that require repeated studies to measure response to 
therapy. These studies paved the way for a series of pilot studies examining FLT-PET 
imaging for a variety of tumors. We elected to use an activity of up to 10 mCi per injection for 
the proposed dynamic imaging studies, based on dosimetry estimates (see section 11.2) 
3.4.1 [18F] FLT PET imaging to image cellular proliferation and treatment response 
 
Preclinical studies have identified the potential of FLT as a PET imaging agent for cellular 
proliferation. Cellular proliferation has a number of potential advantages over imaging 
with FDG-PET, particularly the low background activity of normal brain tissue in contrast 
to the high FDG uptake (glucose utilization) by normal brain tissue. In addition, FLT is 
expected to be more specific to malignant processes since high glucose metabolism, 
measured by FDG PET, is also seen in a variety of benign conditions, including 
inflammation and tissue healing. Changes in cellular proliferation occur early in response 
to treatment and proliferation imaging likely provides an earlier and more definitive 
assessment of response than imaging with FDG, which can be compounded by a variety 
of issues, including cellular repair. In the case of cytostatic agents, which stop cell 
division but not necessarily lead to cell death, tumor proliferation declines, but tumor 
energy metabolism may not change. All these considerations provide an impetus for PET 
cellular proliferation imaging, especially as a tool for measuring early response [13]. 
Although preclinical models demonstrate the potential utility of FLT-PET for measuring 
therapeutic response, limited data are available for this use in humans. Preliminary 
studies used FLT to monitor neoadjuvant breast cancer treatment and showed that FLT 
could measure changes early in the course of treatment [14]. Our own ongoing studies in 
large cell lymphoma confirm this. The appropriate clinical application of FLT is for 
characterizing known tumors and assessing their response to treatment through serial 
imaging studies. 
Most early series focused on testing the feasibility of FLT-PET imaging and comparing 
FLT uptake with in vitro measures of tumor proliferation, typically the Ki-67 (MIB-1) index. 
Some studies also compared FLT-PET with FDG-PET, given the established clinical role 
of FDG for staging in the tumor types studied. Studies have shown good correlation 
between FLT uptake and the Ki-67 index for a variety of tumors [15, 16]. In cases where 
FDG-PET was also performed, the correlation for FLT uptake versus Ki-67 index was 
much better than the correlation for FDG uptake versus Ki-67. In one study, when FLT- 
PET was compared side to side with FDG-PET in 25 patients with newly diagnosed or 
previously treated gliomas, it was found that FLT- PET was more sensitive to FDG-PET 
to image recurrent high-grade gliomas, correlated better with Ki-67 values and was a 
more powerful predictor of tumor progression and survival [17]. 
[18F] FLT PET imaging of the brain has been used by the University of Washington, 
Wayne State University, UCLA, MSKCC, and others to image proliferation. 

Page 11 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
 
3.4.2 [18F] FLT PET imaging and MR imaging of the brain 
 
It is difficult to distinguish between genuine tumor progression and radionecrosis using 
conventional gadolinium MRI imaging or FDG-PET imaging of the brain [18 - 20]. To 
enable improved discrimination of radionecrosis versus progression of disease, fluoro-L- 
thymidine (FLT)-PET imaging may be useful as it allows for a noninvasive assessment of 
cell proliferation in vivo, a key feature of malignancy. 
3.5 Rationale for this study 
 
Despite the treatment advances in the treatment of brain metastases, prognosis remains 
poor and there are no specific biomarkers available to predict response of brain metastases 
to available therapies. FLT-PET has been used as an imaging biomarker in patients with 
brain tumors to predict response to anti-angiogenic therapy. This was achieved by 
performing serial FLT PET imaging [21]. 
 
Following WBRT, patients often progress clinically or on MR imaging. Furthermore, radiation 
necrosis, a well-known phenomenon can complicate cranial radiotherapy and patients could 
decline quickly, often not because of disease progression in the brain, but as a result of mass 
effect and edema caused by necrosis [22]. Also, there is a suggestion that targeting VEGF 
can reduce radionecrosis by decreasing capillary leakage and the associated brain edema 
[23, 24] as well as potentiate the antitumor effects of external beam radiotherapy [17]. A  
small randomized controlled trial has shown benefit of antiangiogenic therapy for established 
radionecrosis [Grommes et al. Proceedings of AAN; 2010]. This however has not been 
confirmed in a well-powered randomized trial. As an antiangiogenic agent, sorafenib could 
potentially reduce complications of cranial radiation such as increased edema and 
radionecrosis. We therefore aim to explore the effect of sorafenib on the development of 
suspected or proven radionecrosis. 
 
Our hypothesis is that FLT-PET will be a more accurate non-invasive biomarker than MRI in 
patients with metastatic breast cancer with metastases to the brain treated with WBRT with 
or without sorafenib. This is expected based on the higher specificity of FLT for viable 
residual disease. The hypothesis will be tested by having patients undergo 
 
FLT PET and MR at baseline, FLT PET within 7-10 days after radiotherapy (for early 
response assessment) and again dual imaging at 10-12 weeks post WBRT. 
3.6 Analysis of surgical specimen 
 
Comparing FLT PET findings with tissue analysis will enable us to determine if imaging 
results are concordant with histological findings and thus allow for confirmation of this 
hypothesis. In this manner, we propose to generate a bridge between tissue analysis and 
FLT-PET brain imaging studies. For patients needing to undergo craniotomy for resection of 
a brain metastasis after WBRT, tissue findings (radionecrosis versus viable tumor) will be 
correlated with radiologic assessment in an exploratory manner. 

