Conditions: Breast Cancer
Keywords: Postmenopausal ER-positive, PR-positive, HER2-negative Low and intermediate risk
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
The purpose of this study is to see whether adding everolimus to hormone treatment before breast surgery will increase the chances of shrinking the breast cancer in those patients with hormone-responsive breast cancer and a lower Oncotype DX® Recurrence Score ( 25 or less), compared to prior experience with hormone therapy alone. Everolimus is a drug currently approved for use by the United States Food and Drug administration (FDA) for the treatment of patients with advanced or metastatic kidney or breast cancer. Everolimus is considered investigational for non-metastatic breast cancer patients.

Detailed description:
This is a single arm open-labeled neoadjuvant phase II clinical trial evaluating everolimus in combination with an aromatase inhibitor in postmenopausal women with hormone receptor positive/HER2 negative breast cancers with low and intermediate risk (\< 25) Recurrence Scores by Oncotype Dx.

Arms:
arm 1: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks

Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily:

* Anastrozole 1 mg
* Letrozole 2.5 mg
* Exemestane 25 mg

Protocol document:
Prot_SAP_000.pdf: 
NCT02236572
Neoadj ph 2 AI Plus Everolimus in Postmenopausal Women w/ ER Pos/HER2 Neg, Low Risk 
Score
Protocol and SAP
Last Approved: 9/16/2016


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A neoadjuvant phase II trial of aromatase inhibitors in 
combination with everolimus in postmenopausal women with 
hormone receptor positive/HER2 negative breast cancers with low 
and intermediate risk (< 25) Oncotype Dx Recurrence Scores 
CRAD001JUS228T 
Study Principal Investigator: 
Maysa M. Abu-Khalaf, M.D. 
Associate Professor of Medicine 
Section of Medical Oncology 
Sidney Kimmel Cancer Center 
Thomas Jefferson University 
Email: maysa.abu-khalaf@jefferson.edu 


 
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Title of Trial: 
A phase II clinical trial evaluating neoadjuvant endocrine therapy with everolimus in 
postmenopausal women with hormone receptor positive/HER 2negative breast 
cancers with low and intermediate risk (<25) Oncotype Dx Recurrence Scores 
 Protocol 
Number: 
CRAD001JUS228T 
Sponsor: 
Thomas Jefferson University 
Trial Duration: 
24 months 
Phase of Trial:  II 
Trial Centers: 
Thomas Jefferson University: Sidney Kimmel Cancer Cener 
Yale University: Smilow Cancer Hospital-Main Campus, Smilow Hospital Care 
Centers 
Patient 
Population 
This study will enroll postmenopausal women with hormone receptor positive/HER-
2 negative Stage II-III breast cancer with low to intermediate risk (< 25) Oncotype 
Dx Recurrence Scores, who have not had surgical resection of their breast cancer. 
Objectives: 
Primary objectives 
• 
The primary objective of the study is to determine  the percent of  
postmenopausal patients with stage II-III hormone receptor positive/ HER2 negative 
breast cancers and an Oncotype Dx  recurrence score  < 25, who achieve a PEPI 
score of 0 following neoadjuvant  treatment with everolimus and an aromatase 
inhibitor  
 
Secondary objectives 
1) 
To assess the tolerability and side effect profile of neoadjuvant aromatase 
inhibitor therapy and everolimus  
2) 
To identify biologic markers predictive of clinical and pathologic response 
(pathologic complete response or PEPI 0) to neoadjuvant aromatase inhibitor 
therapy and everolimus in postmenopausal hormone receptor positive/HER2 
negative breast cancer patients selected by Oncotype Dx Recurrence Score < 25, on 
tissue biopsies obtained at baseline and at end of treatment   
Number of 
Patients: 
Up to 33 patients will be enrolled on the clinical trial.  
Trial Design: 
This is an open label, non-randomized phase II clinical trial evaluating the efficacy 
and safety of neoadjuvant endocrine therapy with everolimus in postmenopausal 
women with hormone receptor positive/HER2 negative breast cancers with low and 
intermediate risk (< 25) Oncotype Dx Recurrence Scores 
 
Trial Drug(s), 
Dose, and Mode 
of 
Administration 
Eligible patients will receive daily aromatase inhibitor therapy (anastrozole 1 mg, or 
letrozole 2.5 mg or exemestane 25 mg) in combination with everolimus 10 mg daily. 
Both study agents will be administered orally for a total of 26 weeks.  


 
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Inclusion 
Criteria: 
1. Patients must have a histologically confirmed diagnosis of hormone receptor 
positive, HER2 negative invasive breast carcinoma. 
2. Tumors must be estrogen and/or progesterone receptor positive according to 
ASCO/CAP 2010 guidelines as either ER or PR ≥ 1% positive nuclear 
staining by immunohistochemistry. Estrogen and/or progesterone 
receptor results by Oncotype Dx will not be accepted.  
3. Tumors must be HER2 negative as defined according to ASCO/CAP 2013, 
as HER2 0 – 1+ by IHC or non-amplified FISH or CISH. If HER2 IHC 
is 2+, FISH/CISH must be performed and must not be positive (must be 
a ratio of < 2), but otherwise FISH/CISH is not required if IHC is 0 or 1+ 
by institutional standards.  
4. Patients must not have had prior ipsilateral breast-conserving surgery or total 
mastectomy and be eligible for neoadjuvant treatment.  
5. Clinical Stage II-IIIC (T2-4 N0-3 M0)  by mammogram, ultrasound or MRI 
6. Baseline Oncotpye Dx recurrence score  < 25.  
7. Staging studies with a CT scan of the chest and abdomen and bone scan, or a 
PET/CT  is required for clinical stage III, and are considered optional for 
stage II breast cancers.  
8. Patients with multifocal, multicentric and synchronous bilateral breast 
cancers are allowed: 
• 
Multifocal disease is defined as more than one invasive cancer < 2 
cm from the largest lesion within the same breast quadrant. 
• 
Multicentric disease is defined as more than one invasive cancer ≥ 2 
cm from the largest lesion within the same breast quadrant or more 
than one lesion in different quadrants. 
• 
Synchronous bilateral disease is defined as invasive breast cancer in 
both breasts, diagnosed within 30 days of each other. 
• 
In patients with multicentric or bilateral invasive breast cancers, all 
sampled lesions must be hormone receptor-positive and HER2-
negative. Any lesion measuring > 1 cm must have an Oncotype Dx  
and the score must be < 25. Lesions less than 1 cm in size are not 
required to have an Oncotype Dx. One lesion (typically the largest) 
should be designated as the target lesion for which clinical and 
radiographic response to the neoadjuvant therapy will be judged.  
• 
Patients with a hormone receptor-positive, HER2-negative invasive 
cancer that meets study criteria may have ductal carcinoma in situ in 
another quadrant of the same breast or in the contralateral breast even 
if the DCIS is hormone receptor-negative.    
9. Patients must have adequate bone marrow function, as defined by peripheral 
granulocyte count of ≥ 1,500/mL, hemoglobin ≥ 9 g/dL and a platelet 
count ≥ 100,000/ mL within 28 days prior to registration.  
10. Patients must have adequate hepatic function obtained within 28 days prior 
to registration and documented by all of the following: 
• 
Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert's Syndrome) 
• 
ALT and AST ≤ 1.5 x Institutional Upper Limit of Normal (IULN) 


 
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• 
Alkaline phosphatase ≤ 1.5 x IULN 
11. Patients must have adequate renal function with serum creatinine level ≤ 
IULN within 28 days prior to registration.  
12. Patients must have a fasting cholesterol ≤ 300 mg/dl OR ≤7.75 mmol/L and 
triglycerides ≤ 2.5 x IULN obtained within 28 days prior to registration. 
Patients may be on lipid lowering agents to reach these values. 
13. Patients must have a ECOG performance status of 0-2. 
14. Patients must be able to take oral medications. 
15. Postmenopausal women (women are considered post-menopausal and not of 
child-bearing potential if they are > 18 years of age and have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms or 
biochemically postmenopausal by estradiol and FSH levels) prior to 
enrollment, or have had surgical bilateral oophorectomy (with or without 
hysterectomy) prior to registration. Medical ovarian suppression with 
LHRH agonists to render a patient postmenopausal will not be 
acceptable.  
16. Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written 
informed consent prior to any screening procedures in accordance with 
institutional and federal guidelines. 
Exclusion 
Criteria: 
1. Patients must not have inflammatory breast cancer (T4d) and must not have 
metastatic breast cancer (Stage IV disease). 
2. Patients must not have prior exposure to mTOR inhibitors (e.g. rapamycin, 
everolimus, sirolimus, temsirolimus, deforolimus).  
3. Patients must not have prior treatment with any investigational drug within 
the preceding 28 days and must not be planning to receive any other 
investigational drug for the duration of the study. 
4. Patient may not have any impairment of gastrointestinal function or 
gastrointestinal disease that may significantly alter the absorption of the 
drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome or small bowel resection). 
5. Uncontrolled diabetes mellitus as defined by HbA1c >8% within 28 days 
prior to registration despite adequate therapy.  
6. Patients who have any severe and/or uncontrolled cardiac disease within ≤ 6 
months prior to start of everolimus, including:  unstable angina pectoris, 
Symptomatic congestive heart failure of New York heart Association 
Class III or IV, myocardial infarction, serious uncontrolled cardiac 
arrhythmia, or any other clinically significant cardiac disease 
7. Patients must not have an organ allograft or other history of immune 
compromise.  
8. Patients must not be receiving chronic, systemic treatment with 
corticosteroids or other immunosuppressive agent. Topical or inhaled 
corticosteroids are allowed. 
9. Patients must not have a known history of HIV seropositivity 


 
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10. Patients must not have a known diagnosis of  hepatitis B or C. Patients with 
the following risk factors must  have hepatitis screening pre-treatment: 
• 
Blood transfusions prior to 1990 
• 
Current or prior IV drug users 
• 
Current or prior dialysis 
• 
Household contact with a hepatitis B or C patient 
• 
Current or prior high-risk sexual activity  
• 
History of jaundice. 
11. Patients must not have any known uncontrolled underlying pulmonary 
disease or  severely impaired lung function (spirometry and DLCO 50% 
or less of normal and O2 saturation 88% or less at rest on room air), 
12. Active (acute or chronic) or uncontrolled severe infection.  
13. Patients who have received live attenuated vaccines within 1 week of start of 
Everolimus, or have plans to receive such vaccination while on protocol 
treatment. Patient should also avoid close contact with others who have 
received live attenuated vaccines. Examples of live attenuated vaccines 
include intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella and TY21a typhoid vaccines; 
14. , Patients who are currently part of or have participated in any clinical 
investigation with an investigational drug within 1 month prior to dosing; 
15. Patients must not have taken within 14 days prior to registration , be taking, 
nor plan to take while on protocol treatment, strong CYP3A4 inhibitors, 
and/or CYP3A4 inducers.   
16.  Patients with active bleeding diathysis. 
Statistical 
Methodology: 
This is  a single arm phase II study to evaluate neoadjuvant endocrine therapy with 
everolimus in postmenopausal women with hormone receptor positive/HER2 
negative breast cancers with low and intermediate risk ( < 25) Oncotype Dx 
recurrence score. The primary endpoint is response defined as a PEPI-0 rate. A 
treatment with minimal activity would be expected to have PEPI-0 rate of 25%. 
Alternatively, a treatment will be considered worthy of further study if its true PEPI-
0 rate is 45% or better. Simon’s optimal two-stage design is employed for this 
single-arm phase II trial. The sample size is 27. Assuming 10-20% ineligibility rate, 
we plan to enroll up to 33 patients totally. 


