Clinical trial NCT02774681
Conditions: Breast Carcinoma Metastatic in the Brain Estrogen Receptor Negative HER2/Neu Negative HER2/Neu Positive Progesterone Receptor Negative Recurrent Breast Carcinoma Stage IV Breast Cancer
Sponsor: Northwestern University
Start date: 2016-08-31; Completion date: 2020-02-16
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate if the study drug palbociclib has anti-tumor activity against the breast cancer that has spread to the brain and also to determine the overall radiographic response rate in the CNS. Palbociclib is an anti-cancer medication that has been shown to stop cancer cells from growing. It has been approved in hormone positive breast cancer, along with other hormone therapies and has been found to be effective. The preclinical studies suggest that the drug may also have activity in other types of breast cancer, such as HER2 positive breast cancer. The purpose of this study is to see if the study drug is effective in patients with brain metastasis, who have HER2-positive breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the radiographic response rate in the central nervous system (CNS) in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival (PFS) and overall survival (OS) in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib.

II. To determine time to CNS progression in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib.

III. To determine systemic overall response rate (ORR) in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib.

IV. To determine the safety and tolerability of palbociclib in patients with and HER2-positive breast cancer.

TERTIARY OBJECTIVES:

I. To evaluate circulating tumor deoxyribonucleic acid (DNA) at baseline, 2 month and 4 months; particularly to assess cyclin D1 aberrations, and if this is predictive of responses.

II. To evaluate genomic landscape of available CNS and non-CNS tumors, and describe any discordance.

III. To evaluate cognitive function and quality of life at baseline, 2 and 4 months in patients receiving palbociclib.

OUTLINE:

Patients receive palbociclib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with HER2 positive breast cancer may also receive trastuzumab intravenously (IV) as standard of care concurrently with palbociclib.

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months, and then every 6 months for up to 3 years.

Arms: arm 1: Patients receive palbociclib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with HER2 positive breast cancer may also receive trastuzumab IV over 30-90 minutes every 3 weeks.
Interventions: intervention 1: Cognitive Assessment intervention 2: Palbociclib intervention 3: Quality-of-Life Assessment intervention 4: Trastuzumab
Intervention descriptions: intervention 1: Ancillary studies intervention 2: Given PO intervention 3: Ancillary studies intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II Single Arm Study of Palbociclib in Patients with Metastatic 
HER2-positive Breast Cancer with Brain Metastasis 
 
Principal Investigator:              Massimo Cristofanilli, MD  
                                                    Professor of Medicine 
                                                    Associate Director of Translational Research and Precision Medicine 
                                                    Department of Medicine-Hematology and Oncology 
                                                    Robert H Lurie Comprehensive Cancer Center 
                                                    Feinberg School of Medicine 
                                                    710 N Fairbanks Court, Olson Building, Suite 8-250A 
                                                    Chicago, IL 60611 
                             Tel: 312-503-5488 
                             Email: Massimo.cristofanilli@nm.org 
 
 
NU Sub-Investigator(s): 
Northwestern University 
Robert H. Lurie Comprehensive Cancer Center 
Priya Kumthekar, MD 
Jonathan Strauss 
Luis Blanco 
Sofia Garcia 
 
Northwestern Lake Forest Hospital 
Valerie Nelson, MD 
 
Affiliate Site PIs: 
Jenny Chang, MD 
Houston Methodist Hospital/Houston Methodist Cancer Center 
6445 Main Street, P24-326 
Houston, Texas 77030 
Tel: 713-441-9948 
jcchang@houstonmethodist.org 
 
 
Biostatistician: 
Alfred Rademaker 
rademaker@northwestern.edu 
 
Study Intervention(s): 
Palbociclib (Ibrance) 
 
IND Number: 
 Exempt 
IND Holder: 
 N/A 
Funding Source: 
Pfizer 
Version Date: 
August 15, 2017 (Amendment 5) 
 
Coordinating Center: 
Clinical Research Office 
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University 
676 N. St. Clair, Suite 1200 
Chicago, IL  60611 
http://cancer.northwestern.edu/CRO/index.cfm 
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Table of Contents 
 
 
STUDY SCHEMA ............................................................................................................................ 5 
 
 
STUDY SUMMARY ......................................................................................................................... 6 
 
 
1.0 
Introduction – BACKGROUND & RATIONALE .................................................................. 7 
 
 
2.0 OBJECTIVES & endpoints .................................................................................................... 11 
 
 
3.0 PATIENT ELIGIBILITY ............................................................................................................ 11 
 
 
4.0 TREATMENT PLAN ................................................................................................................ 14 
 
 
5.0 STUDY PROCEDURES........................................................................................................... 18 
 
 
6.0 ENDPOINT ASSESSMENT ..................................................................................................... 22 
 
 
7.0 ADVERSE EVENTS ................................................................................................................ 23 
 
 
8.0 DRUG INFORMATION ............................................................................................................ 27 
 
 
9.0 CORRELATIVES/SPECIAL STUDIES.................................................................................... 30 
 
 
10.0 STATISTICAL CONSIDERATIONS ...................................................................................... 32 
 
 
11.0 STUDY MANAGEMENT ........................................................................................................ 33 
 
 
REFERENCES............................................................................................................................... 37 
 
 
APPENDICES ................................................................................................................................ 39 
 
 
APPENDIX 1 .................................................................................................................................. 39 
 
 
APPENDIX 2……………………………………………………………………………………………….39 
 
 
APPENDIX 3 .................................................................................................................................. 40 
 
History of Amendment summary of changes……………………………………………………....41 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&PE 
History & Physical Exam 
HER-2 
Human epidermal growth factor receptor 2 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NSGY 
Neurosurgery 
ORR 
Overall Response Rate or Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO (or p.o.) 
Per os/by mouth/orally 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SV 
Screening visit 
SOC 
Standard of Care 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SRS 
Stereotactic radiosurgery 
 
WBC 
White Blood Cells 
WBRT 
whole brain radiation therapy 
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STUDY SCHEMA 
 
 
HER2-positive Metastatic 
breast cancer Asymptomatic 
brain metastasis Any WBRT 
must have occurred 
>60 days ago 
 
 
 
 
 
Multi- center, Single arm 
Open label, 2 cohorts 
 
 
 
 
 
 
 
(HER-2 positive) 
Palbociclib 125 mg (PO) 
Days 1 through 21, 7 days off 
(Cycle=28 days)* 
 
 
* Concomitant use of 
Trastuzumab (SOC) 
permitted 
 
 
 
 
MRI brain and CT/ bone scan every 2 months Research blood and 
questionnaires: baseline, 2, 4 months Endpoints: CNS response rate 
(modified RANO-BM), OS, PFS, time to CNS progression 
 
 
 
 
 
CR/PR/SD continue treatment until POD 
If CNS POD: Patient off study treatment. 
CNS therapy (i.e. WBRT, SRS, NSGY) per MD discretion 
 
 
 
 
 
 
Once off treatment continue follow-up q 3 months up to 1 year, then 
q 6 months up to 3 years 
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STUDY SUMMARY 
Title 
A Phase II, multi-center, open label study of Palbociclib in patients with 
Metastatic HER2-positive Breast Cancer with Brain Metastasis 
Short Title 
Palbociclib in HER2-positive Breast Cancer Brain Metastasis 
Version 
August 15, 2017 (Amendment 5) 
Study Design 
A phase 2 study enrolling patients with metastatic HER2-positive breast 
cancer who have asymptomatic brain metastasis.. Patients will be treated 
with 125mg of PO palbociclib (21 days on, 7 days off). In addition, they 
can be enrolled and treated concurrently with Trastuzumab. MRI of the 
brain will monitor for disease progression. Upon progression (CNS or 
systemic) patients will off study treatment and will receive CNS directed 
therapy (such as WBRT, SRS, surgery) per treating physician discretion. 
Study Center(s) 
Lead Site: Northwestern University Robert H. Lurie Comprehensive 
Cancer Center 
Affiliate Sites: Houston Methodist Hospital 
Objectives 
Primary Objective: 
1.   To determine the overall radiographic response rate in the CNS. 
Secondary Objectives: 
1.   To determine PFS, OS 
2.   Time to CNS progression 
3.   Overall response rate systemically 
4.   Safety and tolerability 
Sample Size 
Maximum accrual limit: 25patients 
Evaluable patients : 20(Her2-positive) 
Diagnosis & Key 
Eligibility Criteria 
Key Inclusion Criteria: 
1.   Histologically confirmed metastatic HER2-positive breast cancer 
2.   Measurable brain metastasis (at least 1 lesion >=5mm) 
3.   No systemic therapy 2 weeks prior to initiating palbociclib 
4.   ECOG Performance status ≤ 2 
5.   Trastuzumab allowed Adequate bone marrow and organ function 
(ANC >=1000, platelets >=100 000, hemoglobin >=10, 
GPT/GOT/bilirubin <3xULN (or <5xULN if liver metastasis), 
creatinine <1.5xULN) 
Key Exclusion Criteria: 
1.   Any clinically significant neurologic symptoms attributed to CNS 
metastasis 
2.   Leptomeningeal disease 
3.   Significant medical illness per investigators discretion 
Treatment Plan 
Patients will be treated with 125mg of PO palbociclib (21 days on, 7 days 
off). They will continue therapy while there is no evidence of disease 
progression. Upon CNS disease progression, patient will be off study 
treatment and will be treated with CNS directed therapy (such as WBRT, 
SRS, surgery) per treating physician discretion. If systemic progression 
occurs, patients will come off study 
Statistical Methodology 
To detect a radiographic response rates increase from 23% to 40% in 
the HER2-positive cohort,. A Bayesian posterior probability will be 
calculated after the response status in 20 patients has been assessed. 
The goal is that there is at least an 80% probability that the response 
rate exceeds 40% in the HER-2 positive cohort Then the total number of 
evaluable patients to be accrued is 20. 
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Introduction – BACKGROUND & RATIONALE 
 
1.1 
Disease Background 
 
1.1.1 
Breast cancer incidence and subtypes. 
Breast cancer is the most common non-dermatological malignancy in women with 
an estimated 232, 670 new diagnoses in 2014; and is the second leading cause of 
cancer death in women with an estimated 40, 000 women in the United States 
succumbing to the disease in 2014(1). Breast cancer is a heterogeneous disease 
comprised of several molecular subtypes, which are commonly extrapolated into 
clinical subtypes based on receptor status(2). The specific receptors which are 
assessed in standard clinical practice are the estrogen receptor (ER), 
progesterone receptor (PR), and human epidermal growth factor 2-neu (HER2) 
receptor.  
 
1.1.2 
Breast cancer and brain metastasis. 
Of patients diagnosed with early stage disease, less than 3% will develop brain 
metastasis, however, this number increases to approximately 10-16% in patients 
with metastatic disease (3, 4). Different subtypes of breast cancer have different 
incidences of brain metastasis, with the highest being luminal B (12%), HER2- 
positive (12%), luminal-HER2 (8%), and TNBC (7%), and the least common is 
luminal A subtype (0.7%). Approach to treatment of brain metastasis is a 
multidisciplinary effort involving medical and radiation oncologists, and 
neurosurgeons; primary modalities of therapy include surgery, stereotactic 
radiosurgery (SRS), whole brain radiation therapy (WBRT), and systemic 
treatments which can penetrate the blood brain barrier. 
 