Page 12 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
 
 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
We will perform a pilot study of serial FLT-PET imaging of the brain at baseline (< 4 weeks 
prior to initiation of WBRT), up to 7-10 days post-WBRT and 10-12 weeks after WBRT in 
patients with metastatic breast cancer to the brain (N=20) treated with WBRT with or without 
sorafenib. We will assess and quantify the radiographic response of WBRT, measure the 
impact of sorafenib on radiographic response, determine early treatment response and 
distinguish tumor progression from radionecrosis. 
This exploratory study will include two cohorts with 10 patients each. Cohort 1 will include the 
first ten patients treated with WBRT concomitantly with sorafenib (on a separate phase I  
trial). Cohort 2 will include patients treated with standard WBRT alone. Patients in both these 
cohorts will also be assessed with standard non-invasive MRI in addition to [18F] FLT PET at 
baseline (< 4 weeks of WBRT) and 10-12 weeks after completion of WBRT. Patients will later 
be followed with MR imaging of the brain every 3 months (+/- 7 days) during the first year, 
every 6 months (+/- 7 days) thereafter until CNS progression or death. These follow-up scan 
time-points are considered standard of care. Of note, patients with a negative FLT-PET at 
baseline will be taken off study. 
 
Tissue from patients who have medical indication for craniotomy and have a signed consent 
will be assessed for radiation necrosis and these findings will be correlated with the imaging 
studies and treatment (Section 9.3). 
 
4.3 
Intervention 
 
All patients will be imaged using FLT-PET scans at baseline (within 4 weeks of initiation of 
WBRT), 7-10 days after completion of WBRT and then 10-12 weeks after WBRT. 
Patients will also be evaluated with MRI imaging at baseline and then 10-12 weeks after 
WBRT. 
Patients will be followed with MRI every 3 months (+/- 7 days) for the first year and then 
every 6 months (+/- 7 days) thereafter which is the standard of care. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
[18F] FLT 
The radiotracer, 18F-FLT, has been synthesized by the MSKCC cyclotron facility for approximately 
two years, and has been used in humans in this and other institutions in this country and Europe. 
The primary source of the FLT will be the MSKCC cyclotron facility; however, alternative commercial 
sources are available to ensure consistent supply of FLT. If a commercial supplier of FLT is used for 
a particular study (such as Cardinal Health), the supplier will be required to meet all of the 
acceptance criteria outlined in the FDA-approved MSKCC FLT IND (#104742) prior to  
administration. The FLT will be tested to ensure radiochemical purity is > 95% and for pyrogenicity. 

Page 13 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
FLT will be administered as part of an FDA-approved IND application, based on dosimetry estimates 
(see section 8.2). Whereas the primary source of the FLT will be the MSKCC cyclotron facility, 
alternative commercial sources are available and used provided that supplier meet all of the 
acceptance criteria outlined in the FDA-approved MSKCC FLT IND (#104742) prior to  
administration. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Histologically-confirmed (confirmation done at MSKCC) metastatic adenocarcinoma of 
the breast 
• 
Radiologic evidence of new and/or progressive brain metastases (≥10 mm in longest 
dimension) by MRI imaging of the Brain 
• 
Planned WBRT based on number (≥ 3 lesions) and/or size (≥ 1 cm) of brain metastases. 
• 
Age ≥18 years; males and females 
• 
Patients who require additional clinically indicated stereotactic radiosurgery (SRS) in 
addition to WBRT will also be eligible. 
• 
Life expectancy of >12 weeks. 
• 
Karnofsky Performance Status (KPS) ≥ 70%. 
• 
Creatinine ≤2.0 times the upper limit of normal. 
• 
Women of childbearing potential must have a negative serum pregnancy test performed 
within 7 days prior to enrollment, must be non-lactating and must agree to use adequate 
contraception prior to enrollment and for the duration of study participation. 
• 
No limit to prior therapies with last anti-cancer treatment ≥2 weeks from initiation of 
WBRT. Please note: there is no washout period required for trastuzumab, pertuzumab for 
patients who have developed new parenchymal brain metastases while on these agents. 
6.3 
Subject Exclusion Criteria 
 
• 
Leptomeningeal metastases. Please note: leptomeningeal metastases may be allowed if 
it is limited to cranial metastasis (MRI spine should be completed, within 4 weeks of 
enrollment, to show that no other leptomeningeal metastases is present) and is not the 
only metastasis present in the brain. 
• 
Concurrent administration of lapatinib or other tyrosine kinase inhibitors other than 
sorafenib 
• 
Craniotomy or any other major surgery, open biopsy, or significant traumatic injury within 
4 weeks of randomization. 
• 
Concurrent anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy, 
surgery, immunotherapy, biologic therapy, or tumor embolization) other than sorafenib, 
and protocol-specified whole-brain radiotherapy. 
• 
Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, 
preceding enrollment. 
• 
Inability to comply with protocol and /or not willing or not available for follow-up 
assessments. 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
• 
Any condition which in the investigator‟s opinion makes the patient unsuitable for the 
study participation. 
• 
Patient is incontinent of urine or stool (which would make them unable to tolerate lying 
still for 60 minutes). 
• 
Claustrophobia 
• 
Known allergic reaction to Gd-DTPA 
• 
Renal insufficiency with recent (<3 month old) creatinine >2.0 
• 
Any contraindication to MRI (e.g., pacemaker, aneurysm clip, tissue 
expander) 
 
7.1 
RECRUITMENT PLAN 
 
Recruitment of patients will be through the participating investigators from the Breast Service and 
referrals from staff physicians at Memorial Hospital. Patients could be identified through clinic lists. A 
detailed description of the study procedures will be provided to each referring physician and a 
simpler version to each patient by the principal investigator or one of the investigators of this 
research proposal. 
 