 
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Table of contents 
Table of contents ................................................................................................................. 6 
SIGNATURE PAGE FOR PRINCIPAL INVESTIGATOR .............................................. 9 
1.0 
Background ............................................................................................................ 10 
1.1 
Neoadjuvant therapy for hormone receptor positive breast cancer ....................... 10 
1.2 
PI3kinase/AKT/mTOR signaling pathway in hormone receptor positive 
breast tumors. ......................................................................................................... 11 
1.3 
Everolimus ............................................................................................................. 12 
1.3.2 
Non-clinical experience ........................................................................ 14 
2.0 RATIONALE .................................................................................................................... 15 
3.0 STUDY OBJECTIVES ..................................................................................................... 17 
4.0 TRIAL PATIENT POPULATION AND ELIGIBILITY ................................................. 17 
4.1 
Inclusion criteria .................................................................................................... 17 
4.2 
Exclusion criteria ................................................................................................... 19 
5.0 STUDY DESIGN .............................................................................................................. 20 
5.1 
Pre-registration ...................................................................................................... 20 
5.2 
Patient registration ................................................................................................. 21 
6.0 STUDY TREATMENT ..................................................................................................... 21 
6.1 
Study drugs: ........................................................................................................... 21 
6.1.1 
Everolimus (Afinitor®) ......................................................................... 21 
6.1.2 
Anastrazole ............................................................................................ 26 
6.1.2 
Exemestane ........................................................................................... 29 
7.0 DOSE MODIFICATION .................................................................................................. 34 
7.1 
Dose modifications and delays for aromatase inhibitors ....................................... 35 
7.2 
Dose modifications  and delays for everolimus ..................................................... 35 
7.3 
Management of specific toxicities related to everolimus ...................................... 37 
7.3.1 
Management of infections ..................................................................... 38 
7.3.2 
Management of skin toxicity ................................................................. 38 
7.3.5   Management of stomatitis / oral mucositis / mouth ulcers ......................... 39 
7.3.6 Management of nausea ................................................................................. 40 
7.3.8 Management of hyperlipidemia and hyperglycemia .................................... 40 
7.3.4 
Management of non-infectious pneumonitis ......................................... 41 
Management of hepatitis reactivation / flare ......................................................... 42 
8     CONCOMITANT MEDICATIONS ................................................................................. 44 
8.1  
Prohibited concomitant medications ...................................................................... 44 
8.1.1 
Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates .. 45 


 
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9    VISIT SCHEDULE AND ASSESSMENTS ...................................................................... 47 
10 STUDY CALENDAR ....................................................................................................... 52 
11 Evaluation of Safety .......................................................................................................... 56 
11.1.1 
Unanticipated Problems ........................................................................ 56 
11.1.2 
Adverse Event ....................................................................................... 56 
11.1.3 
Laboratory test abnormalities ................................................................ 56 
11.1.4 
Serious Adverse Events ......................................................................... 57 
11.2 
Safety Assessment and Follow-Up ........................................................................ 57 
11.3 
Recording Adverse Events .................................................................................... 57 
11.3.1 
Relationship to Study Intevention ......................................................... 58 
11.3.2 
Expectedness ......................................................................................... 58 
11.3.3 
Severity of Event ................................................................................... 58 
11.3.4 
Intervention ........................................................................................... 58 
11.4 
Safety Reporting .................................................................................................... 59 
11.4.1 
Reporting to IRB ................................................................................... 59 
11.4.2 
Reporting to SKCC DSMC ................................................................... 60 
11.4.3 
Reporting to Drug Supplier ................................................................... 60 
11.1 
Reporting for Subsites ........................................................................................... 61 
11.2 
Coordinating Site ................................................................................................... 62 
12 Study Oversight ................................................................................................................. 62 
13 Clinical Site Monitoring and Auditing .............................................................................. 62 
14 STATISTICAL CONSIDERATION ................................................................................ 63 
14.1 
Primary Endpoint ................................................................................................... 63 
14.2 
Secondary Endpoint ............................................................................................... 63 
14.3 
Sample Size calculation ......................................................................................... 64 
15 Source Documents and Access to Source Data/Documents .............................................. 65 
16 Ethics/Protection of Human Participants ........................................................................... 65 
16.1 
Ethical Standard ..................................................................................................... 65 
16.2 
Institutional Review Board .................................................................................... 65 
16.3 
Informed Consent Process ..................................................................................... 65 
16.4 
Participant Confidentiality ..................................................................................... 66 
17 Data Handling and Record Keeping .................................................................................. 66 
17.1 
Data Management Responsibilities ....................................................................... 66 
17.2 
Study Records Retention ....................................................................................... 66 
17.3 
Protocol Deviations ............................................................................................... 67 
18 Study Finances ................................................................................................................... 67 


 
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18.1 
Funding Source ...................................................................................................... 67 
18.2 
Conflict of Interest ................................................................................................. 67 
18.3 
Participant Stipends or Payments .......................................................................... 67 
19 Publication and Data Sharing Policy ................................................................................. 67 
20 REFERENCES .................................................................................................................. 68 
1.  Definitions .................................................................................................................... 73 
i. 
Guidelines for Evaluation of Measurable Disease ................................ 75 
ii. 
Response Criteria .................................................................................. 76 
 
Appendix A:  RECIST 
Appendix B: PEPI 
Appendix C: SKCC DSMP Reporting  
Appendix D: Off-Site OHR-10 
Appendix E: AE log 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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SIGNATURE PAGE FOR PRINCIPAL INVESTIGATOR 
Title: A phase II clinical trial evaluating neoadjuvant endocrine therapy with everolimus in 
postmenopausal women with ER+/HER2- breast cancers with low and intermediate risk (< 
25) Oncotype Dx Recurrence Scores 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of 
the protocol and in accordance with Good Clinical Practices (GCP) as well as applicable legal 
and regulatory requirements.  I will make all reasonable efforts to complete the study within 
the designated time.   
 
I will provide copies of the protocol and access to all necessary information to study personnel 
under my supervision.  I will discuss this material with them to ensure that they are fully 
informed about the drug and the study.   
 
I understand that the study may be terminated or enrollment suspended at any time by the 
Principal Investigator with or without cause, or by me if it becomes necessary to protect the 
best interests of the study subjects. 
  
 
 
_______________________             ____________________                                        
 
                                                                
 
 
 
 
 
Principal Investigator  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1.0 
Background 
1.1 
Neoadjuvant therapy for hormone receptor positive breast cancer 
 
 
 
 
Endocrine therapy is the cornerstone of treatment for patients with hormone-receptor 
(HR)–positive breast cancer. The presence of hormone receptors, especially estrogen receptor 
(ER), is a clear positive predictor of efficacy of adjuvant hormone therapy (HT) [1] [2]. 
Chemotherapy is less effective in the genomically and immunohistochemically defined 
(ER+/HER2−) luminal subtype when compared with the HER2-enriched and basal-like 
subtypes[3, 4].  Oncotype DX, developed by Genomic Health, is a diagnostic test that 
quantifies the likelihood of disease recurrence in women with early-stage hormone receptor 
positive breast cancer and assesses the likely benefit from certain types of chemotherapy. A 
prospective analysis of archived tissue from 367 postmenopausal, hormone receptor–positive, 
node-positive patients with invasive breast cancer treated on Southwest Oncology Group 
(SWOG) 8814 with tamoxifen or tamoxifen plus chemotherapy, suggests that only the subset 
of patients with intrinsically more biologically aggressive cancers, as defined by a high 
Oncotype Dx Recurrence Score (RS), appears to benefit from the addition of chemotherapy, 
whereas patients with low-intermediate RS may not have a significant benefit from 
chemotherapy. Further analysis incorporating determination of recurrence score by RT-PCR 
showed that after adjusting for number of lymph nodes involved, patients with high 
recurrence score had worse outcomes [5]. Patients treated with chemotherapy followed by 
tamoxifen had a 10-year disease free survival (DFS) of 55% and a 10-year overall survival 
(OS) of 68% [6]. An ongoing large randomized phase III clinical trial (SWOG  1007) is 
designed to evaluate the benefit from chemotherapy for  ER positive breast cancer with 1-3 
positive lymph nodes and  an Oncotype Dx  recurrence score of < 25 (low-intermediate 
recurrence scores).  
 
In recent years, neoadjuvant therapy has been increasingly offered to breast cancer 
patients to facilitate tumor down-staging and to better understand tumor response to therapy 
[7]. Although neoadjuvant endocrine therapy has not been studied as extensively as 
neoadjuvant chemotherapy, neoadjuvant hormonal therapy is, in general, considered to be a 
suitable option for hormone receptor (HR)-positive patients who are unfit for chemotherapy or 
surgery with mild toxicity profile [8-10]. In the European Cooperative Trial in Operable 
Breast Cancer, pathologic complete response (pCR) after neoadjuvant chemotherapy was 
observed in 42% of patients with ER-negative tumors, compared with 12% in the ER-positive 
group [11-13]. In four phase III trials, differences in neoadjuvant treatment outcomes between 
aromatase inhibitors (AIs) and tamoxifen were studied. Clinical response rates ranged from 
38% to 70% for AIs and from 36% to 51% for tamoxifen. Overall AIs have demonstrated 
superior results when compared with tamoxifen in postmenopausal patients [14-17]. 
 
 
More recently, attempts have been made to quantitate response to neoadjuvant 
endocrine therapy. Post-treatment Ki67 can be of prognostic value, as shown by Ellis et al., 
who developed a preoperative endocrine prognostic index (PEPI) score for the prediction of 
recurrence free survival (RFS). The PEPI score incorporates post-treatment pathological 


 
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tumor size, pathological node status, level of ER expression and the proliferative rate (defined 
by the percent of cells expressing Ki67) [8]. 
 
1.2 
PI3kinase/AKT/mTOR signaling pathway in hormone receptor 
positive breast tumors. 
 
 
The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway  plays an 
important role in cell survival, proliferation, angiogenesis and metabolism [18, 19]. mTOR, a 
serine/threonine protein kinase that belongs to the PI3kinase protein family, is frequently 
activated during carcinogenesis via genetic and epigenetic alterations. Abnormalities of the 
PI3kinase/AKT/mTOR signaling pathway are some of the most common molecular anomalies 
in breast cancer, and many of these abnormalities are detected in HR-positive tumors [1]. 
Activation of mTOR pathway leads to PI3K gene activation, phosphatase and tensin homolog 
(PTEN) loss and high levels of AKT expression in 16-48% of breast cancer patients [20-22]. 
A substrate of mTOR complex 1 (mTORC1), called S6 kinase 1, phosphorylates the 
activation function domain 1 of the ER, which is responsible for ligand-independent receptor 
activation[23, 24]. High levels of phosphorylated mTOR were correlated with nodal 
metastasis and poor prognosis in breast cancer patients [25]. Preclinical studies have shown 
that upregulation of the PI3K-mTOR pathway is a mechanism of resistance to endocrine 
therapy, and sensitivity to endocrine therapy can be restored by treatment with everolimus or 
other mTOR inhibitors [26, 27]. Interestingly, the rate of PI3K mutations is highest in 
low/intermediate grade and Luminal A breast cancers [28, 29]. This tumor subset is also 
thought to be less likely to benefit from chemotherapy.  
 