In select patients with larger tumors in surgically accessible areas, surgical 
resection of brain metastasis can be considered. The addition of WBRT to surgery 
can improve CNS progression rates, but has not been shown to improve overall 
survival (5, 6). However, performing surgery with WBRT rather than WBRT alone, 
can improve CNS recurrence rates (20% from 52%) and survival (40 weeks versus 
15 weeks) (7). In patient with few discrete lesions, SRS can provide local control 
rates from 65-94%, and this has become an increasingly popular modality to treat 
brain metastasis (8-10). The addition of SRS to WBRT does not improve survival 
in general (6.5 months versus 5.7 months).However, in patients with single brain 
metastasis or favorable prognosis median survival may be improved (6.5 versus 
4.9 months, 11.6 versus 9.6 months, respectively) (11). 
 
The majority of systemic therapies do not cross the blood brain barrier (BBB), and 
have limited efficacy against CNS metastasis. Certain drugs including high dose 
methotrexate and capecitabine are sometimes used as they can cross the BBB, 
but there are no drugs specifically indicated for brain metastasis. Many agents 
have been investigated for the treatment of brain metastasis, with overall response 
rates (ORR) ranging from 0-40% (average ORR response rates in the CNS for 
chemotherapy are 17%), and time to progression (TTP) or progression free 
survival (PFS) ranging from <2months to 4months (average TTP/PFS 2.5 months) 
(Table 1) (14). For patients with HER-2 positive breast cancer, lapatinib with 
various combinations of chemotherapy has been investigated since lapatinib is a 
small molecule inhibitor that can cross the BBB. While response rates and PFS 
are better with this targeted approach, response rates range from 0-67% (average 
approximately 22.7%), and TTP/PFS ranging from 2.4 – 5.5months (average 
approximately 3.9 months) (Table 2) (12). Key reasons for the wide variability in 
response rates and PFS has to do with previous treatment, where generally those 
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with less previous CNS-directed therapies tend to have high ORR and TTP/PFS 
on these therapies. 
 
 
Table 1. Response rates and TTP/PFS to chemotherapy. 
 
Regimen 
Number of 
Patients (Number 
of Breast Cancer 
Patients) 
Patient Population 
CNS ORR in 
Breast Cancer 
Subset 
TTP/PFS 
Temozolomide 
19 (5) 
Pretreated with systemic therapy 
0% 
<2 months 
Temozolomide 
157 (51) 
80% prior chemotherapy for 
MBC 24% prior WBRT 
4% 
~2 months 
Capecitabine + 
temozolomide 
24 (24) 
33% prior WBRT 
18% 
3 months 
Cisplatin + 
temozolomide 
32 (15) 
~50% prior WBRT 
40% 
2.9 months 
Cisplatin + 
etoposide 
107 (56) 
No prior CNS RT allowed; 36% 
chemotherapy naive 
38% 
4 months 
Sagopilone 
15 (15) 
Progression after CNS RT 
required 
13% 
1.4 months 
Patupilone 
36 (36) 
Progression after CNS RT 
required 
19% 
2.8 months 
Vinorelbine + 
temozolomide 
38 (11) 
Heavily pretreated patients 
0% 
1.9 months 
 
 
Table 2. Response rates and TTP/PFS to lapatinib based therapy. 
 
Regimen 
Number 
of 
Patients 
Patient Population 
CNS ORR 
TTP/PFS 
Lapatinib 
39 
Heavily pretreated 
2.6% 
3.0 months 
Lapatinib 
237 
Progression after CNS RT required 
6% 
2.4 months 
Lapatinib + capecitabine 
50 
Progression after CNS RT and 
through lapatinib monotherapy 
required 
20% 
3.6 months 
Lapatinib + capecitabine 
138 
Heavily pretreated 
18% 
NR 
Lapatinib + capecitabine 
34 
Heavily pretreated 
21% 
5.1 months 
Lapatinib + capecitabine 
22 
Heavily pretreated 
32% 
5.1 months 
Lapatinib + capecitabine 
13 
Heavily pretreated 
38% 
NR 
Lapatinib + capecitabine 
45 
No prior CNS radiotherapy allowed 
67% 
5.5 months 
Lapatinib + topotecan 
9 
Heavily pretreated 
0% 
NR 
Lapatinib + temozolomide 
17 
Heavily pretreated 
NR 
2.8 months 
 
1.1.3 
Palbociclib in breast cancer. 
Palbociclib is an oral small molecule inhibitor of cyclin dependant kinases (CDK) 
4 and 6, which affect the growth cycle (13). The PALOMA-1 study was a Phase II 
randomized study in patients with metastatic ER-positive breast cancer which 
demonstrated the addition of palbociclib to letrozole in the front line setting which 
increased median progression free survival (PFS) from 10.2 months to 20.2 
months (hazard ration (HR) 0.488, 95% confidence interval (CI) 0.319 – 0.748, 
p=0.0004), earning it Food and Drug Administration (FDA) approval (14). The 
results of the PALOMA-3 study was a larger Phase III study, which demonstrated 
the addition of palbociclib to fulvestrant which improved median PFS from 3.8 
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months to 9.2 months (HR 0.42, 95% CI 0.32 – 0.56, p<0.001). These studies 
provide strong rationale for the use of palbociclib in ER-positive breast cancer. 
 
While basal like cancers do not tend to display alterations in cyclin D1 or CDK4/6, 
the PALOMA-1 study did not find these genomic aberrations to predict response 
to therapy. 
 
Till date, palbociclib has been studied in combination with other agents. In this 
study, palbociclib is being studied as monotherapy, as well as in combination with 
trastuzumab. 
 
Palbociclib crosses the blood brain barrier: 
 
Palbociclib has been investigated in brain tumors. In vivo experiments in 
glioblastoma multiformans (GBM) has shown that palbociclib can suppress growth 
of GBM in intracranial xenografts, and prevented tumor-related death of treated 
mice (15). In these experiments, the brains of treated mice were dissected, 
showing that palbociclib was not only present in intracranial tissues, but was 25- 
35x higher in tumor tissue than in normal tissue (15). Another similar study in 
diffuse intrinsic pontine glioma (DIPG) mice models found that palbociclib had 
activity in intracranial tumors, and prolonged survival (16). Yet another study in 
preclinical GBM models, CDK4/6 inhibitors, including palbociclib have been found 
to cross the BBB and have antitumor activity (18). Recent studies, however, have 
shown that certain BBB transports, P-glycoprotein and Breast Cancer Resistance 
Protein (BCRP/ABCG2), can inhibit CNS uptake of palbociclib, although more 
studies are needed (18). Results from ongoing clinical trials in brain tumors 
(NCT02255461, NCT02530320) are ongoing 
 
 
1.1.5  Rationale for target patient population: 
There exists no clinical trial investigating CDK4/6 inhibitors in HER2- positive 
breast cancer, but several preclinical and translational studies exist that provide 
rationale. (21). While basal like cancers do not tend to display alterations in cyclin 
D1 or CDK4/6, the PALOMA-1 study did not find these genomic aberrations to 
predict response to therapy (14). Furthermore, HER2-positive breast cancers, 
have been demonstrated to require cyclin D1 and CDK4 for tumor progression 
and maintenance (5, 7). Palbociclib has been found to have single agent activity 
in transgenic HER2-positive models by causing near complete cessation of tumor 
proliferation, leading to improved survival of mice (7). These data provide rationale 
for the investigation of palbociclib in HER2-positive breast cancers. 
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1.1.6 Safety of trastuzumab in combination with other agents 
 
This study will allow patients with HER2-positive disease to be treated concurrently 
with trastuzumab since it is usual practice to combine anti-HER2 therapy with other 
anti-cancer drugs in HER2-positive disease. In the pivotal study by Slamon and 
colleagues, the addition of trastuzumab to chemotherapy did not increase the risk 
of serious adverse events, other than cardiomyopathy, which is a well-established 
toxicity of trastuzumab (1). In patients who have progressed on trastuzumab, the 
continuation of trastuzumab in combination with other chemotherapy is a common 
practice. In studies that support this approach, the addition of trastuzumab added 
no increased toxicity. In a phase II study randomizing 78 patients to capecitabine 
with or without trastuzumab incidence of grade 3/4 was the same between both 
arms, with the only difference being a slightly higher incidence of grade 1/2 anemia 
in the trastuzumab arm (p=0.02) (2). As expected with trastuzumab, there was an 
increased incidence of decrease in left ventricular ejection fraction (LVEF), only 1 
case was greater than grade 2. Of note, this study did not have a phase 1 
component or safety run-in. In clinical practice, trastuzumab is routinely 
administered with cytotoxic chemotherapy safely (NCCN v3.2015). Routine 
standard of care practice is to evaluate LVEF with echocardiograms or MUGA 
scans routinely on any patients receiving trastuzumab. 
 
 
 
1.1.7 
Rationale for dose selection 
The PALOMA-1 study was a Phase II randomized study in patients with metastatic 
ER-positive breast cancer which demonstrated the addition of palbociclib to 
letrozole in the front line setting which increased median progression free survival 
(PFS) from 10.2 months to 20.2 months (hazard ration (HR) 0.488, 95% confidence 
interval (CI) 0.319 – 0.748, p=0.0004), earning it Food and Drug Administration 
(FDA) approval (14). The recommended FDA dose and schedule of palbociclib is 
125 mg daily for 21 consecutive days followed by 7 days off treatment and its 
dose and schedule is being used in this study 
 
 
1.1.8 Patient Reported Outcomes: Questionnaires 
 
Standard of care therapy to CNS lesions has significant toxicity. Patients who 
undergo WBRT can experience fatigue and decline in cognitive function (2). Patients 
undergoing SRS can have seizures, neurological deficits, nausea, headaches, and 
cognitive decline (3-5). These effects can have a significant impact on quality of life, 
therefore, we wish to assess if treatment with palbociclib affects quality of life, and in 
particular cognitive function. To assess cognitive function we will use the Functional 
Assessment of Cancer Therapy-Cognitive Function version 3.0 (FACT_Cog, ver 3.0) 
and to assess quality of life we will use the Functional Assessment of Cancer 
Therapy-Brain version 4.0 (FACT-Br) (available as stand-alone documents) They are 
both validated questionnaires that have been used in previous studies 
(www.facit.org). 
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2.0 
OBJECTIVES AND ENDPOINTS 
 
2.1       Primary Objective & Endpoint 
 
To determine the radiographic response rate in the CNS in patients with HER2-positive 
breast cancer who have brain metastasis treated with palbociclib. 
 
 
2.2       Secondary Objectives & Endpoints 
 
1) To determine the PFS and OS in patients with HER2-positive breast cancer who have 
brain metastasis treated with palbociclib. 
 
2) To determine time to CNS progression in patients with HER2-positive breast cancer who 
have brain metastasis treated with palbociclib. 
 