Patients will be required to sign a statement of informed consent that meets the requirements of the 
code of Federal Regulations (Federal register Vol.46, No. 17, Jan.27, 1981, part 50) and the IRB of 
this center. The medical record will include a statement that written informed consent was obtained 
(and document in the record the date written consent was obtained before) and the patient is 
enrolled in the study. 
 
All patients who meet the above inclusion and exclusion criteria will be invited to participate in the 
study by their primary oncologist. Study Investigators will invite men and women and all minorities 
on an equal basis as they present to their oncologist during routine cancer care visits. Consenting 
professionals will meet the patients and obtain informed consent. 
 
It is important to note that the first ten patients on cohort 1 on this protocol would have agreed to and 
signed informed consent for a separate but simultaneous phase I trial of sorafenib with WBRT. This 
protocol is currently undergoing the IRB review process simultaneously. 
8.0 
PRETREATMENT EVALUATION 
 
• 
MR Brain will be obtained within 4 weeks prior to initiation of WBRT to ensure evidence of 
new/progressive brain metastases. MR imaging will include images before and after the 
administration of gadolinium-diethylenetriamine - pentaacetic acid (Gd-DTPA). 
• 
FLT-PET will be obtained within 4 weeks prior to initiation of WBRT and within 2 weeks of the 
MR Brain.History and physical Examination within 1 week prior to initiation of WBRT. 
• 
Patients will also undergo CBC, comprehensive metabolic panel within 1 week prior to initiation 
of WBRT. 
• 
Women with childbearing potential will also undergo a serum pregnancy test. See Appendix A for 
study calendar. 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
 
 
 
 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 FLT PET 
 
Twenty patients will receive an injection of up to 10 mCi of FLT, followed by FLT PET scan 
and a blood draw for pharmacokinetic analysis. These twenty patients will also be imaged 
using MR before and after the administration of gadolinium- diethylenetriamine-pentaacetic 
acid (Gd-DTPA). 
9.2.1 Patient Preparation for FLT PET 
 
No specific dietary restrictions or hydration are required for FLT PET scans, however, 
patients will be urged to drink plenty of water before and after the PET studies. [18F]FLT 
will be prepared under RDRC guidelines by the MSK Radiochemistry Core and assessed 
for quality control following "good manufacturing practice" criteria.  The 
radiopharmaceutical will immediately be brought to the Nuclear Medicine Radiopharmacy 
for dispensation in the PET suite.  Patients will receive up to 370 MBq (10 mCi) [18F]-FLT 
by intravenous infusion. 
9.2.2 FLT PET scanning 
 
Following scout view, a low dose CT (80mA) of the brain will be obtained for an anatomic 
localization and attenuation correction. Following intravenous injection of [18F] FLT, 
dynamic PET emission data of the brain will be obtained for up to 60 min to obtain kinetic 
information on tumor uptake for modeling. Image acquisition shall start immediately after 
injection using the following sequence: 4 frames of 15 seconds, 4 frames of 30sec, 7 
frames of 1-minute, then 10 frames of 5-minutes, i.e. for a full scan duration of 60- 
minutes. After the 60 minutes dynamic scan, if the patient is capable and willing, an 
additional 10 minute static acquisition will be acquired at 90 minutes. Dynamic FLT scans 
will be using standard clinical protocol. Patients may take a break and get off the table,  
for instance for bathroom break before the additional 10 minute static acquisition. 
 
FLT PET scans will be obtained at baseline (within 4 weeks of WBRT and within 2 week 
after MR imaging), 7-10 days after WBRT and 10-12 weeks after WBRT. 
9.3 MR imaging of the brain 
 
MR imaging before and after the administration of gadolinium-diethylenetriamine-pentaacetic 
acid (Gd-DTPA) will be obtained within 2 weeks of the PET scan. All baseline imaging scans 
(FLT-PET and MR Brain) will be obtained within 4 weeks prior to initiation of WBRT. MR 
imaging will be repeated 10-12 weeks after WBRT. MR imaging during the follow-up scan 
only will include the T1-Perfusion sequence (DCE) images. 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
FLT-PET scans are the research scans and MR imaging is considered standard of care. 
 