Everolimus (Afinitor, Novartis) is an oral sirolimus (formerly called rapamycin) derivative 
that inhibits its mTOR through allosteric binding to mTORC1 potently [23, 30]. Everolimus 
has been recently approved for use in patients with advanced breast cancer progressing on a 
nonsteroidal aromatase inhibitors in combination with the steroidal aromatase inhibitor 
exemestane based on the results of BOLERO-2 which showed a PFS benefit in favor of the 
exemestane and everolimus combination arm compared to exemestane alone[31]. The 
BOLERO-2 study randomized 724 patients with metastatic hormone receptor positive breast 
cancer who had progressed on prior  estrogen-deprivation therapy to receive exemestane or 
exemestane in combination with everolimus. The initial analysis, based on investigator 
assessment, demonstrated a significant improvement in progression-free survival (hazard ratio 
0.43; 95% CI 0.35-0.54). On central review, the median time to progression was 4.1 months in 
the exemestane arm and 10.6 months in the combination arm. In addition, response rate and 
clinical benefit rate were both significantly superior with the combination, and while there 
was some increase in toxicity, there was no difference in quality of life during treatment in the 
two arms of the study [32]. The most common Grade 3 or 4 adverse events were stomatitis, 
anemia, hyperglycemia, fatigue and pneumonitis. Therefore, the combination of endocrine 
therapy and everolimus resulted in an increased antitumor effect in groups of patients without 
prior therapy, limited prior therapy and even extensive prior endocrine treatment suggesting 
that targeting mTOR activation may be implicated in restoring endocrine resistance. 
 
 


 
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1.3 
Everolimus 
 
Everolimus is a novel derivative of rapamycin. It has been in clinical development 
since 1996 as an immunosuppressant in solid organ transplantation. Everolimus is approved in 
Europe and other global markets (trade name: Certican®) for cardiac and renal 
transplantation, and in the United States (trade name: Zortress®) for the prevention of organ 
rejection of kidney transplantation. Afinitor® and was approved for adults with advanced 
renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafinib in 2009. In 
2010, Afinitor® received United States (US) approval for patients with subependymal giant 
cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC). Everolimus is 
also available as Votubia® in the European Union (EU) for patients with SEGA associated 
with TSC who require therapeutic intervention but are not candidates for curative surgical 
resection. Afinitor® was approved for “progressive pancreatic neuroendocrine tumor (PNET) 
in patients with unresectable, locally advanced, or metastatic disease” in 2011 in various 
countries, including the US and Europe. In 2012 Afinitor® received approval for the 
treatment of postmenopausal women with advanced hormone receptor-positive, HER2- 
negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of 
treatment with letrozole or anastrozole. Furthermore in 2012, Afinitor® received approval for 
the treatment of patients with TSC who have renal angiomyolipoma not requiring immediate 
surgery. In the US, Afinitor® was approved in 2016 for advanced non-functional NET of 
gastrointestinal (GI) or lung origin. 
 
Approximately 44,060 cancer patients (excluding those patients who received 
marketed Afinitor® , those on planned and roll over studies as well as excluding investigator-
sponsored studies) have been treated with everolimus as of  31-Mar-2016 
• 25,356 patients in Novartis-sponsored clinical trials 
• 2,043 patients in the individual patient supply program 
 
1.3.1 Everolimus mechanism of action 
 
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor 
(Table 1, Figure 1). Everolimus selectively inhibits mTOR (mammalian target of rapamycin), 
specifically targeting the mTOR-raptor signal transduction complex. mTOR is a key serine-
threonine kinase in the PI3K/AKT signaling cascade, which is known to be dysregulated in a 
wide spectrum of human cancers [33]. 
Everolimus is being investigated as an anticancer agent based on its potential to act 
• directly on the tumor cells by inhibiting tumor cell growth and proliferation; 


 
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• indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF (vascular endothelial growth factor) production and 
VEGF-induced proliferation of endothelial cells). 
Table 1 
Everolimus - Drug substance 
Chemical name 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-
{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-
19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone 
International non-
proprietary name 
Everolimus 
Figure 1 
Chemical structure of Everolimus 
N
O
OH
C
H3
O
O
CH3
CH3
OH
C
H3
O
O
O
O
H
C
H3
O
CH3
O
C
H3
O
O
CH3
CH3
O
C
H3
 
 
At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. 
It selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase which 
regulates cell growth, proliferation and survival. The mTOR kinase is mainly activated via the 
phosphatidylinositol 3-kinase (PI3-Kinase) pathway through AKT/PKB and the tuberous 
sclerosis complex (TSC1/2). Mutations in these components or in PTEN, a negative regulator 
of PI3-kinase, may result in their dysregulation. Abnormal functioning of various components 
of the signaling pathways contributes to the pathophysiology of numerous human cancers. 
Various preclinical models have confirmed the role of this pathway in tumor development 
[34]. 
 
The main known functions of mTOR include the following [35]. 
• mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels; 
• Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions; 
• The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors; 
• PI3-kinase mutations have been reported in the primary tumor in 10-20% of human 
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• The loss of PTEN protein, either through gene deletion or functional silencing (promoter 
hypermethylation), is reported in approximately 60% of primary human colorectal cancers 
[38]. 
• The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) 
and inhibition of endothelial cell growth and proliferation; 
• Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 
40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, including 
the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased expression of 
HIF-1. 
1.3.2 Non-clinical experience 
 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro 
including lines originating from lung, breast, prostate, colon, melanoma and glioblastoma. 
IC50s range from sub/low nM to µM. Everolimus also inhibits the proliferation of human 
umbilical vein endothelial cells (HUVECS) in vitro, with particular potency against VEGF-
induced proliferation suggesting that Everolimus may also act as an anti-angiogenic agent. 
The anti-angiogenic activity of Everolimus was confirmed in vivo. Everolimus selectively 
inhibited VEGF-dependent angiogenic response at well tolerated doses. Mice with primary 
and metastatic tumors treated with Everolimus showed a significant reduction in blood vessel 
density when compared to controls. 
 
The potential of Everolimus as an anti-cancer agent was shown in rodent models. 
Everolimus is orally bioavailable, residing longer in tumor tissue than in plasma in a 
subcutaneous mouse xenograft model, and demonstrating high tumor penetration in a rat 
pancreatic tumor model. The pharmacokinetic profile of Everolimus indicates sufficient tumor 
penetration, above that needed to inhibit the proliferation of endothelial cells and tumor cell 
lines deemed sensitive to Everolimus in vitro. 
 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well 
tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon, 
epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic 
melanoma). These models included tumor lines considered sensitive and “relatively resistant” 
in vitro. In general, Everolimus was better tolerated in mouse xenograft models than standard 
cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar anti-tumor 
activity. Additionally, activity in a VEGF-impregnated subcutaneous implant model of 
angiogenesis and reduced vascularity (vessel density) of Everolimus-treated tumors (murine 
melanoma) provided evidence of in vivo effects of angiogenesis. 
 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
Everolimus. Molecular analysis has revealed that relative sensitivity to Everolimus in vitro 
correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase and 
the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a correlation with 
PTEN status. 
 
In vivo studies investigating the anti-tumor activity of Everolimus in experimental 
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growth rates rather than produced regressions. These effects occurred within the dose range of 
2.5 mg to 10 mg/kg, orally once a day. 
 
In preclinical models, the administration of Everolimus is associated with reduction of 
protein phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 
(p-S6) and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein 
upstream of mTOR signaling pathway. 
 
All significant adverse events observed in toxicology studies with Everolimus in mice, 
rats, monkeys and mini-pigs were consistent with its anticipated pharmacological action as an 
anti-proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 
recovery period with the exception of the changes in male reproductive organs, most notably 
testes. 
In vitro genotoxicity studies covering relevant genotoxicity end-points showed no 
evidence ofclastogenic or mutagenic activity. 
In male fertility studies in rats, testicular morphology was affected at 0.5 mg/kg and above, 
and sperm motility, sperm head count and plasma testosterone levels were diminished at 5 
mg/kg which corresponded to 0.7 times the estimated clinical exposure at 10 mg/day, and 
caused a decrease in male fertility. There was evidence of reversibility. Female fertility was 
not affected, but everolimus caused an increase of pre-implantation loss in female rats at doses 
> 0.1 mg/kg, suggesting it could also potentially impact fertility in females.  Everolimus 
crossed the placenta and was toxic to the conceptus. In rats, everolimus caused 
embryo/fetotoxicity at systemic exposure below the planned therapeutic level comprising 
mortality and reduced fetal weight. The incidence of skeletal variations and malformations at 
0.3 and 0.9 mg/kg (e.g. sternal cleft) was increased. In rabbits, embryo toxicity was evident by 
an increase in late resorptions. Effects of everolimus on the pre- and postnatal development of 
rats were limited to slightly affected body weight and survival in the F1-generation at ≥0.1 
mg/kg, and did not indicate a specific toxic potential.  
The potential reproductive risk for humans is unknown. However, due to the observed 
malformations in rats, everolimus should be considered potentially teratogenic. Everolimus 
should not be given to pregnant women unless the potential benefit outweighs the potential 
risk for the fetus. Women of childbearing potential should be advised to use highly effective 
contraception methods while they are receiving everolimus and up to 8 weeks after treatment 
has been stopped. It is not known whether everolimus is excreted in human milk. In animal 
studies, everolimus and/or its metabolites were readily transferred into the milk of lactating 
rats. Therefore women who are taking everolimus should not breastfeed. 
 
 
Further details can be found in the Everolimus Investigator’s Brochure. 
2.0 
RATIONALE 
 
 
A phase II randomized study of neoadjuvant letrozole and everolimus vs. letrozole 
alone enrolled 270 postmenopausal patients with tumors larger than 2 cm, and showed 
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patients by proliferation rate or recurrence score and thus likely included a broad mix of ER+ 
cancers. We propose a single arm phase II trial evaluating the combination of everolimus and 
an aromatase inhibitor in postmenopausal women with hormone receptor positive/HER2 
negative breast cancers with low and intermediate risk (< 25) Recurrence Scores by Oncotype 
Dx.  The type of aromatase inhibitor administered during this trial will be at the physician’s 
choice, since they all can be considered equivalent in activity based on the results of the 
ACOSOG Z1031 trial [1]. Our study eligibility will be limited to patients with ‘low to 
moderately aggressive', hormone-responsive tumors, identified by recurrence score < 25, 
similar to the group of patients in whom the omission of adjuvant chemotherapy is being 
tested by the TAILORx and SWOG 1007 studies. Therefore, we propose to use pretreatment 
recurrence score to identify patients most likely to benefit from neoadjuvant endocrine 
therapy, and determine if the addition of the mTOR inhibitor everolimus enhances that 
response.  
 