3) To determine systemic ORR in patients with HER2-positive breast cancer who have 
brain metastasis treated with palbociclib. 
 
4) To determine the safety and tolerability of palbociclib in patients with HER2-positive 
breast cancer. 
 
 
2.3       Exploratory Objectives & Endpoints 
 
1)To evaluate circulating tumor DNA at baseline, 2 month and 4 months; particularly to 
assess cyclin D1 aberrations, and if this is predictive of responses. 
 
2) To evaluate genomic landscape of available CNS and non-CNS tumors, and describe 
any discordance. 
 
3) To evaluate cognitive function and quality of life at baseline, 2 and 4 months in patients 
receiving palbociclib. 
 
 
3.0 
PATIENT ELIGIBILITY 
The target population for this study is patients with metastatic HER2-positive breast cancer who 
have asymptomatic brain metastasis. This will be a multi-center trial. Northwestern 
University will serve as the lead site and coordinating center for this study. Participating sites will 
include Houston Methodist Hospital. 
 
A total of 20 evaluable subjects will be accrued. Approximately 1-2 potentially eligible patients are 
seen per month, and it is anticipated that at least 1 per month will be accrued (once all sites are up 
and running). Potential patients may be referred to the Principal Investigator (PI) at Northwestern 
University, Dr. Massimo Cristofanilli, at (312) 695-0990, or to the local PI at each participating site. 
 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer to 
Section 11 for complete instructions regarding registration procedures. 
 
3.1       Inclusion Criteria 
 
3.1.1  Histologically confirmed HER2-positive metastatic breast cancer (HER-2 3+ by 
immunohistochemistry. If IHC score of 2, FISH ratio must be greater than 2.0. If 
FISH less than 2.0, HER2 copy number must be greater than 6. NOTE: Brain 
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lesions are not required to have pathologic confirmation. ER-positive patients are 
allowed. 
 
3.1.2   Patients must have a life expectancy of at least 12 weeks at the time of 
registration 
 
3.1.3   Patients must be age ≥ 18 years. Both females and males are eligible. 
 
3.1.4   ECOG performance status≤ 2(Appendix 1) 
 
3.1.5   Measurable disease in the brain, defined as at least 1 lesion measuring ≥ 5 mm 
on imaging at the time of registration 
 
3.1.6   If patients are on corticosteroids, they must have been on a stable or decreasing 
dose ≥ 5 days prior to obtaining their baseline Gd-MRI of brain. This MRI is to be 
obtained within 28 days of registration. NOTE: If patient needs escalation of 
steroids prior to therapy, or are on unstable doses of steroids they are not eligible. 
 
3.1.7   Patients who underwent neurosurgery (NSGY, whole brain radiation therapy, or 
stereotactic radiosurgery (SRS) to a brain lesion must have a new measureable 
lesion. Previously surgically excised lesion/tumor bed, may be used as a 
measurable lesion if disease has progressed since surgery (NOTE: SRS may be 
done to a lesion that will not be used for response evaluation and should be done 
> 2 weeks prior to registration. Any WBRT must have occurred>60 days ago. Any 
NSGY procedure must have been completed >3 weeks prior to registration and 
baseline imaging). 
 
3.1.8  Patients must not have received systemic therapy within 2 weeks of initiating 
palbociclib. NOTE: Patients on trastuzumab can remain on the drug if previously 
taking, or may start if not. No break or washout period required. Patients with ER- 
positive disease may not concurrently take endocrine therapy, however, no 
washout is required if they were previously on endocrine therapy. However, 
lapatinib, ado-trastuzumab-emtansine, and pertuzumab are prohibited and a 
minimum wash out period of 2 weeks is required. 
 
3.1.9  Patients must exhibit adequate bone marrow, liver, and renal function, within 14 
days prior to registration, defined as: 
 
 ANC ≥ 1,000/mm3 (growth factor support is permitted) 
 Platelets ≥ 100,000/mm3 (may be reached by transfusion) 
 Hemoglobin ≥ 10 gm/dl (may be reached by transfusion) 
 GPT/GOT and bilirubin < 3 x ULN (or < 5 x ULN in case of liver metastasis) 
 Creatinine < 1.5 x ULN 
 
3.1.10  Females of child-bearing potential (FOCBP) and males must agree to use 
adequate contraception (see Appendix 2) prior to study entry, for the duration of 
study participation, and for 2 weeks following completion of therapy. Should a 
female patient become pregnant or suspect she is pregnant while participating 
in this study, she should inform her treating physician immediately. Likewise, if 
the female partner of a male patient becomes pregnant while participating in this 
study, he should inform his treating physician immediately 
 
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy 
• 
Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months) 
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3.1.11  Female patients must have a negative urine pregnancy test within 7 days prior to 
registration. If urine test is positive, it should be followed by serum pregnancy 
test. 
 
 
3.1.12 Patients must sign an informed consent prior to registration and before undergoing 
any study-specific procedures indicating that they are aware of the investigational 
nature of this study. 
 
3.1.13 Patient must have the ability to swallow and retain oral medication. 
 
 
3.1.14 Patient must have the ability to comply with all study requirements. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Any uncontrolled neurological symptom attributed to CNS metastasis. 
 
3.2.2 
Brain metastasis must not be impending herniation or other significant vasogenic 
edema requiring increasing steroid doses. Lesions must not have frank 
hemorrhage. 
 
3.2.3 
Patients with leptomeningeal disease are not eligible for participation 
             Please note: leptomeningeal enhancement is not an exclusion 
 
3.2.4 
Any significant medical illnesses or infection that, in the investigator’s opinion, 
cannot be adequately controlled with appropriate therapy or would compromise 
the patient’s ability to tolerate this therapy are not eligible for participation 
 
3.2.5 
Known HIV positive status 
 
3.2.6 
Known active Hepatitis B and/or C 
 
 
3.2.7 
Previous treatment with palbociclib 
 
3.2.8 
Patients who have a history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to palbociclib are not 
eligible. 
AND/OR 
Patients who have had prior exposure to compounds of similar chemical or biologic 
composition to palbociclib are not eligible hypersensitivity to any component of 
palbociclib are not eligible for participation. 
 
 
3.2.9   Female patients who are pregnant or nursing are not eligible. 
 
 
3.2.10  Patients who have an uncontrolled intercurrent illness including, but not limited to 
any of the following, are not eligible: 
 
•     Ongoing or active infection requiring systemic treatment 
•     Symptomatic congestive heart failure 
•     Unstable angina pectoris 
• 
Cardiac arrhythmia: except atrial fibrillation(AF) and supraventricular 
tachycardia(SVT) that are controlled by medication 
• 
Psychiatric illness/social situations that would limit compliance with study 
requirements 
•     Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints 
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3.2.11  Patients being treated with any other experimental agents/clinical trials are not 
eligible for participation. If the patient is on any investigational agent, a wash-out 
period of minimum 2 weeks prior to registration is mandatory for the patient to be 
eligible for the study. 
 
3.2.12  Patients who are on any prohibited medication (see Section 4.4.1). A wash-out 
period of minimum 2 weeks prior to registration is mandatory for the patient to be 
eligible for the study 
 
 
3.2.13 Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease 
that severely affects the absorption of study drugs, major resection of the 
stomach or small bowel, or gastric bypass procedure. 
 
 
 
4.0 
TREATMENT PLAN 
 
4.1 
Overview 
Treatment should be started within 7 days of registration. Patients will be treated with 
palbociclib 125mg PO for 21 days and then 7 days off to complete one cycle of therapy(I 
cycle=28 days). Treatment cycles will be continued until disease progression or 
unacceptable toxicity. Patients are permitted to take trastuzumab concurrently. Upon 
progression, patients will come off study and will be followed for survival and additional 
therapies. Upon progression, patients will be treated with CNS directed therapy (such as 
WBRT, SRS, surgery) per treating physician discretion 
 
 
 
 
 
4.2 
Treatment Administration 
 
Table 3 
Treatment Administration Summary 
Agent 
Premedication 
Dose 
Route 
Schedule 
Cycle 
Length 
Supportive 
Therapies 
Palbociclib 
None 
125 
mg 
PO 
Days 1 
through 21, 
7 days off 
afterwards 
4 weeks 
(28 days) 
None 
 
 
4.2.1 
Palbociclib 
 
Palbociclib 125mg PO daily for 21 days, then 7 days off. A cycle comprises of a 
28 day period. 
 
Patients will self-administer drug. Drug should be taken with food. Patients should 
be encouraged to take their dose at approximately the same time each day. There 
are no pre-medications or supportive medications required. Palbociclib capsules 
should be swallowed whole (no chewing, crushing or opening them prior to 
swallowing). No capsule should be ingested if it is broken, cracked, or otherwise 
not intact. 
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Patient will be given a pill diary for recording their daily pill intake. This diary will 
be reviewed by the study Coordinator at every visit. Patients should bring back 
unused pills and any empty bottles at each visit. The pills will be collected by the 
coordinator and taken back to the pharmacy for a pill count 
 
4.2.2   Missed doses: 
If a patient misses a dose, it can be taken up to 12 hours prior to the next scheduled 
dose. If the patient vomits after taking the study drug, an additional dose should 
not be taken that day. The next prescribed dose should be taken at the usual time. 
Any skipped or missed doses will be reported to the study coordinator and treating 
physicians and should be recorded in the pill diary. If a patient misses any 3 doses 
(may not be consecutive) within one cycle of the treatment, the patient may be 
discontinued from the study. 
 
4.2.3 
In the HER2-positive cohort, patients may be given palbociclib as monotherapy, 
at the above mentioned dose OR continue/start on trastuzumab as standard of 
care concurrently with palbociclib 
Refer to section for 4.5 for dosing instructions for Trastuzumab. 
 
 
 
4.3 
Toxicity Management & Dose Delays/Modifications 
 
Any patient who receives at least one dose of study therapy will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity according to the 
timeframe referenced in the Schedule of Events table). Toxicity will be assessed according 
to the NCI CTCAE version 4.03. 
 
Trastuzumab dose modifications will be done per standard of care. 
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Table 5 
Toxicity 
Grade/Description 
Palbociclib 
Hematologic Toxicities 
Neutropenia 
Grade 1 or 2 
Maintain dose level. 
Grade 3 
No dose adjustment is required. 
Consider repeating complete blood count 
monitoring within one week. Withhold initiation of 
next cycle until recovery to Grade ≤2. 
[I.e. grade 3 neutropenia that corrects to grade 1/2 is 
acceptable and does not require dose reduction (unless 
febrile)] 
Grade 3 ANC + Fever 
≥38.5ºC and/or infection 
Withhold palbociclib and initiation of next cycle 
until recovery to Grade ≤2 (≥1000/mm3). 
Resume at next lower dose. 
Grade 4 
Withhold palbociclib and initiation of next cycle 
until recovery to Grade ≤2. 
Resume at next lower dose. 
Thrombocytopenia 
Grade 1 or 2 
Maintain dose level. 
Grade 3 
No dose adjustment is required. 
Consider repeating complete blood count 
monitoring within one week. Withhold initiation of 
next cycle until recovery to Grade ≤2. Dosing can 
be withheld for a maximum of 28 days 
Grade 4 
Withhold palbociclib and initiation of next cycle 
until recovery to Grade ≤2. 
Resume at next lower dose. 
Non-hematologic Toxicities 
Any 
Grade 1 or 2 
Maintain dose level. 
Grade ≥ 3 (persisting 
despite medical 
treatment) 
Withhold until symptoms resolve to(Dosing can be 
withheld for a maximum of 28 days 
• 
Grade ≤1; 
• 
Grade ≤2 (if not considered a safety risk for 
the patient) 
Resume at the next lower dose. 
Note: Dosing can be withheld for a maximum of 28 days. If dosing cannot be resumed after this period, 
the drug will be permanently discontinued. 
 