 
 
 
9.4 Tissue Analysis 
 
For patients who need to undergo a craniotomy for resection of a brain metastases after 
WBRT, tissue findings (radionecrosis versus viable tumor) will be correlated with radiologic 
assessment in an exploratory manner. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 FLT PET 
Schema illustrating the duration of FLT scans and the time-point for the blood draw 
 
Intervention 
Low dose CT 
FLT PET Dynamic Scan 
for 60 min 
FLT PET 10 min 
Static scan 
(optional) at 90 min 
Low Dose CT 
X 
[18F] FLT injection1 
X 
X 
Blood Draw
2
 
X 
 
 
1 
A low-dose CT will be obtained following scout view. After 10 mCi of [18F] FLT infusion, 
dynamic FLT scans will be obtained for 60 min. If the patient agrees then static scans will be 
obtained at 90 min and will last for 10 min. 
2 
One blood draw will be done 60 min (+ 10 min window) after the FLT injection. 
10.1.1 Blood Samples during FLT PET 
 
A venous catheter will be placed in a superficial hand or arm vein for administration of the 
radiopharmaceuticals.  A second venous catheter will be placed in the opposite hand or 
arm for venous blood sampling.  If a central venous catheter is present, it will be used for 
blood sampling or radiopharmaceutical administration, and only a single venous catheter 
will be placed. All catheters will be removed at the end of the day. One 3 ml venous blood 
samples will be drawn in a green top tube 60 minutes (+ 10 min window) post- 
radiopharmaceutical injection from a vein in the arm opposite that used to inject the 
radiopharmaceutical by research staff.  [18F] radioactivity in the [18F] FLT blood/plasma 
sample will be measured by research staff. 
10.1.2 FLT PHARMACOKINETIC ANALYSIS 
 
Pharmacokinetic modeling will be done on a voxel-wise basis across the entire 
segmented tumor. This kinetic modeling algorithm will compute voxel-wise parameter 
estimates of the compartmental model parameters (K1, k2, k3, and k4) defining tracer 
exchange between the blood and tumor tissue compartments, as well as Vb, the 
intravascular blood volume fraction, which will be estimated as a fifth parameter. 
Parametric maps will then be determined using the estimated proliferation rate constant 

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IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
(k3) values that, for kinetic FLT PET data, are expected to reflect the spatial distribution 
of rates of cellular proliferation.  A composite parameter, Ki (K1k3/(k2+k3) estimating the 
irreversible uptake of FLT at equilibrium, will also be evaluated due to its decreased 
sensitivity to noise and robustness as a measure of irreversible uptake.  The information 
derived from these analyses will not be used for treatment planning, but shall 
retrospectively be used in the assessment of treatment response. Non-invasive input 
functions will be obtained from the image data using regions of interest of the superior 
sagittal sinus. These measurements will be compared with arterial blood activity- 
concentrations from an image containing the internal carotid artery and will be calibrated 
using the measurement of a single intravenous blood sample acquired at one post- 
injection time point. 
 
The utility of static (SUV) versus parametric measures derived from compartmental 
analysis (i.e., k3 and Ki) of 18F-FLT PET represent different approaches. The SUV metric 
provides a simple measure of the amount of FLT within the defined region of interest at a 
specific time e.g. 60-minues post injection. This metric is rapidly obtained and has 
become the main reporting metric used in FDG PET studies assessing treatment 
response. 
However, when response metrics are sought following aggressive therapies that may 
significantly impact upon radiotracer delivery to the tumor, such as following high dose 
radiotherapy or the use of anti-angiogenic agents, compartmental analysis may offer the 
advantage in that such approaches estimate the rate of tracer entrapment accounting for 
the radiotracer input function. 
 
To summarize, patient assessment and evaluation will be based on voxel-wise and 
region of interest (ROI) measurements of the tumor.  The tumor will be identified on the 
CT image of the PET/CT. Standardized uptake values (SUVs) will be estimated from the 
late time frames of the study. Kinetic rate constants (K1 - k4) and the composite 
parameter Ki will be estimated from the dynamic data. These measurements will be 
made on both an ROI and voxel-wise basis.  Input functions necessary for the kinetic 
modeling will be made from the either the sagittal sinus or the carotid artery.  Measures 
from both imaging methods (static SUV and parametric measures) will be used in 
analyses. 
10.2 MR Imaging 
 
MR imaging will be done as routine before and after Gd-DTPA. 
 
The time-points of FLTPET and MR Imaging for this study are shown in the study calendar below: 
 
Study Calendar 
 
Tests 
Screening 
(within 4 weeks 
of WBRT) 
7-10 days after 
WBRT 
10-12 weeks 
after WBRT 
MRI Brain* 
X 
X 
FLT-PET* 
X 
X 
X 

Page 18 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
*MRI and FLT-PET will all be done within 4 weeks prior to initiation of WBRT. MRI will be 
done within 2 weeks of the FLT-PET scan. MR imaging during the follow-up scan only will 
also include T1-perfusion images (DCE). 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
The PET scan has no known or expected side-effects. The radiotracer drug, FLT, has been given to 
patients in other studies and no side effects have been reported. However, in the unlikely event that 
an adverse reaction ( such as an allergic reaction) to the radiopharmaceutical occurs, the results will 
be documented and reported by the Principal Investigator to the Institutional Review Board  
Chairman and IND Committee. Patients could experience claustrophobia due to the MRI scanner. If 
they have difficulty tolerationg the study, it will be stopped. THE PET/CT scanner is not confining like 
the MRI scanner. Additionally, patients are advised not to become preganant or father a baby while 
on this study. Women should also not breastfeed the baby. Patients will be required to use birth 
control while on study. Very rarely, patients can develop nephrogenic systemic fibrosis which has 
been correlated with the use of gadolinium based contrast material used during the MRI scans. 
Placement of a catheter for infusion of 18F-FLT and blood samples may cause pain, bruising, itching, 
infections and venous scarring. Standard medical care will be used to minimize these risks. 
 