Our primary endpoint will be to evaluate response defined as a PEPI -0. Results from 
ACOSOG Z1031 demonstrated no difference in clinical response or surgical outcomes 
between luminal A vs luminal B tumors in postmenopausal patients treated with  three 
different aromatase inhibitors, however,  there were  significantly higher responses defined by 
a Preoperative Endocrine Prognostic Index (PEPI) score of 0 in luminal A vs luminal B 
tumors (27.1% v 10.7 %; P=.0004) [1].  A PEPI score 0 was also highest in tumors with Ki67 
levels <10% at baseline.  Kelly et al compared risk assignment by PAM 50 Breast cancer 
intrinsic classifier and Oncotype DX recurrence score in 151 hormone receptor positive stage 
I-II breast cancers [2]. The majority (83%) of low recurrence score cases were found to be 
luminal A subtype by PAM 50. Additionally, half of the intermediate recurrence scores were 
re-categorized as low risk luminal A subtypes by PAM 50.  While there are no available 
reports of the incidence of PEPI-0 following neoadjuvant AI therapy in hormone receptor 
positive breast cancer patients with an Oncotype of < 25, Ellis et al did report a PEPI-0 of 
27% in the Luminal A subset in ACOSOG  Z1031. Therefore this will be used as our 
benchmark. Patients with clinical stage I –III (just like ACOSOG Z1031) hormone receptor 
tumors and RS <25 will be eligible for the study. 
 
An ongoing large randomized phase III clinical trial (SWOG  1007) is designed to 
evaluate the benefit from chemotherapy for ER positive breast cancer with 1-3 positive lymph 
nodes and  an Oncotype Dx  recurrence score of < 25 (low-intermediate recurrence scores). It 
is likely that this tumor subset is more sensitive to a combination of an mTOR inhibitor and 
endocrine therapy.  Our proposed neoadjuvant trial will provide rapid and complementary 
information to assess whether everolimus might improve the efficacy of endocrine therapy in 
breast cancers with low to intermediate recurrence scores. 
 


 
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3.0 STUDY OBJECTIVES 
Primary objectives: 
• The primary objective of the study is to determine  the percent of  postmenopausal 
patients with stage II-III hormone receptor positive/ HER2 negative breast cancer and 
an Oncotype Dx recurrence score  < 25 who achieve a PEPI score of 0 following 
neoadjuvant  treatment with everolimus and an aromatase inhibitor  
 
Secondary objectives: 
1) To assess the tolerability and side effect profile of neoadjuvant aromatase inhibitor 
therapy and  everolimus  
2) To identify biologic markers predictive of clinical and pathologic response (pathologic 
complete response or PEPI 0) to neoadjuvant aromatase inhibitor therapy and 
everolimus in postmenopausal hormone receptor positive/HER2 negative breast cancer 
patients selected by Oncotype Dx Recurrence Score < 25, on tissue biopsies obtained 
at baseline and after completion of study treatment   
4.0 
TRIAL PATIENT POPULATION AND ELIGIBILITY 
This trial which will enroll postmenopausal women with hormone receptor positive /HER2 
negative breast cancers with low and intermediate risk (< 25) Recurrence Scores by Oncotype 
Dx.  The sample size for this study is 27 patients. Assuming that 10% of enrolled patients will 
be inevaluable , we plan to enroll  up to 33 in total. Patients must have required baseline 
evaluations performed prior to the first dose of study drug and must meet all inclusion and 
exclusion criteria. The written informed consent must be obtained from the patient prior to 
enrollment. The following criteria apply to all patients enrolled onto the study unless 
otherwise specified. 
4.1 
Inclusion criteria  
 
1. Patients must have a histologically confirmed diagnosis of hormone receptor positive, 
HER2 negative invasive breast carcinoma. 
2. Tumors must be estrogen and/or progesterone receptor positive according to 
ASCO/CAP 2010 guidelines as either ER or PR ≥ 1% positive nuclear staining by 
immunohistochemistry. Estrogen and/or progesterone receptor results by Oncotype 
Dx will not be accepted.  
3. Tumors must be HER2 negative as defined according to ASCO/CAP 2013, as HER2 0 
– 1+ by IHC or non-amplified FISH or CISH. If HER2 IHC is 2+, FISH/CISH 
must be performed and must not be positive (must be a ratio of < 2), but otherwise 
FISH/CISH is not required if IHC is 0 or 1+ by institutional standards.  
4. Patients must not have had prior ipsilateral breast-conserving surgery or total 
mastectomy and be eligible for neoadjuvant treatment.  
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6. Baseline Oncotpye Dx recurrence score  < 25.  
7. Staging studies with a CT scan of the chest and abdomen and bone scan, or a PET/CT  
is required for clinical stage III, and are considered optional for stage II breast 
cancers.  
8. Patients with multifocal, multicentric and synchronous bilateral breast cancers are 
allowed: 
• Multifocal disease is defined as more than one invasive cancer < 2 cm from the 
largest lesion within the same breast quadrant. 
• Multicentric disease is defined as more than one invasive cancer ≥ 2 cmfrom 
the largest lesion within the same breast quadrant or more than one lesion in 
different quadrants. 
• 
Synchronous bilateral disease is defined as invasive breast cancer in both 
breasts, diagnosed within 30 days of each other.In patients with multicentric or 
bilateral invasive breast cancers, all sampled lesions must be hormone 
receptor-positive.. Any lesion measuring > 1 cm must have an Oncotype Dx  
and the score must be < 25. Lesions less than 1 cm in size are not required to 
have an Oncotype Dx.One lesion (typically the largest) should be designated as 
the target lesion for which clinical and radiographic response to the 
neoadjuvant therapy will be judged.  
• Patients with a hormone receptor-positive, HER2-negative invasive cancer that 
meets study criteria may have ductal carcinoma in situ in another quadrant of 
the same breast or in the contralateral breast even if the DCIS is hormone 
receptor-negative.    
9. Patients must have adequate bone marrow function, as defined by peripheral 
granulocyte count of ≥ 1,500/mL, hemoglobin ≥ 9 g/dL and a platelet count ≥ 
100,000/ mL within 28 days prior to registration.  
10. Patients must have adequate hepatic function obtained within 28 days prior to 
registration and documented by all of the following: 
• Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert's Syndrome) 
• ALT and AST ≤ 1.5 x Institutional Upper Limit of Normal (IULN) 
• Alkaline phosphatase ≤ 1.5 x IULN 
11. Patients must have adequate renal function with serum creatinine level ≤ IULN within 
28 days prior to registration.  
12. Patients must have a fasting cholesterol ≤ 300 mg/dl OR ≤7.75 mmol/L and 
triglycerides ≤ 2.5 x IULN obtained within 28 days prior to registration. Patients 
may be on lipid lowering agents to reach these values. 
13. Patients must have a ECOG performance status of 0-2. 
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15. Postmenopausal women (women are considered post-menopausal and not of child-
bearing potential if they are > 18 years of age and have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms or biochemically postmenopausal by 
estradiol and FSH levels)) prior to enrollment or have had surgical bilateral 
oophorectomy (with or without hysterectomy) prior to registration. Medical 
ovarian suppression with LHRH agonists to render a patient postmenopausal will 
not be acceptable.  
16. Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed 
consent prior to any screening procedures in accordance with institutional and 
federal guidelines. 
4.2 
Exclusion criteria 
1. Patients must not have inflammatory breast cancer (T4d) and must not have metastatic 
breast cancer (Stage IV disease). 
2. Patients must not have prior exposure to mTOR inhibitors (e.g. rapamycin, 
everolimus, sirolimus, temsirolimus, deforolimus).  
3. Patients must not have prior treatment with any investigational drug within the 
preceding 28 days and must not be planning to receive any other investigational 
drug for the duration of the study. 
4. Patient may not have any impairment of gastrointestinal function or gastrointestinal 
disease that may significantly alter the absorption of the drug (e.g. ulcerative 
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small 
bowel resection). 
5. Uncontrolled diabetes mellitus as defined by HbA1c >8% within 28 days prior to 
registration despite adequate therapy.  
6. Patients who have any severe and/or uncontrolled cardiac disease within ≤6 months 
prior to start of Everolimus, including:  unstable angina pectoris, Symptomatic 
congestive heart failure of New York heart Association Class III or IV, myocardial 
infarction, serious uncontrolled cardiac arrhythmia, or any other clinically 
significant cardiac disease 
7. Patients must not have an organ allograft or other history of immune compromise.  
8. Patients must not be receiving chronic, systemic treatment with corticosteroids or 
other immunosuppressive agent. Topical or inhaled corticosteroids are allowed. 
9. Patients must not have a known history of HIV seropositivity 
10. Patients must not have a known diagnosis of  hepatitis B or C. Patients with the 
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• Current or prior IV drug users 
• Current or prior dialysis 
• Household contact with a hepatitis B or C patient 
• Current or prior high-risk sexual activity 
• History of jaundice. 
11. Patients must not have any known uncontrolled underlying pulmonary disease or  
severely impaired lung function (spirometry and DLCO 50% or less of normal and 
O2 saturation 88% or less at rest on room air), 
12. Active (acute or chronic) or uncontrolled severe infection.  
13. Patients who have received live attenuated vaccines within 1 week of start of 
Everolimus, or have plans to receive such vaccination while on protocol treatment. 
Patient should also avoid close contact with others who have received live 
attenuated vaccines. Examples of live attenuated vaccines include intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and 
TY21a typhoid vaccines; 
14. Patients who are currently part of or have participated in any clinical investigation 
with an investigational drug within 1 month prior to dosing; 
15. Patients must not have taken within 14 days prior to registration , be taking, nor plan 
to take while on protocol treatment, strong CYP3A4 inhibitors, and/or CYP3A4 
inducers.   
16. Patients with active bleeding diathysis. 
5.0 
STUDY DESIGN 
This is a single arm open-lableled, multicenter neoadjuvant phase II clinical trial evaluating 
everolimus in combination with an aromatase inhibitor in postmenopausal women with 
hormone receptor positive/HER2 negative breast cancers with low and intermediate risk (< 
25) Recurrence Scores by Oncotype Dx.   
5.1 
Pre-registration 
 
• Postemnopausal patients who have a hormone receptor  positive,  HER2 negative 
breast cancer appropropriate for neoadjuvant therapy and who have not undergone 
prior Oncotype Dx testing, will be consented and pre-registered prior to submission of 
tissue from their diagnostic biopsy for Oncotype Dx analysis for the purpose of 
clinical trial screening. 
 
• Patients with a RS < 25 will be offered the opportunity to participate in this clinical 
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• Patients with a non-diagnostic Oncotype Dx analysis from their initial biopsy will be 
offered the opportunity to undergo a repeat biopsy for Oncotype Dx testing to 
determine if they are eligible to participate in the study. 
• Patients with a Recurrence Score (RS) >25 cannot proceed to the treatment phase of 
the study, but may be offered the opportunity to participate in other neoadjuvant trials 
or be treated off study.  
 