Any required dose reductions should be made according to the dose levels specified in the 
palbociclib package insert. If dose reductions are required per section 4.3, they should be made 
according to the following table: 
 
Starting Dose Level 
125 mg/per day 
Level -1 
100 mg/day 
Level -2 
75 mg/day 
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4.4 
Concomitant Medications and dietary restrictions 
 
Concomitant medications should be recorded from time of registration to the end of 
study visit. 
 
4.4.1 Prohibited concomitant medications 
 
Patients taking palbociclib should avoid the following medications: 
 
• 
CYP3A4 Inhibitors, Inducers and Substrates: See Appendix 3 for a list 
of Strong CYP3A4 Inhibitors; Strong and moderate Inducers and 
Substrates 
(Note: The palbociclib package insert recommends avoidance of strong 
CYP3A inhibitors and inducers, moderate CYP3A inducers and sensitive 
CYP3A4 substrates with narrow therapeutic indices. If strong inhibitors 
cannot be avoided, it is recommended to reduce palbociclib dose to 
75mg daily. If the strong inhibitor is discontinued, dose may be 
increased after 3-5 half-lives of the inhibitor) 
 
•            Clozapine 
 
•            Dipyrone 
 
•            Fusidic Acid 
 
•            Natalizumab 
 
•            Pimecrolimus 
 
•            Tacrolimus 
 
•            Tofacitinib 
 
Also, prohibited are: 
 
•     lapatinib, 
 
•     trastuzumab-emtansine, 
 
•     pertuzumab. 
4.4.2  Dietary restrictions/prohibited food products 
 
Palbociclib is to be taken with food. However, Grapefruit and grapefruit juice and 
products containing grape fruit should be strictly avoided. Seville oranges, blood 
oranges and starfruit should also be avoided. 
 
 
 
4.5 
Other Modalities or Procedures 
 
Patients may be concomitantly treated with trastuzumab, which is typically given at a 
loading dose of 8mg/kg IV infused over 90 minutes followed by a maintenance dose of 
6mg/kg infused over 30-90minutes every 3 weeks. Note: if continuing trastuzumab from 
previous treatment, loading dose should not be administered 
 
At progression, patients will undergo CNS directed therapy, which may include WBRT; 
SRS; or NSGY as per treating physician’s discretion. 
 
4.6 
Duration of Therapy 
 
Patients may continue to receive palbociclib until any of the following occur: 
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•     Disease progression (systemic and/or CNS progression) 
•     Development of an inter-current illness that prevents further administration of treatment 
•     Unacceptable adverse event(s) 
•     Patient decides to withdraw from either study treatment or the as a whole study 
• 
The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures) 
 
4.7 
Duration of Follow Up 
 
Patients will have the first follow up visit at 3 months (i.e. 3 months after discontinuation of 
treatment) at which time the following will be performed: 
• 
CBC with differential 
• 
Assessment of AEs/SAEs 
• 
Physical examination (full physical per SOC) 
• 
Assessment of ECOG performance status 
• 
Concomitant medication review 
 
After this, patients will be followed up at 6, 9 and 12 months, and then every 6 months to a 
maximum of 3 years to collect survival data. Patients receiving subsequent therapy will be 
followed and treatment information will be collected. 
NOTE: patients who are followed at an outside institution and do not have an oncologist at 
Northwestern or an affiliated study site may be contacted by the study personnel at these 
time points to assess vital statistics (alive/dead). 
 
 
 
4.8 
Removal of Subjects from Study Treatment and/or Study as a Whole 
 
Patients can be taken off the study treatment and/or study at any time at their own request. 
Or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation must be clearly documented on 
the appropriate eCRF and may include: 
 
•     Patient voluntarily withdraws from treatment 
•     Patient withdraws consent 
•     Patient is unable to comply with protocol requirements 
•     Patient demonstrates disease progression 
•     Patient experiences unacceptable toxicity 
• 
Treating physician determines that continuation on the study would not be in the 
patient’s best interest 
•     Patient becomes pregnant 
• 
Patient develops a second malignancy that requires treatment which would interfere 
with this study 
• 
Patient becomes lost to follow-up (LTF). This is defined as 3 attempts, made 1 week 
apart, to contact patient by preferred method of contact. 
 
4.9 
Patient Replacement 
 
If a patient is enrolled in the study but comes off study before cycle 1 day 1 of treatment, 
the patient may be replaced. 
 
 
5.0 
STUDY PROCEDURES 
 
 
 
 
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Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9* 
x 
Follow-up visits 
 
Procedure/Study 
Day 
SV 
(Screening 
period)1 
C1D12 
C1D15 
(±3D) 
C2D1 
(±3D) 
C2D15 
(±3D) 
C3D1 
(±3D) 
C4D1 
(±3D) 
C5D1 
(±3D) 
C6 
and 
up D1 
(+/- 
3D) 
Off 
treatment 
3M 
(±1Month) 
6M 
(±1month) 
9M (±1 
month) 
12M + 
q6M to 
3 yrs 
(±1 
month) 
Informed Consent 
X 
Medical History 
and eligibility 
X 
Palbociclib (21d on, 
7d off)3 
 
R 
 
 
R 
 
 
R 
 
R 
 
R 
 
R 
Trastuzumab 
(Herceptin) 
[Optional]3 
Loading dose of 8mg/kg IV infused over 90 minutes; then a 
maintenance dose of 6mg/kg infused over 30-90minutes q3 weeks. ; If 
continuing trastuzumab from previous treatment, loading dose should 
not be administered 
ECHO (For pts on 
optional Trastuzumab) 
X10 
 
 
 
 
X10 
 
 
X10 
CT chest, abdomen, 
pelvis; nuclear bone 
scan4 
X 
X 
X 
X4 
X 
MRI brain4 
X 
X 
X 
X 
Assessment of 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
x 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
x 
x 
x 
x 
Physical examination, 
weight & Height5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Pregnancy test6 
X 
Serum chemistry7 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research blood 
samples 
R 
R 
R 
Archival Tissue 
sample8 
R 
Questionnaires9 
R 
R 
R 
 
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X=Standard of Care; R=Research 
 
1 Screening period=28 days, unless otherwise specified for certain tests. 
 
2Treatment (D1) should occur within 7 days of registration.(Note; On C1D1 patients will be 
required to take an appointment with the treating physician wherein vitals will be taken and 
patient will be assessed for any AEs) 
 
3 Continue 28 day palbociclib cycle until PD or toxicity 
Patients may receive concurrent trastuzumab every 3 weeks per standard dosing.  
 
4 Repeat every 56 days. 
 
5 Every physical exam will be a full physical exam and is standard of care. Height will be 
measured only at baseline. 
 
 
6 If pre or perimenopausal: Urine test within 7 days of registration. If urine positive, to be 
followed by serum pregnancy test. 
 
7 Serum Chemistry will include calcium, chloride, creatinine, sodium, potassium, blood urea 
nitrogen, bicarbonate, glucose, total bilirubin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), albumin, and total protein. This is to be 
conducted within 14 days prior to Day1 
 
8 Genotyping of CNS and non-CNS tumors will be performed from available tissue. Genotyping 
will be performed through commercial next generation sequencing assays. 
 
9 Cognitive function will be assessed at C1D1, C3D1and C5D1, will be collected using the 
Functional Assessment of Cancer Therapy-Cognitive Function version 3.0 (FACT_Cog, ver 3.0. 
Quality of life measures will be measured by Functional Assessment of Cancer Therapy-Brain 
(FACT-Br) Version 4 Both questionnaires are to be completed before dosing. The questionnaires 
are required to be completed by the patient, under the supervision of the study coordinator 
 
10 Patients who undergo treatment with trastuzumab must have standard of care monitoring 
(SOC) with an echocardiogram every 3 months (an echocardiogram 3 months preceding the first 
dose of trastuzumab while on study will be accepted). Dose adjustments will also be done per 
SOC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.0 
ENDPOINT ASSESSMENT 
 
6.1 
Definitions 
6.1.1   Measurable Lesions 
CNS lesions must be accurately measured in at least one dimension (greatest diameter) 
with a minimum size of 5mm by MRI. Systemic lesions will be accurately measured in 
at least one dimension (greatest diameter) with a minimum size of 10mm by CT imaging. 
Bone scans will be used to assess bone metastasis. 
 
 
6.1.2   Non-measurable Lesions 
Defined as all other lesions less than 10mm. Examples of non-measurable lesions 
include leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory 
breast disease, and lymphangitic involvement of skin or lung. 
 
 
6.1.3   Response criteria 
 
The Modified RANO-BM criteria 
(NOTE: The modification is based on the grounds that RANO-BM uses a size criteria 
requiring >=10mm, whereas this study will allow a size of >=5mm (MRI will use 1.5mm 
slices or less). 
 
Table 6 
Category 
Description 
Complete Response 
(CR) 
Disappearance of all lesions. 
Partial Response(PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease(PD) 
At least a 20% increase in the sum of diameters of 
target lesions, taking  as reference the smallest sum 
on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of 
one   or   more   new   lesions   is   also   considered 
progression.) 
Stable Disease(SD) 
Neither  sufficient  shrinkage  to  qualify for  PR  nor 
sufficient increase to qualify for  PD, taking as 
reference the smallest sum of diameters while on 
study. 
 
6.2 
Primary Endpoint 
 
The primary endpoint of this study to assess the radiographic response rate in the CNS by 
modified Response Assessment in Neuro-Oncology Criteria Brain Metastasis (modified 
RANO-BM) (20)(refer Section 6.1.3). 
 
Any patient who has completed at least 2 cycles of treatment will be evaluable for this 
endpoint 
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6.3       Secondary Endpoints 
1.   Secondary endpoints include PFS and OS, where PFS is defined as the time from 
treatment initiation to documented disease progression, and OS is defined as the time 
from treatment initiation until death due to any cause. 
Any patient who has completed at least 2 cycles of treatment will be evaluable for 
this endpoint 
 
2.   Time to CNS progression will be defined as the time from treatment initiation to 
documented disease progression (modified RANO-BM criteria) in the CNS. 
Any patient who has completed at least 2 cycles of treatment will be evaluable for 
this endpoint 
 
3.   Systemic ORR (defined as PR or CR) will be assessed by Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 (23). 
Any patient who has completed at least 2 cycles of treatment will be evaluable for 
this endpoint 
 
4.   The number, frequency, and severity of adverse events (as defined by the NCI 
CTCAE version 4.03) will be recorded. 
Any patient who receives at least one dose of study therapy will be evaluable for 
toxicity endpoints 
 
6.4       Exploratory Endpoints 
 
1.   Circulating tumor DNA will be collected from whole blood at baseline, 2 and 4 months 
through commercial next generation sequencing assays. A sample of 20ml whole 
blood will be collected and processed as described in Section 9.0 
 
2.   Genotyping of CNS and non-CNS tumors will be performed from archival tissue that 
will be obtained at baseline. Genotyping will be performed through commercial next 
generation sequencing assays. 
 