11.1 
PET SCANNING 
 
Potential risks to the patient are small and present more of an inconvenience (multiple scans 
on consecutive days). The PET has a large bore to accommodate the whole body and the 
environment is much less confining than the head cage of a MR tomograph. 
11.2 
DOSIMETRY 
 
Ta ble 1. F18-Fluoro thymidine (FLT) Pa tie nt Do sime try 
Absorbed Dose 
1 FLT PET -CT scans 
TOTAL for 
0.9 
CT 
rads 
3*0.9 
F18-FLT
2
 
10 mCi F18-FLT 
3 FLT PET -CT 
scans 
Target Organ 
rad/mCi 
rad/10 
mCi 
rad 
rad 
Adrenals 
0.0766 
0.77 
1.67 
5.00 

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IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
 
Bone Surfaces 
0.0585 
0.58 
1.48 
4.45 
Brain 
0.0125 
0.13 
1.03 
3.08 
Breasts 
0.0310 
0.31 
1.21 
3.63 
Gall Bladder Wall 
0.0625 
0.63 
1.53 
4.58 
Heart Wall 
0.0618 
0.62 
1.52 
4.55 
Kidneys 
0.132 
1.32 
2.22 
6.65 
Large Intestine - Lower 
Wall 
0.0168 
0.17 
1.07 
3.21 
Large Intestine - Upper 
Wall 
0.0459 
0.46 
1.36 
4.08 
Lens of Eye 
0.0389 
0.39 
1.29 
3.87 
Li ver 
0.1680 
1.68 
2.58 
7.74 
Lungs 
0.0374 
0.37 
1.27 
3.82 
Muscle / Other tissue 
0.0622 
0.62 
1.52 
4.56 
Pancreas 
0.0851 
0.85 
1.75 
5.25 
Red Marrow 
0.0888 
0.89 
1.79 
5.36 
Skin 
0.0164 
0.16 
1.06 
3.19 
Small Intestine 
0.0525 
0.53 
1.43 
4.28 
Stomach Wall 
0.0522 
0.52 
1.42 
4.27 
Testes 
0.0488 
0.49 
1.39 
4.17 
Thyroid 
0.0385 
0.38 
1.28 
3.85 
Total Body 
0.0466 
0.47 
1.37 
4.10 
Urinary Bladder Wall 
45-mi n Voiding Interval 
0.0297 
0.30 
1.20 
3.59 
1-hr Voiding Interval 
0.0396 
0.40 
1.30 
3.89 
1.5-hr Voiding Interval 
0.0593 
0.59 
1.49 
4.48 
2-hr Voiding Interval 
0.0791 
0.79 
1.69 
5.07 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 

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Administrative Update 2 : 18-Jan-2019 
 
 
 
MR Imaging 
 
Response assessment for MR Imaging of the brain during the follow-up period will be done by using 
Macdonald Criteria [25] as follows: 
 
 
12.1 Measurable lesion 
 
In the presence of multifocal disease, up to five bi-dimensionally measurable enhancing 
mass lesions will be followed for objective response. The bidimensional perpendicular 
measurements for each lesion should always be assessed in the same plane of axis (axial, 
coronal, sagittal or other). The largest perpendicular diameters of enhancement for each 
mass lesion will be recorded. Any and all remaining enhancing lesions will be followed as a 
single site and classified as an evaluable lesion. Objective response of the measurable 
lesion will be assessed by comparison of the changes in the product of the largest 
perpendicular measurements of the lesion at each visit. Comparisons of objective 
assessments for a measurable lesions(s) excluding progressive disease, are based upon 
major changes in tumor size on the Gd-MRI scan compared to the baseline scan. 
Determination of progressive disease is based upon comparison to the previous scan with 
the smallest measurements. Comparisons should always be made with measurements 
assessed in the same plane of axis (axial, coronal, sagittal or other). 
12.2 Evaluable lesion(s) 
 
For multifocal disease, all remaining enhancing tumor lesions, beyond the 5 measurable or 
any lesions that cannot be measured, will be followed as a single site and classified as an 
evaluable lesion. For an evaluable lesion(s), comparison of assessments for response 
designation will be assessed based upon major changes in tumor size on Gd-MRI scan. 
Comparisons of assessments for evaluable lesions(s) excluding progressive disease, are 
based upon major changes in tumor size on Gd-MRI scan compared to the baseline scan. 
Determination of progressive disease is based upon comparison to the previous scan with 
the smallest amount of evaluable tumor. Tumors may be classified as complete response 
(CR), partial response (PR), stable disease (SD), or progressive disease (PD). 
 