5.2 
Patient registration 
The patient must voluntarily consent after being informed of the experimental nature of the 
treatment, potential benefits, alternatives, side-effects, risks and discomforts. Human 
protection committee approval of this protocol and the informed consent form are required. 
Registration must occur prior to the initiation of protocol therapy.  All patients will be 
registered for the trial by a research staff member following the policy of the Clinical Trial 
Office at Sidney Kimmel Cancer Center. 
6.0 
STUDY TREATMENT 
Eligible patients will be enrolled and will receive treatment with an aromatase inhibitor  plus 
everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 
with both the standard dose of one of the following 3 aromatase inhibitors (physician’s 
choice) plus everolimus 10 mg by mouth  daily: 
• Anastrozole 1 mg 
• Letrozole 2.5 mg  
• Exemestane 25 mg  
 
The study drug (everolimus) will be dispensed by the research pharmacy at the participating 
site. Tablets should be administered orally once daily at the same time every day, either 
consistently with or consistently without food. The tablets should be swallowed whole with a 
glass of water and should not be chewed or crushed. If vomiting occurs, no attempt should be 
made to replace the vomited dose. Patients should be instructed that if they miss a dose on one 
day, they must not take any extra dose the next day, but instead resume their next dose at the 
regularly scheduled time. Study drug compliance should be reviewed with the patient during 
each clinic visit. Missed doses should be documented. 
 
6.1 
Study drugs:  
6.1.1 
Everolimus (Afinitor®)  
 
a.  
PHARMACOLOGY 
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both agents inhibit growth factor-driven cell proliferation, including that of T-cells 
and vascular smooth muscle cells. The everolimus and FKBP12 complex selectively 
inhibits mTOR (mammalian target of rapamycin), an intracellular protein kinase 
implicated in the control of cellular proliferation of neoplastic cells, specifically in the 
progression of cells from G1 to S phase. Everolimus also reduces angiogenesis by 
inhibiting VEGF and HIF-1 expression.  
 
b.  
PHARMACOKINETICS 
1. Absorption: Everolimus levels peak in 1-3 hours after oral administration. There is 
rapid but moderate absorption. 
2. Distribution: Everolimus is about 74% protein bound in healthy subjects and 
patients with moderate hepatic impairment. 
3. Metabolism: Everolimus is extensively metabolized by CYP3A4 and forms 6 weak 
metabolites. It is also a P-glycoprotein substrate. 
4. Elimination: Everolimus is extensively eliminated via the bile. The elimination half-
life of everolimus is about 30 hours and is prolonged in patients with hepatic 
impairment. Everolimus is primary excreted through the feces. 
 
c.  
ADVERSE EFFECTS 
 
1. Adverse events with possible relationship to Everolimus:  
The most common ADRs, suspected to be related to treatment by the investigator (incidence 
≥1/10) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, 
diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, edema 
peripheral, hyperglycemia, asthenia, pruritus, weight decreased, pruritus, asthenia, peripheral 
edema, hypercholesterolemia, epistaxis, cough and headache. 
 
The most common grade 3/4 ADRs, suspected to be related to treatment by the investigator 
(incidence ≥1/100 to <1/10) were stomatitis, anemia, hyperglycemia, fatigue, infections, 
pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, lymphopenia, 
proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate aminotransferase 
(AST) increased, alanine aminotransferase (ALT) increased, and pneumonia and diabetes 
mellitus. 
 
The below table presents the frequency category of ADRs reported in the pooled safety 
analysis. 
 
ADRs are listed according to MedDRA system organ class. Within each system organ class, 
the adverse reactions are ranked by frequency, with the most frequent reactions first. In 
addition, the corresponding frequency category using the following convention (CIOMS III) 
is also provided for each adverse reaction: very common (≥1/10); common (≥1/100 to <1/10); 
uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not 
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Infections and infestations 
Very common -  Infections 
 
Blood and lymphatic system disorders 
Very common  - Anemia, thrombocytopenia 
Common          - Neutropenia, leukopenia, lymphopenia 
Uncommon      - Pancytopenia 
Rare   
-Pure red cell aplasia 
 
Immune system disorders 
Uncommon        - Hypersensitivity 
 
Metabolism and nutrition disorders 
Very common   - Decreased appetite, hyperglycemia, hypercholesterolemia 
Common          - Hypertriglyceridemia, hyperlipidemia, hypophosphatemia, diabetes mellitus, 
hypokalemia, dehydration 
 
Psychiatric disorders 
Common           - Insomnia 
 
Nervous system disorders 
Very common    - Dysgeusia, headache 
Uncommon        - Ageusia 
 
Cardiac disorders 
Uncommon        - Congestive cardiac failure 
 
Vascular disorders 
Common            - Hemorrhage, hypertension 
Uncommon        - Deep vein thrombosis 
 
Respiratory, thoracic and mediastinal disorders 
Very common     - Pneumonitis, epistaxis, cough 
Common 
    - Dypsnea 
Uncommon         - Hemoptysis, pulmonary embolism 
Rare                    - Acute respiratory distress syndrome 
 
Gastrointestinal disorders 
Very common    - Stomatitis, diarrhea, nausea 
Common          -  Vomiting, dry mouth, abdominal pain, oral pain, dyspepsia, dysphagia 
 
Skin and subcutaneous tissue disorders 
Very common  -  Rash, pruritus 
Common           - Dry skin, nail disorder, acne, erythema, hand-foot syndrome 
Rare   
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Musculoskeletal and connective tissue disorders 
Common            - Arthralgia 
 
Renal and urinary disorders 
Common             - Proteinuria, renal failure 
Uncommon         - Increased daytime urination, acute renal failure 
 
Reproductive system and breast disorders 
Common         - Menstruation irregular 
Uncommon     - Amenorrhea 
 
General disorders and administration site conditions 
Very common      - Fatigue, asthenia, edema peripheral 
Common              - Pyrexia, mucosal inflammation 
Uncommon          - Non-cardiac chest pain, impaired wound healing 
 
Investigations 
Very common       - Weight decreased 
Common               - Alanine aminotransferase increased, aspartate aminotransferase increased, 
blood 
                                 creatinine increased 
 
a Includes all reactions within the ‘infections and infestations’ system organ class including common: 
pneumonia, urinary tract infection 
and uncommon: bronchitis, herpes zoster, sepsis, abscess, and isolated cases of opportunistic 
infections (e.g. aspergillosis, and rare: viral myocarditis, candidiasis and hepatitis B) 
b Includes different bleeding events from different sites not listed individually 
c Includes very common: pneumonitis and common: interstitial lung disease, lung infiltration, 
alveolitis, pulmonary 
alveolar hemorrhage, and pulmonary toxicity 
d Includes very common: stomatitis; common: aphthous stomatitis, mouth and tongue ulceration; 
uncommon: 
glossitis, glossodynia 
e reported as palmar-plantar erythrodysaesthesia syndrome 
 
2.  Pregnancy and Lactation: Pregnancy category D. It is not known if everolimus is 
excreted in human milk. 
 
3. Drug Interactions: Everolimus is metabolized by CPY3A4 in the liver and to some 
extent the intestinal wall. Due to the extensive number of everolimus drug interactions, 
a complete patient medication list,including everolimus, should be screened prior to 
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4. Hepatic Impairment: Dosage adjustment of everolimus is recommended  
if  patients develop hepatic impairment during study treatment. Please refer to Dosage 
Modification section ( section 7.0). 
 
 
d.  
ADMINISTRATION 
Everolimus should be administered orally, once daily preferably in the morning with a 
glass of water and no more than a light fat-free meal.Tablets should be swallowed 
whole with a glass of water. Grapefruit or citrus juices should be avoided. The tablets 
must not be chewed orcrushed. If patients are unable to temporarily swallow whole 
tablet during the duration of the clinical trial,  patients  may disperse tablet completely 
in 30 mL water  for approximately 7 minutesand drink immediately; rinse container 
with additional 30 mL water and swallow. 
 
e.  
STORAGE & STABILITY 
  Medication labels will comply with US legal requirements and be printed in English. 
They will supply no information about the patient. The storage conditions for 
Everolimus will be described on the medication label. 
 
The intact blister packs should be stored at controlled room temperature (15°- 30°C) 
and protected from light. Current stability data permit shelf life of 24 months for 5 mg 
tablet variant based on solid dispersion dried by paddle dryer and 36 months for 5 mg 
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below 30° C in the original double sided aluminum blister and protected from light 
and moisture. 
 
f. 
HOW SUPPLIED 
Everolimus 10 mg (5 mg tablets will be supplied for dose de-escalation) tablets will be 
supplied by Novartis Pharmaceuticals Corporation. Everolimus will be supplied as 
tablets blisterpacked under aluminum foil in units of 10 tablets. Blisters should be 
opened only immediately prior to ingestion as the drug is both hygroscopic and light-
sensitive. 
 
Refer to label for expiration date and storage conditions. The extent of absorption of 
everolimus through topical exposure is not known.  Therefore, caregivers are advised 
to avoid contact with suspensions of Afinitor Tablets.  Wash hands thoroughly before 
and after preparation of either suspension. 
 
On Day 1 of each cycle, subject will be dispensed the appropriate amount of study 
medication and will be instructed to return remaining medication and packaging at the 
next visit.  
 
3.  
Drug Handling and Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing, and return of all study drugs received.  
 
4.  
Drug Return and/or Disposition Instruction 
All unused drug, unopened and unused blister cards remaining when a subject goes off 
treatment, and expired blister cards should be returned to research pharmacy. 
 
6.1.2  Anastrazole  
 
a.  
PHARMACOLOGY  
Mechanism of Action: Anastrozole is a selective non-steroidal aromatase inhibitor. 
Estrogens are mainly derived from the action of the aromatase enzyme,which converts 
adrenal androgens (primarily androstenedione and testosterone)to estrone and 
estradiol. Anastrozole significantly lowers serum estradiol concentrations and has no 
detectable effect on formation of adrenal corticosteroids or aldosterone. 
 
b.  
PHARMACOKINETICS 
1. Absorption: Anastrozole is well absorbed (85% bioavailability) and its absorption is 
not affected by food. Maximum plasma concentrations occur within 2 hours. Plasma 
concentrations approach steady-state levels by about the seventh day of once daily  
 
2. Distribution: Anastrozole is distributed throughout the systemic circulation and is 
approximately 40% protein bound. 
 


 
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3. Metabolism: Anastrozole is extensively (85%) hepatically metabolized viaN-
dealkylation, hydroxylation, and glucuronidation. Three metaboliteshave been 
identified in plasma and urine, and there are several unidentified minor metabolites. 
The main circulating metabolite, triazole, is inactive. The other known metabolites are 
a glucuronide conjugate of hydroxy-anastrozole and a glucuronide conjugate of 
anastrozole. Although hepatic cirrhosis reduces apparent oral clearance of anastrozole, 
no dosage adjustments are needed because plasma concentrations remain within the 
same range for patients without hepatic  
disease 
4. Elimination: Anastrozole is eliminated predominantly through the feces (75%) with 
some renal excretion (10%). Anastrozole has a terminal elimination half-life of 
approximately 50 hours. Renal clearance of anastrozole does decrease proportionally 
with creatinine clearance, but overall this has very little effect on total body clearance. 
No dosage adjustments are therefore necessary for patients with impaired renal 
function 
 
 
c.  
ADVERSE EFFECTS 
 
1. Adverse Events with Possible Relationship to Anastrozole  
 
Likely (>20%) 
• Vasodilatation 
• Hotflashes 
.  
Less likely (< 20%) 
• Anemia  
• Leukopenia 
• Edema 
• Hypertention 
• Cataracts 
• Abdominal pain 
• Constipation 
• Diarrhea 
• Dyspepsia 
• Nausea 
• Vomiting 
• Xerostomia 
• Fever 
• Pain 
• Malaise 
• Thrombophlebitis 
• Flu-like syndrome 
• Weight gain or loss 