3.   Patient reported outcome questionnaires: 
 
Cognitive function will be assessed at C1D1, C3D1and C5D1 and will be collected 
using the Functional assessment of Cancer Therapy-Cognitive function Version 3.0 
(Fact –Cog) (available as stand-alone document) 
 
Quality of life measures will be assessed at C1D1, C3D1, C5D1 and will be measured 
by Functional Assessment of Cancer Therapy-Brain (FACT-Br) Version 4.0 
(available as stand-alone document) 
 
The questionnaires will be completed by the patient under the supervision of the study 
coordinator 
 
. 
 
 
7.0 
ADVERSE EVENTS 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert 
H. 
Lurie 
Comprehensive 
Cancer 
Center 
of 
Northwestern 
University 
(http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay2014.pdf). The level 
of risk attributed to this study requires high level monitoring, as outlined in the DSMP. In addition, 
the study will abide by all safety reporting regulations, as set forth in the Code of Federal 
Regulations. 
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7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial (see Section 5 for time points). In addition, certain 
adverse events must be reported in an expedited manner to allow for optimal monitoring 
and patient safety and care. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be followed until: 
 
• 
the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline; 
•     any abnormal laboratory values have returned to baseline; 
•     there is a satisfactory explanation other than the study drug for the changes observed; 
or 
•     death. 
 
7.2 
Definitions & Descriptions 
 
7.2.1    Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
 
Recording of AEs should be done in a concise manner using standard, acceptable 
medical terms. In general, AEs are not procedures or measurements, but should 
reflect the reason for the procedure or the diagnosis based on the abnormal 
measurement. Preexisting conditions that worsen in severity or frequency during 
the study should also be recorded (a preexisting condition that does not worsen is 
not an AE). Further, a procedure or surgery is not an AE; rather, the event leading 
to the procedure or surgery is considered an AE. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should 
be recorded as the AE whenever possible.  However, a complete description of 
the signs, symptoms and investigations which led to the diagnosis should be 
provided. For example, if clinically significant elevations of liver function tests are 
known to be secondary to hepatitis, “hepatitis” and not “elevated liver function 
tests” should be recorded. If the cause is not known, the abnormal test or finding 
should be recorded as an AE, using appropriate medical terminology (e/g/ 
thrombocytopenia, peripheral edema, QT prolongation). 
 
7.2.2    Severity of AEs 
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 
is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
 
• 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
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• 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
• 
Fatal (grade 5): the event caused death. 
 
 
7.2.3 
Serious Adverse Events (SAEs) 
All SAEs, regardless of attribution, occurring from time of signed informed consent, 
through 30 days after the last administration of study drug, must be reported upon 
discovery or occurrence. 
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that: 
• 
Results in death. 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• 
Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe. 
• 
Requires in-patient 
hospitalization 
or 
prolongation of 
existing 
hospitalization for ≥ 24 hours. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical intervention 
to prevent one of the outcomes listed in the definition of “Serious Adverse 
Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
 
 
7.2.4 
Unanticipated Problems Involving Risks to Subject or Others 
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria: 
• 
Is unanticipated in terms of nature, severity, or frequency 
• 
Places the research subject or others at a different or greater risk of harm 
• 
Is deemed to be at least possibly related to participation in the study. 
 
7.3 
Adverse Event Reporting 
7.3.1 
Routine Reporting 
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will be 
reviewed by the Data Monitoring Committee (DMC) according to the study’s phase 
and risk level, as outlined in the DSMP 
(http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay201 
4.pdf) 
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7.3.2 
Determining if Expedited Reporting is Required 
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly. 
1)         Identify the type of adverse event using the NCI CTCAE v 4.03. 
2)         Grade the adverse event using the NCI CTCAE v 4.03. 
3)         Determine whether the adverse event is related to the protocol therapy. 
Attribution categories are as follows: 
•     Definite: AE is clearly related to the study treatment. 
•     Probable: AE is likely related to the study treatment. 
•     Possible: AE may be related to the study treatment. 
•     Unlikely: AE not likely to be related to the study treatment. 
•     Unrelated: AE is clearly NOT related to the study treatment. 
4)         Determine the prior experience of the adverse event. 
Expected  events  are  those  that  have  been  previously  identified  as 
resulting from administration of the agent. An adverse event is considered 
unexpected, for expedited reporting purposes only, when either the type 
of event or the severity of the event is not listed in: 
•     the current protocol 
•     the drug package insert 
•     the current Investigator’s Brochure 
 
7.3.3 
Expedited Reporting of SAEs/Other Events 
7.3.3.1 Reporting to the Northwestern University QAM/DMC 
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form is 
required. 
 
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include: 
•     Protocol description and number(s) 
•     The patient’s identification number 
•     A description of the event, severity, treatment, and outcome (if known) 
•     Supportive laboratory results and diagnostics 
•     The hospital discharge summary (if available/applicable) 
 
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting. 
 
7.3.3.2 Reporting to the Northwestern University IRB 
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their 
local IRB guidelines for reporting to their local IRBs. 
• 
Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the 
NU IRB within 24 hours of notification. Any death of an NU subject that 
is actively on study treatment (regardless of whether or not the event 
is possibly related to study treatment 
• 
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification. 
•     All other deaths of NU subjects not previously reported, other non-NU 
subject deaths that were unanticipated and unrelated, and any other 
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SAEs that were not previously reported as UPIRSOs will be reported 
to the NU IRB at the time of annual continuing review. 
 
7.3.3.3 Reporting to the FDA 
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life- 
threatening. 
 
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not fatal 
or life-threatening. This includes any previous SAEs that were not initially 
deemed reportable, but are later determined to meet the criteria for 
reporting (i.e. by the DMC). 
 
. 
 
7.3.3.4 Reporting to Pfizer 
All SAEs, regardless of attribution, occurring during the study or within 30 
days of the last administration of study drug must be reported to the PI 
upon discovery or occurrence, within 24 hours. Additionally, the 
investigator or qualified designee must complete the Pfizer SAE Form and 
send it electronically to Pfizer contact Manali.Talathi@pfizer.com 
 
8.0 
DRUG INFORMATION 
8.1 
Palbociclib 
8.1.1 
Other names 
Ibrance 
 
8.1.2 
Classification – cyclin-dependant kinase inhibitor 
 
8.1.3 
Mode of action 
Palbociclib is a reversible small molecule cyclin-dependent kinase (CDK) inhibitor 
which is selective for CDK 4 and 6. CDKs have a role in regulating progression 
through the cell cycle at the G1/S phase by blocking retinoblastoma (Rb) 
hyperphosphorylation. Palbociclib reduces proliferation of breast cancer cell lines 
by preventing progression from the G1 to the S cell cycle phase. 
 
8.1.4 
Storage and stability 
All investigational products should be kept in a secure and dry place. Drug is to be 
stored at 20oC to 25oC (68oF to 77oF); excursions are permitted between 15oC to 
30oC (59oF to 86oF) 
 
8.1.5 
Protocol dose specifics 
Palbociclib 125mg PO daily for 21 days, then 7 days off 
 
8.1.6 
Preparation 
No preparation is required. 
 
8.1.7 
Route of administration for this study 
Oral. It is to be taken with food, except grapefruit and grapefruit products. Seville 
orange, blood orange and star fruit should also be avoided. The capsule is be 
swallowed as whole. 
 
8.1.8 
Incompatibilities 
Please refer to Sections 4.4 
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8.1.9 
Availability & Supply 
 
Palbociclib (commercial) will be supplied by Pfizer. 
It will be supplied in bottles of 21 capsules. One bottle of 21 capsules will be 
dispensed to the patient at the beginning of each cycle. Contact for drug supply is 
Manali Talathi, email: Manali.Talathi@pfizer.com. A drug order form is available 
as stand- alone document. 
 
 
 
 
 
 
Table 7 
Package 
Configuration 
Capsule 
Strength(mg) 
Route Capsule Description 
Bottles 
of 
21 
capsules 
125 
Oral 
opaque, hard gelatin 
capsules, size 0, 
with caramel cap and 
body, printed with 
white ink “Pfizer” on the 
cap, 
“PBC 125” on the body 
Bottles 
of 
21 
capsules 
100 
Oral 
opaque, hard gelatin 
capsules, size 0, 
with caramel cap and 
body, printed with 
white ink “Pfizer” on the 
cap, 
“PBC 100” on the body 
Bottles 
of 
21 
capsules 
75 
Oral 
opaque, hard gelatin 
capsules, size 0, 
with caramel cap and 
body, printed with 
white ink “Pfizer” on the 
cap, 
“PBC 75” on the body 
 
 
8.1.10  Side effects 
 
8.1.10.1 :  Palbociclib 
 
(Note: side effects are based on studies evaluating palbociclib use in 
combination with letrozole) 
 
 
Most Likely 
 
 Central nervous system: Fatigue (41%; grade 3/4: 2%), peripheral 
neuropathy (13%) 
 
 Dermatologic: Alopecia (22%) 
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 Gastrointestinal: Nausea (25%; grade 3: 2%), stomatitis (25%), 
diarrhea (21%; grade 3: 4%), decreased appetite (16%; grade 3: 
1%), vomiting (15%) 
 
 Hematologic &  oncologic: Abnormal absolute lymphocyte count 
(81%; grade 3: 17%; grade 4: 1%; decreased lymphocytes), 
neutropenia (75%; grade 3: 48%; grade 4: 6%), leukopenia (43%; 
grade 3: 19%), anemia (35%; grade 3: 5%; grade 4: 1%), 
thrombocytopenia (17%; grade 3: 2%) 
 
 Infection: Infection (55%; grade 3/4: 5%) 
 
 Neuromuscular & skeletal: Weakness (13%; grade 3: 2%) 
 
 Respiratory: Epistaxis (11%) 
Less Likely 
  Cardiovascular: Pulmonary embolism (4% to 5%) 
 
  Respiratory: Upper respiratory tract infection (31%; grade 3: 1%) 
 
 
 
 
8.1.10.2 Palbociclib plus Trastuzumab 
 
The risks associated with this combination therapy are unknown. Trastuzumab is 
considered to be a well-tolerated drug that does not increase toxicity of companion 
therapies (see Background Section 1.1.6). Thus, HER-2 positive patients may 
concurrently receive trastuzumab as standard of care .The standard dose outlined 
in Section 4.2 and 4.5 
(Note: Drug accountability m e a s u r e s  will be done according to 
NM Investigational Pharmacy Standard Operating Procedures.) 
 
 
8.1.11  Nursing implications 
 
Patients will self-administer drug. These instructions should be clearly 
communicated to the patient. 
 