A complete response will always be disappearance of all enhancing tumor. Progressive 
disease will always include any new enhancing tumor. 
12.3 Criteria for current objective status 
 
At each tumor assessment visit the current objective status is determined. This takes into 
account measurable and evaluable lesion(s). Comparisons of assessments for measurable 
and evaluable lesions, excluding progressive disease, are based upon major changes in 
tumor size on Gd-MRI scan compared to the baseline scan. The assessment is adapted from 
Macdonald et al. Determination of progressive disease is based upon comparison to the 
previous scan with the smallest measurements. Scan changes are emphasized, but are 
interpreted in light of steroid use and to a lesser extent, neurological findings. Categories of 
overall response include: 

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IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
Complete response (CR): Disappearance of all enhancing tumor on consecutive MRI scans 
at least one month apart, off steroids and neurologically stable or improved. No new lesions 
may arise. 
Partial response (PR): Greater than or equal to a 50% reduction (< 100%) in the sum of the 
products of the largest perpendicular diameters of contrast enhancement for measurable 
lesions and if an evaluable lesion(s) is present at baseline, no worsening for an evaluable 
lesion(s) on consecutive Gd-MRI scans at least one month apart, steroids stable for 72 hours 
prior to each scan at the same dose administered at the time of the previous scan or at a 
reduced dose, and neurologically stable or improved. No new lesions may arise. 
Progressive disease (PD): Greater than or equal to a 25% increase in size of the product of 
the largest perpendicular diameters of contrast enhancement for any measurable lesions or if 
an evaluable(s) lesion is present at baseline, worsening for an evaluable lesion(s) or any new 
tumor on Gd-MRI scans or greater than or equal to 25% increase in the unidimensional 
measurement of the any lesion in an additional plane of axis, steroids are stable for 72 hours 
prior to each scan at the same dose administered at the time of the previous scan or at an 
increased dose, with or without neurological progression. The following will also apply: 
Unknown (UNK): If any measurable or evaluable lesions have not been assessed or the 
assessment was made using a technically inferior method compared to baseline, the current 
objective status is “unknown”, even if the bulk of disease was evaluated. An exception would 
be if the objective status is PD because either a new lesion was detected, evaluable disease 
clearly worsened or the remaining lesions classify for a PD even without the lesions which 
were not assessed, i.e. the sum of all lesions which can still be measured show an increase 
of more than 25% over the smallest sum of all measurable lesions which were present at 
baseline. 
Stable disease (SD): All other situations. 
 
12.4 Best response 
 
The best response for each patient is determined from the sequence of objective statuses. 
The terminology for the five categories of objective status is identical to those that describe 
best response. 
12.4.1 Determination of best response 
 
The best response for each patient is determined from the sequence of objective 
statuses according to the following rules: 
 
CR = at least two determinations of CR a minimum of 4 weeks apart before progression, 
preceded by lower statuses, or preceded, separated or followed by unknown statuses. 
 
PR = at least two determinations of PR or better a minimum of 4 weeks apart before 
progression (but not qualifying for CR), preceded by lower statuses, or preceded, 
separated or followed by UNK statuses. 

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IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
SD = at least one determination of stable disease or better 
 
PD = a determination of progression in one of the first two assessments 
 
UNK = the status is UNK only if all assessments before progression are UNK. 
 
If there is a defined objective that includes the assessment/measurement of therapeutic 
response to the defined treatment intervention, then detailed description of the measure, 
methods to be used (e.g., scales and/or definitions to assess response) and the criteria to 
determine each level of therapeutic response should be included. 
 
FLT-PET 
 
Response assessment for FLT-PET will be as follows: 
 
SUV max and average (42% threshold) for brain lesions will be measured (for FLT using summed 
images 45-60min). In addition, we will explore other measures such as metabolic tumor volume. For 
comparison, activity will also be measured in remote normal cortex and white matter. Tumor - to- 
normal ratios will be computed. Treatment induced changes in these parameters will be expressed 
as % decrease in radiotracer uptake. Tentatively, a decline by 25% [26] will be considered 
significant. 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
• 
If the patient has a negative FLT-PET at baseline 
• 
If the patient is no longer able to participate in the protocol and imaging schedule. 
• 
If the patient‟s primary physician and the PI consider that further participation in the protocol 
would not be in the best interest of the patient. 
• 
If at any time the patient is found to be ineligible for the protocol as designated in the section on 
Criteria for Patient/Subject Eligibility (e.g., a change in diagnosis), the patient will be removed 
from the study. 
14.0 
BIOSTATISTICS 
 
This is a small pilot study involving 20 patients with brain metastases from breast cancer. The first 
cohort will include the first ten patients that are enrolled to a separate but simultaneous phase I 
study evaluating patients receiving concurrent sorafenib + whole brain radiotherapy (WBXRT). The 
goal of the phase I study is to determine the MTD of sorafenib in breast cancer patients with brain 
metastases receiving WBRT.  Ten additional patients who do not enter the parallel phase I trial and 
receive WBXRT without sorafenib, will be consented to this imaging study.  Both cohorts have the 
same eligibility criteria. 
 
The first ten patients recruited into the Phase I trial of sorafenib + whole brain radiotherapy will have 
to agree to consent to the FLT-PET imaging study.  The cohort receiving WBRT alone will be 
recruited independently. 
 
The primary objective of this study is to examine radiographic response to WBRT by two modalities: 
FLT-PET and MRI.  MRI is considered standard of care and response assessments are recorded as 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
CR, PR, PD, SD, and unknown (see section 12.0). FLT–PET response assessments will be 
recorded as SUV-MAX and a decline by 25% is considered as significant (see Section 12.0).  MRI 
measurements will be recorded at baseline and 10 to 12 weeks post WBRT.  FLT-PET 
measurements will be recorded at baseline, 10 days post WBXRT, and 10-12 weeks post WBXRT. 
 