 
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• Hypercholesteremia 
• Arthralgia 
• Arthritis 
• Back pain 
• Breast painm 
• Carpal tunnel syndrome 
• Myalgia 
• Neck pain 
• Osteoporosis 
• Paresthesia 
• Weakness Confusion 
• Dizziness 
• Fatigue 
• Headache 
• Somnolence  
• Anxiety 
• Depression 
• Insomnia 
• Mood disturbance 
• Nervousness  
• Pelvic pain 
• Urinary tract infection 
• Vaginal bleeding 
• Vaginal discharge 
• Vaginitis  
• Rhinitis 
• Pharyngitis 
• Sinusitis  
• Alopecia 
• Pruritis 
• Rash 
• Lymphedema 
 
Rare but serious (<3%) 
• Angina 
• Ischemic cerebrovascular event 
• Myocardial infarction 
• Venous thromboembolic event.  
• Alkaline phosphatase increased 
• Liver function tests  increased  
• Fracture  
• Bronchitis  
• Dyspnea 


 
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 * < 1%, postmarketing, and case reports: anaphylaxis, angioedema,bilirubin increased, CVA, 
cerebral ischemia, cerebral infarct, cutaneous vasculitis (including Henoch-Schönlein 
purpura), endometrial cancer, erythema multiforme, hepatitis, jaundice, joint pain, joint 
stiffness, liver inflammation, liver pain, liver swelling, myocardial ischemia, pulmonary 
embolus, retinal vein thrombosis; skin reactions (eg, blisters, lesions, ulcers); Stevens-Johnson 
syndrome, trigger finger, urticaria.  
 
2. Pregnancy and Lactation: Pregnancy category X. Fetal toxicity was observed in animal 
studies. It is not known if anastrozole is excreted intobreast milk. 
3. Drug Interactions: Anastrozole is a weak CYP3A4 inhibitor. Due topotential drug 
interactions, a complete patient medication list, including anastrozole, should be screened 
prior to initiation of anastrozole.  
 
d.  
DOSING & ADMINISTRATION 
Anastrozole should be administered orally, with or without food. 
 
e.  
STORAGE & STABILITY 
Refer to the current FDA-approved package insert for storage, stability and special handling 
information. 
 
f.  
HOW SUPPLIED 
1. Anastrozole is commercially available in 1 mg tablets.,  and  will not be supplied.  
 
6.1.2 Exemestane  
 
a.  
PHARMACOLOGY 
Mechanism of Action: Exemestane is an irreversible, steroidal aromatase inactivator, 
structurally related to the natural substrate androstenedione. It acts as a false substrate for the 
aromatase enzyme, and is processed to an  intermediate that binds irreversibly to the active 
site of the enzyme causing its inactivation, an effect also known as “suicide inhibition.” 
Exemestane significantly lowers circulating estrogen concentrations in postmenopausal 
women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. 
 
b.  
PHARMACOKINETICS 
1. Absorption: Following oral administration of radiolabeled exemestane, at least 42% of 
radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased 
by approximately 40% after a highfat breakfast. 
 
2. Distribution: Exemestane is distributed extensively into tissues. Exemestane is 90% bound 
to plasma proteins and the fraction bound is independent of the total concentration. Albumin 
and α1-acid glycoprotein both contribute to the binding. The distribution of exemestane and 
its metabolites into blood cells is negligible.  
 


 
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3. Metabolism: Exemestane is extensively metabolized, with levels of the unchanged drug in 
plasma accounting for less than 10% of the total radioactivity. The initial steps in the 
metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of 
the 17- keto group with subsequent formation of many secondary metabolites. Each 
metabolite accounts only for a limited amount of drug-related material. The metabolites are 
inactive or inhibit aromatase with decreased potency compared with the parent drug. One 
metabolite may have androgenic activity (see Pharmacodynamics, Other Endocrine 
Effects). Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 
3A4) is the principal isoenzyme involved in the oxidation of exemestane. 
 
4. Elimination: Following administration of radiolabeled exemestane to healthy  
postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces 
were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The 
amount of drug excreted unchanged in urine was less than 1% of the dose. 
 
c.  
ADVERSE EFFECTS 
1. Adverse Events with Possible Relationship to Exemestane 
 
Likely (>20%) 
• Vasodilatation 
• Arthralgia 
 
Less likely (< 20%) 
• Edema 
• Chest pain 
• Visual disturbances 
• Abdominal pain 
• Anorexia 
• Appetite increased 
• Constipation 
• Diarrhea 
• Dyspepsia 
• Nausea 
• Vomiting 
• Endometrial hyperplasia 
• Endometrial polyps 
• Hypoesthesia 
• Fever 
• Pain 
• Serum creatinine increased 
• Weakness 
• Flu-like syndrome 
• Weight gain  
• Back pain 


 
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• Cramping 
• Limb pain 
• Carpal tunnel syndrome 
• Osteoarthritsis 
• Osteoporosis 
• Paresthesia 
• Confusion 
• Dizziness 
• Fatigue 
• Headache 
• Anxiety 
• Depression 
• Insomnia 
• Urinary tract infection 
• Upper respiratory tract infections 
• Cough 
• Rhinitis 
• Pharyngitis 
• Sinusitis  
• Alopecia 
• Pruritis 
• Rash 
• Hyperhidosis 
 
Rare but serious (<3%) 
• Angina 
• Cardiac failure 
• Myocardial infarction 
• Trigger finger 
• Infection 
• Alkaline phosphatase increased 
• Bilirubin increased  
• Transaminases increased 
• Fracture  
• Neuropathy 
• Osteochindrosis 
• Bronchitis  
• Dyspnea 
• Lymphedema 
• Thromboembolism 
 
2. Pregnancy and Lactation: Pregnancy Category X. Exemestane is notindicated for 
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infants. It is not known if exemestane isexcreted into human breast milk; however, it has been 
detected in the breast milk of animals. 
3. Drug Interactions: Exemestane is an inducer of CYP3A4 (weak/moderate) and a substrate 
of CYP3A4 (major). Due to potentialexemestane drug interactions, a complete patient 
medication list, including exemestane, should be screened prior to initiation of 
exemestane. 
  
d. DOSING & ADMINISTRATION 
Exemestane is administered in 25 mg tablets  orally once daily after a meal. 
 
e.  STORAGE & STABILITY 
Refer to the current FDA-approved package insert for storage, stability and special handling 
information.  
 
f. HOW SUPPLIED 
1. Exemestane is available in 25 mg tablets. 
2. Exemestane is commercially available and will not be supplied.  
 
6.1.2 Letrozole  
 
a.  
PHARMACOLOGY 
Mechanism of Action: Letrozole binds to the heme group of aromatase, which 
catalyzes the conversion of androgens to estrogens. Inhibition of aromatase 
significantly decreases plasma estrogen levels. 
 
b.  
PHARMACOKINETICS 
1. Absorption: Letrozole is rapidly and well absorbed. Absorption is not affected by food. 
 
2. Distribution: The volume of distribution of letrozole is approximately 1.9 L/kg. It is weakly 
protein bound. 
 
3. Metabolism: Letrozole is metabolized in the liver via CYP3A4 and CYP2A6 to an inactive 
carbinol metabolite. Letrozole is also a stronginhibitor of CYP2A6 in vitro. 
 
4. Elimination: Letrozole is primarily excreted in the urine, predominantly as a glucuronide 
carbinol metabolite. The elimination half-life is approximately 2 days. 
 
c.  
ADVERSE EFFECTS 
1.  Adverse Events with Possible Relationship to Letrozole 
 
Likely (>20%) 
• Hotflashes 
.  
Less likely (< 20%) 


 
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• Edema 
• Hypertention 
• Cataracts 
• Abdominal pain 
• Constipation 
• Diarrhea 
• Dyspepsia 
• Nausea 
• Vomiting 
• Nightsweats 
• Pain 
• Hypercalcemia 
• Weight gain or loss 
• Hypercholesteremia 
• Arthralgia 
• Arthritis 
• Back pain 
• Bone pain 
• Limb pain 
• Myalgia 
• Osteoporosis 
• Weakness  
• Dizziness 
• Fatigue 
• Headache 
• Somnolence  
• Anxiety 
• Depression 
• Urinary tract infection 
• Vaginal bleeding 
• Vaginal irritation 
• Cough  
• Alopecia 
• Pruritis 
• Rash 
 
Rare but serious (<3%) 
• Chest pain 
• Cerebrovascular event 
• Thromboembolic event 
• Infection 
• Viral infection 
• Influenza 


 
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• Fracture  
• Dyspnea 
• Pleural effusion 
 
*< 1%, postmarketing, and case reports: anaphylactic reaction, angioedema, appetite 
increased, arterial thrombosis, blurred vision, cardiac failure, carpal tunnel syndrome, dry 
skin, dysesthesia, endometrial cancer, endometrial hyperplasia, endometrial proliferation, 
erythema multiforme, eye irritation, fever, hepatitis, hypoesthesia, irritability, leukopenia, 
liver enzymes increased, memory impairment, nervousness, palpitations, paresthesia, 
stomatitis, tachycardia, taste disturbance, thirst, thrombocytopenia, toxic epidermal necrolysis, 
trigger finger, urinary frequency increased, urticaria, vaginal discharge, xerostomia 
 
2. Pregnancy and Lactation: Pregnancy category X. It is not known if letrozole is excreted in 
human milk. 
 
3. Drug Interactions: Letrozole is a strong CYP2A6 inhibitor and moderate CYP2C19 
inhibitor. Due to potential drug interactions, a complete patient medication list, including 
letrozole, should be screened prior to initiation of letrozole. Refer to the current FDA-
approved package insert for additional information.  
 
4. Hepatic Impairment: Letrozole in metabolized in the liver and dose adjustment is 
recommended in hepatic impairment. 
 
 
d.  
DOSING & ADMINISTRATION 
 Letrozole is administered  in 2.5 mg tablets orally once daily with or without food. 
 
e.   
STORAGE & STABILITY 
Refer to the current FDA-approved package insert for storage, stability and special handling 
information. 
 
f.  
HOW SUPPLIED 
Letrozole is commertially available in 2.5 mg tablets, and will not be supplied.  
7.0 
DOSE MODIFICATION  
 
NCI Common Terminology Criteria for Adverse Events. This study will utilize the 
CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 for toxicity 
and Serious Adverse Event reporting. A copy of the CTCAE Version 4.0 can be downloaded 
from the CTEP home page (http://ctep.cancer.gov). The dose modifications are for events that 
are possibly, probably or definitely related to the study drug.  
 