 Drug should be taken with food. 
  Patients should be encouraged to take their dose at approximately the 
same time each day. 
 There are no pre-medications or supportive medications required. 
  If the patient vomits or misses a dose, an additional dose should not be 
taken that day. The next prescribed dose should be taken at the usual 
time. 
 Patient will be given a pill diary for recording their daily pill intake. This 
diary will be reviewed by the study Coordinator at every visit. 
 Any skipped or missed doses will be reported to the study coordinator 
and treating physicians and should be recorded in the pill diary 
 Palbociclib capsules should be swallowed whole (no chewing, crushing 
or opening them prior to swallowing). No capsule should be ingested if it 
is broken, cracked, or otherwise not intact. 
 Patients  should  be  instructed  to  inform  the  PI  about  any  signs  or 
symptoms they experience which are different and/or exceeds their 
normal levels. 
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9.0 
CO 
9.1 
RELATIVES/SPECIAL STUDIES 
Sample Collection Guidelines 
Research blood samples will be collected at baseline and 2 months and 4 months from 
treatment initiation. 20 mL of whole blood should be collected in two 10mL plastic 
lavender top tubes (K2EDTA), which will be used for commercial genotyping.. All blood 
samples will be shipped at room temperature to NU PCF-CTUwithin 24hr of blood draw. 
If, for some reason, blood is not shipped within 24 hours, it may be stored at -80 degrees 
Celsius and shipped at the next possible date. Study coordinators will keep an account of 
all samples that are collected and shipped. 
A formalin fixed paraffin embedded (FFPE) tumor tissue sample or newly obtained 
formalin fixed biopsy of a tumor lesion (not previously irradiated) will be procured. This 
may be CNS or non-CNS systemic tumor tissue. At a later date (to be specified by the 
PI), these samples will be shipped by NU PCF-CTU to Foundation medicine for 
commercial genotyping. Foundation Medicine requires 40 microns of tissue for analysis. 
This can be done either as 10 slides cut at 4 microns or 8 slides cut at 5 microns. 
 
 
 Patient should be counseled to avoid grapefruit and grapefruit juice, 
Seville oranges and blood oranges, and star fruit (See section 4.4 2) 
 
 
8.1.12  Return and Retention of Study Drug 
All unused investigational products will be returned to a Pfizer-authorized depot 
or disposed of upon authorization by Pfizer according to the investigational site 
policy. 
 
8.2 
Trastuzumab (Herceptin) 
 
This is an FDA approved drug and is used as standard of care for HER2-positive breast 
cancer patients. It is a recombinant humanized monoclonal antibody directed against the 
human epidermal growth factor receptor 2 (HER2). After binding to HER2 on the tumor 
cell surface, trastuzumab induces an antibody-dependent cell-mediated cytotoxicity 
against tumor cells that overexpress HER2. HER2 is overexpressed by many 
adenocarcinomas, particularly breast adenocarcinomas. 
 
Dose: A loading dose of 8mg/kg IV infused over 90 minutes followed by a maintenance 
dose of 6mg/kg infused over 30-90minutes every 3 weeks. Note: if continuing 
trastuzumab from previous treatment, loading dose should not be administered. 
 
Trastuzumab will be given as standard of care therapy. If patient is enrolled in the study 
and prefers to take their trastuzumab doses in an institution other than the one where 
they are undertaking this study treatment (palbociclib), they would follow the same 
standard of care dosing as outlined above. 
 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any Extra blood or tissue samples will remain at Northwestern University’s Path Core for 
future research use. 
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Please refer to the laboratory manual for further details 
 
9.2 
Sample Processing, Storage, and Shipment 
Blood samples will be collected at room temperature and sent to NU PCF-CTU 
within 24 hours. 
 
 
Pathology Core-Clinical Trials Unit 
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University 
710 N. Fairbanks Ct, Olson 8-415 
Phone: 312.908.0603 
Fax: 312.503.2792 
PCF-CTU@northwestern.edu 
 
(Note: The samples will be processed and stored here until it is shipped to Guardant Health 
at a later date which is to be specified by the PI). 
 
Please refer to the laboratory manual for further details (including availability of sample 
collection kits). 
 
 
FFPE samples of available CNS and non-CNS tissue will be sent to NU PCF-CTU 
Pathology Core-Clinical Trials Unit 
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University 
710 N. Fairbanks Ct, Olson 8-415 
Phone: 312.908.0603 
CTUtissuerequests@northwestern.edu 
 
(Note: The samples will be stored here until it is shipped to Foundation Medicine at a later 
date which is to be specified by the PI). 
 
Please refer to the laboratory manual for further details. 
 
 
9.3 
Assay Methodology 
Qiagen circulating nucleic acid kit will be used for extraction of ctDNA from plasma. 
QuickExtract formalin fixed paraffin embedded (FFPE). DNA Extraction kit will be used for 
extraction of DNA from tumor FFPE samples from CNS and non-CNS samples. 
Commercially available primers (Guardant Health, Foundation Medicine) will be used to 
amplify exonic regions. Specifically, the Guardant Health assay for ctDNA will evaluate a 
68 gene panel and the Foundation Medicine assay for FFPE samples will evaluate a 315 
gene panel; both include CCND1, CCND2, CDK4, CDK6, CDKN2A. The amplification 
protocol is optimized for use on degraded products such as ctDNA and FFPE samples. 
Amplification products will then be used in modified indexed Illumina library prep protocol 
for adapter ligation in preparation for sequencing on HiSeq. Libraries will be sequenced on 
a HiSeq using a 2x150 protocol. At least 100X coverage will be obtained from 90% of 
regions sequenced to ensure potential detection of rare mutations in ctDNA and in tumor 
biopsy DNA. 
 
9.4 
Specimen Banking 
 
This is optional. 
 
As stated above, blood samples and FFPE samples of available CNS and non-CNS tissue 
will be sent to NU PCF-CTU and later to Guardant Health and Foundation medicine 
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respectively. Any extra blood or tissue samples will remain at Northwestern University’s 
Path Core for future research use. This should be clearly stated in the consent form and 
communicated to the patient. 
 
10.0 STATISTICAL CONSIDERATIONS 
 
10.1 
Study Design/Study Endpoints 
This will be a single arm phase 2 study enrolling patients with metastatic HER2-positive 
breast cancer who have asymptomatic brain metastasis.. Patients will be treated with 
125mg of PO palbociclib (21 days on, 7 days off), and MRI of the brain will monitor for 
disease progression. Upon progression patients will be treated with local CNS directed 
therapy (such as WBRT, SRS, surgery) per treating physician discretion. 
 
The primary endpoint of this study to assess the radiographic response rate in the CNS 
by modified RANO-BM criteria. 
 
Secondary endpoints include PFS and OS, where PFS is defined as the time from 
treatment initiation to documented disease progression, and OS is defined as the time from 
treatment initiation until death due to any cause. Time to CNS progression will be defined 
as the time from treatment initiation to documented disease progression in the CNS. 
Systemic ORR (defined as PR or CR) will be assessed by RECIST Version 1.1 (23). The 
number, frequency, and severity of adverse events (as defined by the NCI CTCAE version 
4.03) will be recorded. 
 
Exploratory endpoints include circulating tumor DNA will be collected from whole blood 
at baseline, 2 months, and 4 months through commercial next generation sequencing 
assays. Genotyping of CNS and non-CNS tumors will be performed from available tissue 
that will be obtained at baseline. Genotyping will be performed through commercial next 
generation sequencing assays. Cognitive function will be assessed at C1D1, C3D1, C5D1 
and will be collected using the FACT-Cog; and, quality of life with the FACT-Br. 
 
10.2 
Sample Size and Accrual 
A one sample Bayesian design for the primary endpoint of ORR will be used 
 
, It is hypothesized that the current response rate of 23% will increase to 40% by treatment 
with palbociclib. A prior beta distribution with shape parameters 0.75 and 0.50 is selected 
so that the prior probability that the response rate exceeds 23% is 80%.  A sample of 20 
HER-2 patients will be observed, and based on the number of responses out of20, the 
posterior probability that the response rate is greater than 40% will be calculated, with the 
goal that this probability be at least 80%.  If 10/20 responses are seen, there is a 83% 
chance that the true response rate exceeds 40%. 
 
Posterior probabilities may be calculated for any desired true response rate and for any 
number of observed responses. 
 
10.3 
Data Analyses Plans 
The primary analysis will be on the intent-to-treat (ITT) population, including all evaluable 
patients. Response rates will be assessed by modified RANO-BM, where lesions of 5mm 
or more will be allowed (20).  Maximum response prior to disease progression will be 
used. The response rate will be estimated by the proportion of overall response, and its 
80% confidence interval  (CI) and 95% CI will be estimated using the exact binomial 
distribution. 
 
PFS is defined as the time from treatment initiation to documented disease progression. 
OS is defined as the time from the start of treatment until death due to any cause. For 
patients alive at the time of data cut-off, PFS and OS will be censored as of the last tumor 
assessment date or known to be alive, respectively. The PFS and OS will be estimated 
using the Kaplan-Meier method. Time to CNS progression will be defined as the time 
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from treatment initiation to documented disease progression in the CNS will be evaluated 
using the Kaplan-Meier method as well. Systemic ORR (defined as PR or CR) will be 
assessed by RECIST Version 1.1, and estimated by the proportion of overall response, 
and its 80% CI and 95% CI will be estimated using the exact binomial distribution. In 
addition, Bayesian posterior probabilities will be calculated. The number, frequency, and 
severity of adverse events (as defined by the NCI CTCAE version 4.03) will be recorded. 
 
Whole blood will be used to assess ctDNA and mutational profiles. Cyclin and CDK gene 
abnormalities will used as a dichotomous variable (aberrant versus not aberrant) to 
predict clinical benefit or overall response rates using appropriate statistical summaries. 
Cox proportional hazards regression will be used to compare how these biomarkers are 
associated with PFS and OS as well. 
 
Descriptive statistics will be used to assess changes in genomic landscape using ctDNA 
at baseline, 2 and 4 months. Genomic landscapes will be described in available CNS and 
non-CNS tissue to evaluate for concordance in mutational profiles. 
 
Cognitive function and quality of life measures will be scored and summarized using 
descriptive statistics, and changes from baseline, 2 and 4 months will be described with 
nonparametric Wilcoxon rank sum tests or t tests as appropriate (20). The frequency of 
missing values at each time point will also be reported. If data on clinically meaningful 
changes on the cognitive function are available, we will also describe the changes 
according to whether the patient “improved” or “declined”. 
 
 
11.0 STUDY MANAGEMENT 
 
11.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 
 
11.2 
Amendments 
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by Pfizer. 
Amendments will be distributed by the lead institution (Northwestern) to all affiliate sites 
upon approval by the Northwestern University IRB. 
 
11.3 
Registration Procedures 
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Registering a Patient to the Phase II 
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive a subject identification number: 
• Eligibility eCRF (complete in NOTIS) 
• Eligibility checklist (signed and dated by the treating physician – upload 
in NOTIS) 
• Signed and dated informed consent document (upload in NOTIS) 
• Pathology Report (upload in NOTIS) 
 
The QAM will review the registration, register the patient, assign an identification number, 
and send a confirmation of registration to involved personnel. Registration will then be 
complete and the patient may begin study treatment. 
 