This is a small pilot study and as such, we are limited in the scope of our analyses by sample size. 
Data from each modality will be examined descriptively and graphically at baseline and over the 
course of treatment. Specifically, the distribution of response at baseline and the 10-12 week post 
WBXRT timepoint as assessed by MRI and FLT-PET will be examined. The median, mean, min and 
max of SUV max for FLT-PET will be summarized at each timepoint.  Significant or nonsignificant 
change in SUV from baseline to the 10-12 weeks post WBRT timepoint (decline by 25%) will also be 
calculated and the frequency of patients with significant change will be calculated.   These 
descriptive analyses will be done for each cohort separately.  Because FLT-PET can be used to 
assess early treatment response, SUV values and significant SUV change from baseline to 10 days 
post WBRT will be examined descriptively. 
 
As written in Section 10.1, FLT-PET imaging provides assessments in addition to SUV.  These 
additional assessments are kinetic rate constants based on a compartmental model. These 
parameters will also be analyzed using the approach described above (median, mean, min and max 
summarize at each timepoint for each cohort).  . 
 
 
Based on these analyses, we will  explore whether treatment response for the two modalities 
correlate To compare the two modalities, the proportion of patients with significant change in SUV 
(FLT-PET) as a dichotomous variable, will be calculated in the following two MRI response groups: 
CR+PR vs. PD+SD.  The McNemar‟s test for paired samples will be done to test the agreement of 
the two modalities.  In addition, boxplots of SUV will be graphed for each MRI response category for 
each cohort.  Based on the literature in this patient population, there is a 65-70 percent response 
rate as per MRI.  Median duration of response will be calculated and summarized overall and for 
each cohort separately. 
Any clinical, tissue, or other correlations are entirely exploratory in nature. It is expected that 2 
patients will be accrued per month, with accrual for all 20 patients taking approximately 1 year. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. 
 
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. 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
The individual signing the Eligibility Checklist is confirming whether or not the participant is 
eligible to enroll in the study. Study staff are responsible for ensuring that all institutional 
requirements necessary to enroll a participant to the study have been completed. See related 
Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
15.3 
Randomization 
 
There will be no randomization in this study. 
 
16.1 
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 a secure database (CRDB).  Source 
documentation will be available to support the computerized patient record. 
16.2 
Quality Assurance 
 
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. 
16.3 
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 addres s 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.htm 
 
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 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
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. 
17.1 
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 toxicities and side 
effects. 
Risks:  Potential risks to the patient include pain and discomfort related to phlebotomy and 
related to time spent undergoing [
18F] FLT PET and MR scanning.  Specific toxicities and 
side effects related to [18F] FLT PET imaging and MR imaging including radiation exposure 
are described in section 11. 
 
Benefits: We do not expect patients to derive any clinical benefit from this clinical trial.  We 
hope in the future that knowledge from this trial will help evaluating treatment response in 
future patients with metastatic breast cancer to the brain treated with WBRT or WBRT in 
combination with sorafenib, in better distinguishing tumor progression from radionecrosis. 
 
Alternative, non-protocol options will be discussed with the patient. It will be reviewed that 
participation in this clinical trial is voluntary and that the patient may withdraw consent at any 
time. The financial costs of the study will be discussed; FLT PET scans and blood draw for 
PK analysis will be done free of charge. 
17.2 
Privacy 
 
MSKCC‟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). 
17.3 
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 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
• 
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 
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 be 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 saemskind@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. 
 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the report will 
be forwarded to the FDA by the SAE staff through the IND Office 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
18.1 
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. 
 
 
19.0 
REFERENCES 
 
1. Chidel, M.A., et al., Application of recursive partitioning analysis and evaluation of the use of 
whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed 
brain metastases. International Journal of Radiation Oncology Biology Physics, 2000. 47(4): p. 993- 
999. 
2. Gaspar, L.E., et al., Validation of the RTOG recursive partitioning analysis (RPA) classification for 
brain metastases. Int J Radiat Oncol Biol Phys, 2000. 47(4): p. 1001-6. 
 
3. Lin, N.U., et al., Sites of distant recurrence and clinical outcomes in patients with metastatic triple- 
negative breast cancer: high incidence of central nervous system metastases. Cancer, 2008. 
113(10): p. 2638-45. 
 
4. Altundag, K., et al., Clinicopathologic characteristics and prognostic factors in 420 metastatic 
breast cancer patients with central nervous system metastasis. Cancer, 2007. 110(12): p. 2640-7. 
 
5. P. G. Morris, C.G.M., S. Patil, J. Howard, A. Omuro, C. A. Hudis, M. N. Fornier, Brain metastases 
in a large cohort of patients (pts) with triple-negative breast cancer (TNBC): Impact of modern 
therapies on survival, in ASCO Breast Cancer Symposium 2009. 

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IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
6. Gradishar, A double blind randomized phase IIb study evaluating the efficacy and safety of 
sorafenib compared with placebo when administered in combination with paclitaxel in patients with 
locally recurrent or metastatic breast cancer., in San Antonio Breast Cancer Symposium: San 
Antonio 2009. 
 