Missed doses are to be omitted rather than made up. If multiple toxicities are 
experienced, dose modifications will be based on the toxicity requiring the largest dose 
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are based on toxicities observed since the prior toxicity evaluation.  Once dose is reduced, 
patients will continue at new dose. No dose reescalations are allowed.  There are no dose 
modifications for endocrine therapy. 
7.1 
Dose modifications and delays for aromatase inhibitors  
There is no dose modification for anastrazole, letrozole or exemestane. Aromatase inhibitor 
therapy may be held for grade 3 or greater arthralgia or myalgia, and switching to another 
aromatase inhibitir will be allowed if symptoms resolve to grade 2 or less. If the aromatase 
inhibitor is held for greater than 4 consecutive weeks due to toxicity, then study treatment will 
be discontinued.  
7.2 
Dose modifications  and delays for everolimus 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Details of study 
treatment schedule adjustments and dose levels are provided in  Table 2. 
 
Special Populations 
Geriatrics (≥ 65 years) :  
No dosage adjustment is required. 
Renal impairment : 
No dosage adjustment is required. 
Ethnicity : 
Pharmacokinetic characteristics are similar for Caucasian and Japanese subjects. 
Pharmacokinetic studies in Black transplant patients have shown an average 20% higher 
clearance. 
Table 2 
Study treatment schedule adjustments and dose levels  
 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg/day 
-1 
5 mg/day 
-2 
2.5 mg/day 
• If a patient is already at dose level -2 and again meets criteria for dose reduction, 
everolimus will be discontinued and the patient will continue on study treatment with the 
aromatase inhibitor therapy only.   
 
Table 3 and Table 4 list the dosing guidelines for Everolimus-related non-hematologic and 
hematologic toxicities.  
Table 3 
Dosing guidelines for Everolimus-related non-hematologic toxicities 


 
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Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer to Table 0. 
Reactivation of HBV or HCV flare 
 Patients with a known diagnosis  of hepatitis B or C  infection will be 
excluded from study 
participation. Patient who meet criteria for hepatitis B or C screening 
and are found to have positive 
serology indicating an ongoing infection, will be excluded from study 
participation.  For all other  
patient who start study treatment and are subsequently found to have  a 
hepatitis B reactivation or  
hepatitis C flare, please refer to tables 6 and 7. 
Table 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN)* 
Interrupt Everolimus administration until resolution to ≤ grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤ 7 days, Everolimus should be re-started at the dose 
level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
Everolimus until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce Everolimus at one dose level lower, if available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN)* 
 
 
 
Recurrence of grade 4 after dose 
reduction or toxicity requiring 
Everolimus interruption for > 28 days 
Interrupt Everolimus administration until resolution to ≤ grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤ 7 days, Everolimus should be re-started at one dose 
level lower. If resolution takes > 7 days, discontinue Everolimus. 
 
Discontinue Everolimus. 
Intolerable grade 2 mucositis, or grade 
3 AE, except hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia (see Section 
7.3.6) 
Interrupt Everolimus administration until resolution to ≤ grade 1 or 
baseline grade / value. 
If resolution occurs within ≤ 7 days, Everolimus should be re-started at 
the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
Everolimus until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce Everolimus at one dose level lower, if available. 
Patients will be withdrawn from the study if they fail to recover to ≤ 
grade 1 or baseline grade / value within 28 days. 
Any other grade 4 
Hold Everolimus until recovery to grade ≤ 1 or baseline value 
Reintroduce Everolimus at one dose level lower, if available. 
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma) 
Discontinue Everolimus 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of Everolimus is 2.5 mg daily. Below this level, 
Everolimus must be discontinued. 
Recurrence of grade 4 after dose 
reduction 
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Toxicity 
Action 
Any non-hematologic toxicity 
requiring Everolimus interruption for 
> 28 days 
Discontinue Everolimus 
* Should HCV flare be confirmed, the guidelines for flare must take precedence (Table ) 
 
Table 4 
Dosing guidelines for Everolimus-related hematologic toxicities 
Toxicity 
Action 
Grade 2 thrombocytopenia (platelets <75, 
≥ 50x109/L) 
No action 
 
Grade 3 thrombocytopenia (platelets <50, 
≥ 25 x109/L) 
Interrupt Everolimus until resolution to grade ≤1  
If resolution occurs ≤ 7 days, reintroduce Everolimus at the dose 
level prior to interruption. 
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce Everolimus at one dose level lower, if available. 
Grade 4 thrombocytopenia (platelets < 25 
x109/L) 
Interrupt Everolimus until recovery to grade ≤ 1. Then reintroduce 
Everolimus at one dose level lower, if available. 
Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x109/L) 
Interrupt Everolimus until resolution to grade ≤1 or baseline value 
If AE resolution occurs ≤ 7 days, reintroduce Everolimus at the 
same dose level. 
If AE resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce Everolimus at one dose level lower, if available. 
Grade 4 neutropenia or anemia 
Interrupt Everolimus until recovery to grade ≤ 1 or baseline value. 
Reintroduce Everolimus at one dose level lower, if available.* 
Febrile neutropenia 
Interrupt Everolimus until resolution to grade ≤ 1 (or baseline 
value) and no fever. Reintroduce Everolimus at one dose level 
lower, if available.* 
Recurrence of grade 3 toxicity after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of Everolimus is 5 mg every other day (2.5 mg 
daily). Below this level, Everolimus must be discontinued. 
*Recurrence of grade 4 toxicity 
(including febrile neutropenia) after 
dose reduction 
Discontinue Everolimus 
*Any hematologic toxicity requiring 
Everolimus interruption for > 28 days 
Discontinue Everolimus 
 
7.3 
Management of specific toxicities related to everolimus 
Overall, safety data available from completed, controlled and uncontrolled studies indicate 
that everolimus is generally well tolerated at weekly or daily dose schedules. The safety 
profile is characterized by manageable adverse events (AEs). These AEs are generally 
reversible and non-cumulative. 
Adverse events most frequently observed with everolimus are stomatitis, rash, fatigue, 
diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, edema 
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epistaxis, cough and headache. Overall, the most frequently observed laboratory abnormalities 
include decreased hematology parameters including hemoglobin, lymphocytes, platelets, and 
neutrophils (or collectively as pancytopenia); increased clinical chemistry parameters 
including cholesterol, triglycerides, glucose, aspartate transaminases,creatinine, alanine 
transaminases, and bilirubin; and decreased clinical chemistry parameters including phosphate 
and potassium.. The majority of these AEs have been of mild to moderate severity (NCI CTC 
grade 1-2).  
7.3.1 Management of infections 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis or candidiasis and viral infections including 
reactivation of hepatitis B virus, have been described in patients taking Everolimus. Some of 
these infections have been severe (e.g. leading to respiratory or hepatic failure) and 
occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with Everolimus 
Treat pre-existing infections prior to starting treatment with Everolimus. While taking 
Everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation of 
Everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus and treat 
with appropriate antifungal therapy. 
 
7.3.2 Management of skin toxicity 
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with 
the following suggested supportive measures at the discretion of the investigator: oral 
minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, 
diphenhydramine, oral prednisolone (short course), topical corticosteroids, or pimecrolimus. 
  
7.3.3 Management of Hypersensitivity reactions 
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, 
dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or 
without respiratory impairment) have been observed with everolimus. Managment of 
hypersensitivity reactions will be up to the treating co-investigator’s discretion. 
  
 
 


 
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7.3.4 Renal Failure Events 
Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in 
patients treated with everolimus. Renal function of patients should be monitored particularly 
where patients have additional risk factors that may further impair renal function. 
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients 
taking everolimus. Monitoring of renal function, including measurement of blood urea 
nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of 
everolimus therapy and periodically thereafter. 
7.3.5   Management of stomatitis / oral mucositis / mouth ulcers 
Adverse Drug Reaction/severity 
 
Afinitor Dose Adjustment and Management 
Recommendations 
Grade 1Stomatitis  
Minimal symtpoms, normal diet 
 
No dose adjustment required.  
Manage with non-alcoholic or salt water (0.9%) mouth 
wash severaltimes a day. 
Grade 2 stomatitis 
Symptomatic but can eat and 
swallow modified diet 
 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate Afinitor at same dose. 
If stomatitis recurs at grade 2, interrupt dose until recovery 
to grade ≤1. Re-initiate Afinitor at lower dose. 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine,butyl aminobenzoate, tetracaine hydrocholoride, 
methol or phenol)with or without topical corticosteroids 
(i.e. triamcinolone oral paste)*. 
Grade 3 stomatitis 
Symptomatic and unable to 
adequately eat or hydrate orally 
 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate Afinitor at lower dose. 
Manage with topical analgesic mouth treatments (i.e. 
benzocaine,butyl aminobenzoate, tetracaine hydrocholoride, 
methol or phenol) with or without topical corticosteroids 
(i.e. triamcinolone oral paste)* 
Grade 4 stomatitis 
Symptoms associated with life-
threatening consequences 
Grade 4 
Discontinue Afinitor and treat with appropriate medical 
therapy. 
* using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as they may worsen 
mouth ulcers. 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis 
must be monitored even more closely. Patients should be instructed to report the first onset of 
buccal mucosa irritation/reddening to their study physician immediately. 
Stomatitis/oral mucositis/mouth ulcers due to Everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with Everolimus as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, 
please classify the adverse event as such. The suggested paradigm for treatment of 
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1. For mild toxicity (grade 1), no dose adjustment required. Manage with  non-alcoholic 
mouth wash or salt water (0.9%) mouth wash several times a day until resolution. 
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate 
oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., 
local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®). 
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers.  These agents should be avoided. 
4. Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should 
be avoided in all patients due to their strong inhibition of Everolimus metabolism, 
therefore leading to higher Everolimus exposures. Therefore, topical antifungal agents are 
preferred if an infection is diagnosed. Similarly, antiviral agents such as acyclovir should 
be avoided unless a viral infection is diagnosed. 
 
7.3.6 Management of nausea 
Routine premedication for nausea is not necessary, but symptomatic patients should be treated 
with standard antinausea/antiemetic therapy as necessary. If the patient vomits after taking the 
tablets, the dose should not be replaced.  Patients should resume the next regularly scheduled 
dose.  
 
7.3.7 Management of diarrhea 
Diarrhea has been reported with everolimus. In general, diarrhea has been transient, usually 
not of sufficient severity to hinder administration of study drug. Appearance of grade 1-2 
diarrhea attributed to study drug toxicity may be treated with supportive care such as 
loperamide, initiated at the earliest onset (for example 4 mg orally followed by 2 mg orally 
every 2 hours until diarrhea-free for 12 hours). 
 
7.3.8 Management of hyperlipidemia and hyperglycemia 
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in 
patients taking everolimus.  Monitoring of blood cholesterol and triglycerides prior to the start 
of everolimus therapy and periodically thereafter as well as management with appropriate 
medical therapy is recommended. 


 
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Adverse Drug Reaction 
Severity 
Afinitor Dose Adjustment and Management 
Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and monitor. 
 