. 
 
11.4 
Data Submission 
 
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document). 
.  Generally, for all phase II patients, data are due at the end of every cycle. 
 
11.5 
Instructions for Participating Sites 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University: 
•     Signed and completed Letter of Invitation to participate in the study. 
•     Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission. 
• 
Draft informed consent form should for review/approval prior to submission to the 
local IRB 
•     A copy of the official IRB approval letter for the protocol and informed consent. 
• 
CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site. 
•     Form FDA 1572 appropriately filled out and signed with appropriate documentation. 
 
Additional activities may be required prior to site activation (i.e. contract execution, study- 
specific training). Full requirements will be outlined in a memo upon receipt of the signed 
Letter of Invitation. 
 
 
 
11.6 
Data Management and Monitoring/Auditing 
 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to Appendices for additional information). The level of risk attributed to this study 
requires high level monitoring, as outlined in the DSMP 
(http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay2014.pdf) 
 
The assigned QAM, with oversight from the Data Monitoring Committee, will monitor this 
study in accordance with the study phase and risk level. Please refer to the Appendices for 
additional data submission instructions. 
 
11.7 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well- 
being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol. 
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11.7.1  Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
 
For any such emergency modification implemented, an IRB modification form must 
be completed within 5 business days of making the change, and the QAM must be 
notified within 24 hours of such change. 
 
11.7.2  Other Protocol Deviations 
All other deviations from the protocol must be reported to the assigned QAM using 
the appropriate form. 
 
A protocol deviation is any unplanned variance from an IRB approved protocol 
that: 
•     Is generally noted or recognized after it occurs. 
•     Has no substantive effect on the risks to research participants. 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected. 
• 
Did  not  result  from  willful  or  knowing  misconduct  on  the  part  of  the 
investigator(s). 
 
A protocol deviation may be considered an instance of Reportable New Information 
(RNI) if it: 
•     Has harmed or increased the risk of harm to one or more research participants. 
•     Has damaged the scientific integrity of the data collected for the study. 
•     Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
11.8 
Investigator Obligations 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study patients. 
The PI must assure that all study site personnel, including sub-investigators and other 
study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit verification 
of proper entry of data. The study may also be subject to routine audits by the Audit 
Committee, as outlined in the DSMP. 
 
11.9 
Publication Policy 
All potential publications and/or data for potential publications (e.g. manuscripts, abstracts, 
posters, clinicaltrials.gov releases) must be approved in accordance with the policies and 
processes set forth in the Lurie Cancer Center DSMP. . For trials that require high intensity 
monitoring, the assigned QAM will prepare a preliminary data summary (to be approved 
by the DMC) no later than 3 months after the study reaches its primary completion date 
(the date that the final subject is examined or receives an intervention for the purposes of 
final data collection for the primary endpoint). If the investigator’s wish to obtain DMC- 
approved data prior to this point (or prior to the point dictated by study design), the PI must 
send a written request for data to the QAM which includes justification. If the request is 
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approved, data will be provided no later than 4 weeks after this request approval. The data 
will be presented to the DMC at their next available meeting, and a final, DMC-approved 
dataset will be released along with any DMC decisions regarding publication. The 
investigators are expected to use only DMC-approved data in future publications. The 
investigators should submit a copy of the manuscript to the biostatistician to confirm that 
the DMC-approved data are used appropriately.  Once the biostatistician gives final 
approval, the manuscript may be submitted to external publishers. 
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Tsukada Y, Fouad A, Pickren JW, et al. Central nervous system metastasis from breast 
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Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation 
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Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single 
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Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single 
metastases to the brain. N Engl J Med. 1990;322(8):494-500. doi: 10.1056/NEJM199002223220802. 
8. 
Alexander E, 3rd, Moriarty TM, Davis RB, et al. Stereotactic radiosurgery for the definitive, 
noninvasive treatment of brain metastases. Journal of the National Cancer Institute. 1995;87(1):34-40. 
9. 
Flickinger JC, Kondziolka D, Lunsford LD, et al. A multi-institutional experience with stereotactic 
radiosurgery for solitary brain metastasis. International journal of radiation oncology, biology, physics. 
1994;28(4):797-802. 
10. 
Pirzkall A, Debus J, Lohr F, et al. Radiosurgery alone or in combination with whole-brain 
radiotherapy for brain metastases. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 1998;16(11):3563-9. 
11. 
Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without 
stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the 
RTOG 9508 randomised trial. Lancet. 2004;363(9422):1665-72. doi: 10.1016/S0140-6736(04)16250-8. 
12. 
Lin NU. Breast cancer brain metastases: new directions in systemic therapy. 
Ecancermedicalscience. 2013;7:307. doi: 10.3332/ecancer.2013.307. 
13. 
Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 
0332991 and associated antitumor activity in human tumor xenografts. Molecular cancer therapeutics. 
2004;3(11):1427-38. 
14. 
Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, 
HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The 
Lancet Oncology. 2015;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. 
15. 
Michaud K, Solomon DA, Oermann E, et al. Pharmacologic inhibition of cyclin-dependent kinases 
4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer research. 
2010;70(8):3228-38. doi: 10.1158/0008-5472.CAN-09-4559. 
16. 
Barton KL, Misuraca K, Cordero F, et al. PD-0332991, a CDK4/6 inhibitor, significantly prolongs 
survival in a genetically engineered mouse model of brainstem glioma. PloS one. 2013;8(10):e77639. doi: 
10.1371/journal.pone.0077639. 
17. 
Raub TJ, Wishart GN, Kulanthaivel P, et al. Brain Exposure of Two Selective Dual CDK4 and 
CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with 
Temozolomide in an Intracranial Glioblastoma Xenograft. Drug metabolism and disposition: the biological 
fate of chemicals. 2015;43(9):1360-71. doi: 10.1124/dmd.114.062745. 
18. 
de Gooijer MC, Zhang P, Thota N, et al. P-glycoprotein and breast cancer resistance protein 
restrict the brain penetration of the CDK4/6 inhibitor palbociclib. Investigational new drugs. 2015. doi: 
10.1007/s10637-015-0266-y. 
19. 
Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal 
from the RANO group. The Lancet Oncology. 2015;16(6):e270-8. doi: 10.1016/S1470-2045(15)70057-4. 
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20. 
Reeve BB, Hays RD, Bjorner JB, et al. Psychometric evaluation and calibration of health-related 
quality of life item banks: plans for the Patient-Reported Outcomes Measurement Information System 
(PROMIS). Medical care. 2007;45(5 Suppl 1):S22-31. doi: 10.1097/01.mlr.0000250483.85507.04. 
21. 
McClendon AK, Dean JL, Rivadeneira DB, Yu JE, Reed CA, Gao E, et al. CDK4/6 inhibition 
antagonizes the cytotoxic response to anthracycline therapy. Cell cycle. 2012;11(14):2747-55. 
22. 
Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, Gonzalez-Angulo AM, et al. 
MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. The 
Journal of experimental medicine. 2012;209(4):679-96.   
23.. Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, et al. Multiple roles of cyclin- 
dependent kinase 4/6 inhibitors in cancer therapy. Journal of the National Cancer Institute. 
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24.. Vidula N, Rugo HS. Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer: A 
Review of Preclinical and Clinical Data. Clinical breast cancer. 2015. 
25. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy 
plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl 
J Med. 2001;344(11):783-92. 
26. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond 
progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german 
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American Society of Clinical Oncology. 2009;27(12):1999-2006. 
27. Powell C, Guerrero D, Sardell S, Cumins S, Wharram B, Traish D, et al. Somnolence syndrome in 
patients receiving radical radiotherapy for primary brain tumours: a prospective study. Radiotherapy and 
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28. Chin LS, Lazio BE, Biggins T, Amin P. Acute complications following gamma knife radiosurgery are 
rare. Surgical neurology. 2000;53(5):498-502; discussion 
29. Werner-Wasik M, Rudoler S, Preston PE, Hauck WW, Downes BM, Leeper D, et al. Immediate side 
effects of stereotactic radiotherapy and radiosurgery. International journal of radiation oncology, biology, 
physics. 1999;43(2):299-304. 
30 . Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients 
with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a 
randomised controlled trial. The Lancet Oncology. 2009;10(11):1037-44. 
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12.0 APPENDICES 
 
 
APPENDIX 1 
 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100%  bedridden. Completely disabled. Cannot carry on  any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
APPENDIX 2 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
• 
Male condom plus 
spermicide 
• 
Cap plus 
spermicide 
• 
Diaphragm plus 
spermicide 
• 
Copper T 
• 
Progesterone T 
• 
Levonorgestrel-relasing 
• 
Implants 
• 
Hormone shot or 
injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 
NOTE: choice of contraception should be discussed with primary treating oncologist to discuss 
the  risks and benefits of different modalities of contraception. Abstinence is not an acceptable 
method 
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Appendix 3 
 