7. Valcamonico, F., et al., Long-lasting successful cerebral response with sorafenib in advanced 
renal cell carcinoma. J Neurooncol, 2009. 91(1): p. 47-50. 
 
8. Plastaras, J.P., et al., Cell cycle-dependent and schedule-dependent antitumor effects of 
sorafenib combined with radiation. Cancer Research, 2007. 67(19): p. 9443-9454. 
 
9. Den, R., et al., A Phase I Study of Sorafenib and Radiation Therapy for the Treatment of Patients 
with Brain Metastases and Sorafenib, Temozolomide and Radiation Therapy for the Treatment of 
Primary Brain Tumors. Neuro-Oncology, 2009. 11(5): p. 662-662. 
 
10. Mier, W., U. Haberkorn, and M. Eisenhut, [18F]FLT; portrait of a proliferation marker. Eur J Nucl 
Med Mol Imaging, 2002. 29(2): p. 165-9. 
 
11. Shields, A.F., et al., Imaging proliferation in vivo with [F-18]FLT and positron emission 
tomography. Nat Med, 1998. 4(11): p. 1334-6. 
 
12. Vesselle, H., et al., 18F-Fluorothymidine radiation dosimetry in human PET imaging studies. J 
Nucl Med, 2003. 44(9): p. 1482-8. 
 
13. Mankoff, D.A., A.F. Shields, and K.A. Krohn, PET imaging of cellular proliferation. Radiol Clin 
North Am, 2005. 43(1): p. 153-67. 
 
 
 
14. Pio BS, P.C., Satyamurthy N, Czernin J, Phelps ME, Silverman DH et al., PET with fluoro-L- 
thymidine allows early prediction of breast cancer response tochemotherapy [abstract]. J Nucl Med, 
2003. 44(suppl): p. 246P. 
 
15. Vesselle, H., et al., In vivo validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a 
proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission 
tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer 
Res, 2002. 8(11): p. 3315-23. 
 
16. Buck, A.K., et al., 3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography for 
noninvasive assessment of proliferation in pulmonary nodules. Cancer Res, 2002. 62(12): p. 3331-4. 
 
17. Chen, W., et al., Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F- 
FDG. J Nucl Med, 2005. 46(6): p. 945-52. 
 
18. Ricci, P.E., et al., Differentiating recurrent tumor from radiation necrosis: time for re-evaluation 
of positron emission tomography? AJNR Am J Neuroradiol, 1998. 19(3): p. 407-13. 

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IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
19. Prat, R., et al., Relative value of magnetic resonance spectroscopy, magnetic resonance 
perfusion, and 2-(18F) fluoro-2-deoxy-D-glucose positron emission tomography for detection of 
recurrence or grade increase in gliomas. J Clin Neurosci, 2010. 17(1): p. 50-3. 
 
20. Kim, E.E., et al., Differentiation of residual or recurrent tumors from post-treatment changes with 
F-18 FDG PET. Radiographics,1992. 12(2): p. 269-79. 
 
21. Chen et al, Predicting Treatment Response of Malignant Gliomas to Bevacizumab and 
Irinotecan by Imaging Proliferation With [18F] Fluorothymidine Positron Emission Tomography: A 
Pilot Study. J Clin Onc, 2007. 25(30): p. 4714-4721 
 
22. Giglio, P. and M.R. Gilbert, Cerebral radiation necrosis. Neurologist, 2003. 9(4): p. 180-8. 
 
23. Wong ET, Huberman M, Lu XQ, Mahadevan A. Bevacizumab reverses cerebral radiation 
necrosis. J Clin Oncol 2008;26(34):5649-50. 
 
24. Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of 
the brain. Int J Radiat Oncol Biol Phys 2007;67(2):323-6. 
 
25. 
Macdonald DR, Cascino TL, Schold SC, Jr., et al. Response criteria for phase II studies 
of supratentorial malignant glioma. J Clin Oncol 1990; 8:1277-1280 
26. Shields A, Lawhorn-Crews J, Briston D, et al. Analysis and Reproducibility of 3’-Deoxy-3’-[18 
F]Fluorothymidine Positron Emission Tomography Imaging in Patients with Non -Small Cell Lung 
Cancer. Clin Cancer Res 2008;14: 4463-4468. 
 
 
20.0 
APPENDICES 
APPENDIX A: Study calendar 
APPENDIX B: Performance codes status 
 
 
 
APPENDIX A 
 
Study Calendar 
 
Tests 
Screening 
7-10 days after 
WBRT 
10-12 weeks 
after WBRT 
MRI Brain
1
 
X 
X 
FLT-PET1 
X 
X 
X 
FLT PK Blood draw
2
 
X 
X 
X 
History and Physical examination
3
 
X 
CBC, CMP
3
 
X 
Pregnancy test3 
X 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-039 A(17) 
Approval date: 13-Dec-2017 
Administrative Update 2 : 18-Jan-2019 
 
 
 
1MRI and FLT-PET will all be done within 4 weeks prior to initiation of WBRT. MRI will be done 
within one week before the FLT-PET scan. 
2 PK Blood draw will be done 60 min (+ 10 min window) after FLT injection 
3 Blood tests will be done within 1 week of initiation of WBRT 
 
 
 
 
 
 
 
 
 
 
APPENDIX B