Strong CYP3A4 
Inhibitors* 
Strong CYP3A4 
Inducers* 
CYP3A4 Substrates* 
Indinavir 
Ritonavir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Conivaptan 
Boceprevir 
Lopinavir 
mibefradil 
Nelfinavir 
Posaconazole 
Saquinavir 
Telaprevir 
Telithromycin 
Voriconazole 
Grapefruit juice 
Rifampin 
Carbamazepine 
Phenytoin 
St. John’s Wort 
Aprepitant 
Budesonide 
Conivaptan 
Darifenacin 
Darunavir 
Dasatinib 
Eletriptan 
Eplerenone 
Everolimus 
Fluticasone 
Midazolam 
Triazolam 
Diazepam 
Alprazolam 
Lovastatin 
Simvastatin 
Atorvastatin 
Felodipine 
Buspirone 
Sildenafil 
Tadalafil 
Tacrolimus 
Cyclosporine 
Sirolimus 
Clarithromycin 
Erythromycin 
Trazodone 
Haloperidol 
Imatinib 
Carbamazepine 
Vincristine 
Tamoxifen 
Tolvaptan 
Moderate CYP3A4 
Inducers* 
Bosentan 
Efavirenz 
Etravirine 
Modafinil 
Nafcillin 
*This list is not all inclusive. for more information, please refer to 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc 
es/DrugInteractionsLabeling/ucm093664.htm 
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13.0 HISTORY OF AMENDMENT SUMMARY OF CHANGES 
Amendment 1 –May 20, 2016 
Sections(s) 
Affected 
Prior Version 
Amendment 1 
Changes 
Rationale 
Title page 
Included email 
addresses and 
department for each 
northwestern physician 
Removed email addresses and 
department for all 
northwestern university Sub- 
Investigator 
Added :  Valerie nelson, MD as 
Sub-Investigator from 
Northwestern 
Lake 
Forest 
Hospital 
To accommodate 
all content on one 
page. All email 
addresses are 
available in the 
northwestern 
outlook system 
Study Schema 
No previous WBRT 
Any WBRT must have 
occurred >6 months ago 
Per PI, to be 
consistent with 
change in 
inclusion criteria 
3.1.8 
Study 
summary 
and 
Inclusion 
criteria 3.1.5 
ECOG ≥2 
ECOG≤2 
Error 
correction 
Inclusion 
criteria 3.1.1 
Histologically 
confirmed triple 
negative or HER2- 
positive metastatic 
breast cancer 
(estrogen and 
progesterone receptor 
0%, HER-2 3+ by 
immunohistochemistry. 
If IHC score of 2, FISH 
ratio must be greater 
than 2.0. If FISH less 
than 2.0, HER2 copy 
number must be 
greater than 6. NOTE: 
Brain lesions are not 
required to have 
pathologic 
confirmation. 
Added note: HER2-positive 
patients should also be ER- 
negative) 
For 
clarification 
Inclusion 
3.1.2 
Patients should not 
have received >2 lines 
of chemotherapy for 
metastatic disease 
This criteria was removed 
Per PI 
Inclusion 
criteria 3.1.8 
Patients 
who 
underwent 
neurosurgery (NSGY), 
or 
stereotactic 
radiosurgery (SRS) to 
a   brain   lesion   must 
Added : Whole brain radiation 
therapy (WBRT) as well. Any 
WBRT must have occurred>6 
months ago. 
Per PI 
And QA 
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have          a          new 
measureable 
lesion. 
NOTE: SRS may be 
done  to  a  lesion that 
will not be used for 
response 
evaluation 
and should be done > 2 
weeks  prior  .Any 
NSGY procedure must 
have  been  completed 
>3 
weeks 
prior 
to 
registration. 
Any NSGY procedure 
must 
have 
been 
completed >3 weeks 
prior to registration 
Previously surgically excised 
lesion/tumor bed, may be used 
as a measurable lesion if 
disease has progressed since 
surgery 
Also, added 
Any NSGY procedure must 
have been completed >3 
weeks prior to registration and 
baseline imaging. 
Section 4.3 
Toxicity 
Management & 
Dose 
Delays/Modifications 
Table 5 has dose 
modifications for 
Palbociclib wit mention 
of dose reduction. 
A table for dose reduction is 
added just below Table 5 
describing the 2 levels of dose 
reduction(100mg and 75mg) 
that are allowed 
For clarity. 
(A clarification 
memo was earlier 
sent out for this). 
Section 5.0 
Study procedures 
In column 9* 
Dn+28(+/-3D) 
Replaced with 
C6 and up D1(+/-28days) 
Added an ‘X to Column 9 visit 
,to indicate that CT chest of 
abdomen, pelvis,nuclear bone 
scan is to be done every 56 
days 
For clarity 
Section 5.0 
Study 
procedures 
ECOG performance 
status was not 
indicated in C1D1 
ECOG performance status 
was included in C1D1 
Correction 
of error 
Section 5.0 
Study 
procedures 
Footnote 2 
Footnote indicated: 
treatment (D1) should 
occur within 7 days of 
registration. 
.Added: 
(Note; On C1D1 patients will 
be required to take an 
appointment with the treating 
physician wherein vitals will be 
taken and patient will be 
assessed for any AEs) 
For clarity 
Section 9.0 
Correlatives 
Blood samples were to 
be shipped to 
Guardant Health. 
Tissue samples were 
to be shipped to 
foundation medicine 
Blood and tissue samples are 
to be shipped to Northwestern 
university Pathology Core – 
Clinical trial Unit (NU PCF- 
CTU).The samples will be 
stored here till the PI indicates 
that they can be shipped to 
Due to logistical 
and sub-contract 
issues. 
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Guardant health and 
Foundation Medicine. 
Language has been included 
in the protocol with correct 
address for PCF-CTU along 
with reference to laboratory 
manual for detailed 
information. 
Amendment 2–August 2, 2016 
Sections(s) 
Affected 
Prior Version 
Amendment 2 
Changes 
Rationale 
Study Schema 
Section 3.1.7 
Any WBRT must have 
occurred >6 months 
ago 
Any WBRT must have 
occurred >60 days ago 
Per PI 
In order to improve 
accrual 
Section 3.1.1 
Inclusion 
criteria 
Histologically 
confirmed triple 
negative or HER2- 
positive metastatic 
breast cancer 
(estrogen and 
progesterone receptor 
0%, HER-2 3+ by 
immunohistochemistry. 
If IHC score of 2, FISH 
ratio must be greater 
than 2.0. If FISH less 
than 2.0, HER2 copy 
number must be 
greater than 6. NOTE: 
Brain lesions are not 
required to have 
pathologic 
confirmation. (Note; 
HER2-positive 
patients should also 
be ER-negative) 
Removed ; 
HER2-positive patients 
should also be ER-negative. 
Per PI 
In order to allow 
for ER+ disease. 
The goal is to 
improve accrual 
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Amendment 3–January 11, 2017 
Sections(s) Affected 
Prior Version 
Amendment 3 Changes 
Rationale 
Protocol cover page 
Affiliate site :TBD 
Houston Methodist 
Hospital/Houston Methodist 
Cancer Center added as 
Affiliate site. 
PI: Jenny Chang, MD 
Contact information added 
Houston Methodist 
Hospital came on 
board as Affiliate site. 
Throughout 
Single center 
Changed to Multi-center 
Addition of affiliate 
site 
Section 3.0 
Patient eligibility 
Northwestern 
University RHLCCC as 
single center 
Stated that patients 
should be referred to 
lead PI Dr.Santa-Maria 
Northwestern University as 
lead site and Coordinating 
center. Houston Methodist 
Hopsital as affiliate site. 
Added language that 
patients may be referred to 
the local PI at each 
participating site as well. 
Houston Methodist 
Hospital came on 
board as Affiliate site. 
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Amendment 4–January 30, 2017 
Sections(s) Affected 
Prior Version 
Amendment 4 Changes 
Rationale 
Throughout 
Triple negative breast 
cancer patients 
Removed: language 
referring to Triple negative 
breast cancer patients 
Removal of Triple 
Negative breast 
cancer cohort from 
the study. PI wants a 
more homogenous 
population with just 
HER2-positive.No 
TNBC enrolled so far 
in the study. 
Study  schema 
Cohort A(TNBC) and 
B Cohort B(Her-2 
positive ) with details 
Removed Cohort language. 
Only Her2-positive patients 
and related details. 
To be in alignment 
with removal of TNBC 
patients from the 
study. 
Study schema and 
summary 
single-center 
Updated to Multi-center. 
This was previously omitted 
in error 
Affiliate site was 
added in the previous 
amendment. 
Study summary 
Sample size: 
Maximum accrual 33 
patients and 
Evaluable patients: 30 
(15 each for TNBC 
and HER2 positive) 
Key Inclusion criteria: 
Trastuzumab allowed 
for Her2-positive 
patients 
Maximum accrual 25 
patients and 
Evaluable patients: 20 
(Her-2 positive) 
Key Inclusion criteria: 
Modified to : Trastuzumab 
allowed for Her2-positive 
patients. 
Statistical details updated 
to align with the current 
change in sample size and 
In order to align with 
the current change in 
patient population to 
include only HER2- 
positive patients in 
the study. 
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Statistical details 
tailored to the previous 
sample size and 2 
cohorts. A Bayesian 
probability was to be 
calculated after the 
response status in 15 
patients has been 
assessed. 
patient population. A 
Bayesian probability will 
now be calculated after the 
response status in 20 
patients has been 
assessed. 
Section 2.0 
Primary and 
secondary objectives 
had TNBC patients 
Removed all language 
referring to TNBC patients. 
For consistency. 
In order to align with 
the current change in 
patient population to 
include only HER2- 
positive patients in 
the study. 
Section 3.0 
Patient eligibility 
Language referring to 
TNBC patients 
Removed all language 
referring to TNBC patients 
Modified language: sample 
size numbers upadted. 
Added langauge: “ once all 
sites are up and running” 
For consistency and 
to align with current 
upadtes to the 
protocol. 
Section 3.1.1 
Inclusion criteria 
TNBC language 
Removed all language 
referring to TNBC patients 
Added: ER-positive patients 
are allowed. Removed 
other contradictotory 
language 
For clarity and 
consistency 
Section 3.1.8 
Inclusion criteria 
Patients must not have 
received systemic 
therapy within 2 weeks 
of initiating palbociclib. 
It also had a note 
stating that Her2- 
positive patients can 
remain 
onTrastuzumab . 
This part of the note has 
been modified to state that : 
“Patients on trastuzumab 
can remain on the drug if 
previously taking, or may 
start if not. No break or 
washout period required. 
Patients with ER-positive 
disease may not 
concurrently take endocrine 
therapy, however, no 
washout is required if they 
were previously on 
endocrine therapy.” 
For clarity and 
consistency 
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Section 4.1 
Treatment plan 
overview 
TNBC language and 
statement that HER2- 
positive patients can 
take trastuzumb. 
Removed all language 
referring to TNBC patients 
and restated that patients 
are permitted to take 
Trastuzumab(meaning 
HER2 patients), since they 
are the only patients to be 
currently enrolled in the 
study. 
For clarity and 
consistency 
Section 10.2 
Statistics sample 
size and accrual 
Previous statistical 
details 
Statistical details updated 
to tailor to the new cohort of 
HER-2 positive 
patients(alone) that will be 
enrolled in the study. 
Briefly, it states that: 
“A prior beta distribution with 
shape parameters 0.75 and 
0.50 is selected so that the 
prior probability that the 
response rate exceeds 23% 
is  80%.    A  sample  of  20 
HER-2 
patients 
will 
be 
observed, and based on the 
number of responses out 
of20, the posterior probability 
that the response rate is 
greater than 40% will be 
calculated, with the goal 
that  this  probability  be  at 
least 80%.     If 10/20 
responses are seen, there is 
a 83% chance that the true 
response    rate     exceeds 
40%.” 
In order to align with 
the current change in 
patient population to 
include only HER2- 
positive patients in 
the study. 
Amendment 5–August 15, 2017 
Sections(s) Affected 
Prior Version 
Amendment 4 Changes 
Rationale 
Title page 
 
and Section 3.0 
 
Cesar Santa-Maria, 
MD  as PI 
Removed Dr.Santa-Maria 
and added  
Massimo Cristofanili, MD 
as PI with all required 
contact information 
Dr.Santa-Maria is 
leaving Northwestern 
University and is 
handing over the study 
to Dr.Cristofanilli 
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Section 3.0  
 
Patient eligibility 
TNBC also listed as 
target population 
Removed TNBC 
Correction of error. 
TNBC was removed 
from this protocol in 
an earlier amendment. 
Section 3.2.3 
Exclusion criteria 
Patients with 
leptomeningeal disease 
are not eligible for 
participation 
Added a note to state that : 
“leptomeningeal 
enhancement is not an 
exclusion.” 
 
For increased clarity 
Section 1 
Introduction 
and 
Background/ 
Rationale  
and Reference 
section 
List of references, 
including ones for TNBC 
Removed all references 
pertaining to TNBC.  
Re-numbered other 
references accordingly. 
TNBC was removed 
from this protocol in 
an earlier amendment 
 
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