Grade 3 
Temporary dose interruption. 
Re-initiate Afinitor at lower dose. 
Manage with appropriate medical therapy and monitor. 
 
Grade 4 
Discontinue Afinitor and treat with appropriate medical 
therapy. 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits of the patient. Blood tests to monitor hyperlipidemia must be taken in the fasting state. 
Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 
hypertriglyceridemia or higher (> 300 mg/dL - 500 mg/dL; >3.42 mmol/L- 5.7 mmol/L) 
should be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. 
atorvastatin, pravastatin, fluvastatin) or appropriate triglyceride-lowering medication, in 
addition to diet. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy should 
be determined for individual patients based on their risk of cardiovascular complications of 
hyperlipidemia. 
  
Hyperglycemia has been reported inpatients taking everolimus. The fasting state of patients 
should be verified when interpreting results. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus and periodically thereafter. Optimal glycemic 
control should be achieved before starting a patient on Everolimus. More frequent monitoring 
is recommended when everolimus is co-administered with other drugs that may induce 
hyperglycemia. 
 
7.3.4 Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
Everolimus. Some of these have been severe and on rare occasions, a fatal outcome was 
observed.  
 
• A diagnosis of non-infectious pneumonitis should be considered in patients presenting 
with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough 
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excluded by means of appropriate investigations. Patients should be advised to report 
promptly any new or worsening respiratory symptoms. 
 
If non-infectious pneumonitis develops, the guidelines in Table 0 should be followed. 
Consultation with a pulmonologist is recommended for any case of pneumonitis that develops 
during the study.  
Table 0 
Management of non-infectious pneumonitis 
Grading of Pneumonitis: 
Grade 1 (Asymptomatic, radiographic findings only) 
Grade 2 (Symptomatic, not interering with Activities of Daily Living) 
Grade 3 (Symptomatic, Interfering with Activities of Daily Living. O2 indicated) 
Grade 4 (Life-threatening, ventlatory support indicated) 
Worst grade 
pneumonitis 
Suggested investigations 
Management of 
pneumonitis 
Everolimus dose adjustment 
Grade 1 
CT scans with lung windows. 
No specific therapy 
is required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
CT scan with lung windows. Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy and/or BAL. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency if no recurrence. 
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy if 
symptoms are 
troublesome. 
Rule out infection and consider 
interruption of Everolimus until 
symptoms improve to Grade ≤ 1. 
Re-initiate Everolimus at one dose 
level lower.  
Discontinue Everolimus if failure to 
recover within ≤ 28 days. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Monitoring at each 
visit until return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence. Bronchoscopy with biopsy 
and/or BAL is recommended. 
Consider  
corticosteroids 
if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Rule out infection and interrupt 
Everolimus until symptoms improve 
to Grade ≤ 1. 
Consider re-initiating Everolimus at 
one dose level lower (approximately 
50% lower than the dose previously 
administered depending on individual 
clinical circumstances) 
Discontinue Everolimus if failure to 
recover within ≤ 28 days., or toxicity 
recurs at grade 3. 
Grade 4 
CT scan with lung windows and 
required pulmonary function testing, if 
possible, includes: spirometry, DLCO, 
and room air O2 saturation at rest. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency 
if 
no 
recurrence. 
Bronchoscopy with biopsy and/or BAL 
is recommended if possible. 
Consider 
corticosteroids 
if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Rule out infection and discontinue 
Everolimus. 
 
Management of hepatitis reactivation / flare 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
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with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce the 
risk of Hepatitis B virus reactivation and associated morbidity and mortality70. A detailed 
assessment of Hepatitis B/C medical history and risk factors must be done for all patients at 
screening.  Patients with the following risk factors must  have hepatitis screening pre-
treatment: 
• Blood transfusions prior to 1990 
• Current or prior IV drug users 
• Current or prior dialysis 
• Household contact with a hepatitis B or C patient 
• Current or prior high-risk sexual activity 
• History of jaundice 
 
Patients with a known diagnosis  of hepatitis B or C  infection will be excluded from study 
participation. Patient who meet criteria for hepatitis B or C screening and are found to have 
positive serology indicating an ongoing infection, will be excluded from study participation.  
For all other  patient who start study treatment and are subsequently found to have  a hepatitis 
B reactivation or  hepatitis C flare, please refer to tables 6 and 7. 
Table 6 
Guidelines for the management of hepatitis B reactivation 
 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as: 
[Increase of 1 log in HBV-DNA 
relative to baseline HBV-DNA 
value OR new appearance of 
measurable HBV-DNA] 
 
Treat: Start a second antiviral medication 
AND 
Interrupt Everolimus administration until resolution:  
1. 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-started at one dose 
lower, if available. If the patient is already receiving the lowest dose of Everolimus 
according to the protocol, the patient should restart at the same dose after resolution. 
Both antiviral therapies should continue at least 4 weeks after last dose of Everolimus.  
If resolution occurs > 28 days Patients should discontinue Everolimus but continue 
both antiviral therapies at least 4 weeks after last dose of Everolimus. 
For patients with baseline 
results: 
Negative HBV-DNA and HBsAg 
AND 
[Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb] 
------------------------------------- 
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication 
AND 
Interrupt Everolimus administration until resolution: 
2. 
≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-started at one dose 
lower, if available . If the patient is already receiving the lowest dose of Everolimus 
according to the protocol, the patient should restart at the same dose after resolution. 
Antiviral therapy should continue at least 4 weeks after last dose of Everolimus. 
If resolution occurs > 28 days Patients should discontinue Everolimus but continue 
antiviral therapy at least 4 weeks after last dose of Everolimus. 
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations/Other: Viral 
Reactivation), unless considered life threatening by the investigator, in which case they should be recorded as grade 4. Date 
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Table 7 
Guidelines for the management of hepatitis C flare 
Baseline results 
HCV flare definition* 
HCV flare management 
Detectable HCV-RNA 
 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue Everolimus 
Knowledge of past hepatitis C 
infection with no detectable 
HCV-RNA 
New appearance of detectable HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue Everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations - Other: Viral Flare), 
unless considered life threatening by the investigator; in which case they should be recorded as grade 4. Date of 
viral flare is the date on which both the clinical criteria described above were met. (e.g., for a patient whose 
HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the date 
of viral flare is 22 JAN 2011). 
8     CONCOMITANT MEDICATIONS 
Patients must be instructed not to take any medications (over-the-counter or other products) 
during the protocol treatment period without prior consultation with the investigator. The 
investigator should instruct the patient to notify the study site about any new medications she 
takes after the start of study drug. All medications (other than study drug) and significant non-
drug therapies (including physical therapy and blood transfusions) taken within 28 days of 
starting study treatment through the 30-day safety follow up visit should be reported on the 
CRF. 
8.1  Prohibited concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is allowed, including drugs given prophylactically (e.g. antiemetics ± steroids), 
with the following exceptions: 
• No other investigational therapy must be given to patients. 
• No chronic treatment with systemic steroids (unless for the treatment of pneumonitisas 
described in Section 7.3.7) or another immunosuppressive agent. Topical or inhaled 
corticosteroids are allowed. 
• No anticancer agents other than the study medications administered as part of this 
study protocol must be given to patients. If such agents are required for a patient then 
the patient must be removed from protocol treatment. 
• Growth factors (e.g. G-CSF, G-GM-CSF) are not to be administered prophylactically 
but may be prescribed by the treating physician for rescue from severe hematologic 
events. 
• Immunosuppressants may affect the response to vaccination and vaccination during 
treatment with Everolimus may therefore be less effective. The use of live vaccines 
should be avoided during treatment with Everolimus. Examples of live vaccines are: 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, 
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• Drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A4 (as 
indicated in Section 8.1.1) must be avoided in association with blinded drug as these 
can alter metabolism. Strong inhibitors or inducers of the isoenzyme CYP3A4 must 
not be administered as systemic therapy. 
8.1.1  Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates 
 
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the multidrug 
efflux pump, PgP (PgP, MDR1, and ABCB1). Therefore, extent of absorption and subsequent 
elimination of systemically absorbed everolimus may be influenced by products that are 
substrates, inhibitors, or inducers of CYP3A4 and/or PgP. Concurrent treatment with strong 
CYP3A4-inhibitors should be avoided. Refer to Table 8 and 9 for a comprehensive list of 
inducers and inhibitors of CYP3A4 and  a list of relevant substrates, inducers and inhibitors of 
PgP. Inhibitors of PgP may decrease the efflux of everolimus from brain or tumor and 
therefore increase everolimus concentrations in these tissues. In vitro studies showed that 
everolimus is a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the 
concentrations of products eliminated by these enzymes. Thus, caution should be exercised 
when co-administering everolimus with CYP3A4 and CYP2D6 substrates with a narrow 
therapeutic index. Clinical studies have been conducted in healthy subjects to assess 
pharmacokinetic drug interactions between everolimus and potential CYP3A modifiers 
(ketoconazole, verapamil, erythromycin, rifampin, midazolam, and HMGCoA reductase 
inhibitors (statins). 
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. 
Therefore, the following are recommended: 
• Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided. They may increase the 
serum concentration of Everolimus. 
• Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution. They may increase the serum concentration of 
Everolimus. If a patient requires co-administration of moderate CYP3A4 inhibitors or PgP 
inhibitors, reduce the dose of everolimusby approximately 50% . Additional dose 
reductions to every other day may be required to manage toxicities. If the inhibitor is 
discontinued, the Everolimus dose should be returned to the dose used prior to initiation of 
the moderate CYP3A4/PgP inhibitor after a washout period of 2 to 3 days. Everolimus 
dose reductions are required for patients being treated for subependymal giant cell 
astrocytoma or renal cell carcinoma.  
• 
Grapefruit or Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided. 
• If patients require co-administration of a strong CYP3A4 inducer, consider doubling the 
daily dose of everolimus(based on pharmacokinetic data), using increments of 5 mg or 
less. This dose of everolimus is predicted to adjust the AUC to the range observed without 
inducers. However, there are no clinical data with this dose adjustment in patients 
receiving strong CYP3A4 inducers. If the strong inducer is discontinued, consider a 
washout period of at least 3 to 5 days (reasonable time for significant enzyme de-
induction), before the everolimus dose is returned to the dose used prior to initiation of the 
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• This dose adjustment of Everolimus is intended to achieve similar AUC to the range 
observed without inducers. However, there are no clinical data with this dose adjustment 
in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the 
Everolimus dose should be returned to the dose used prior to initiation of the strong 
CYP3A4/PgP inducer. 
Please refer to Table 8 listing relevant inducers and inhibitors of CYP3A and Table 9.0 for a 
list of relevant substrates, inducers, and inhibitors of PgP. 
Table 8.0 
Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme 
CYP3A 
Inducers 
Strong inducers: 
Avasamibe, carbamazepine,  enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), 
St. John’s wort (hypericum perforatum),  
Moderate inducers: 
bosentan, efavirenz, etravirine, genistein, lersivirine, lopinavir, modafinil, nafcillin, ritonavir, semagacestat 
[talviraline], thioridazine, tipranavir 
Weak inducers: 
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, boceprevir, brivacetam, clobazam, danshen, 
dexamethasone, Echinacea, eslicarbazepine, garlic (allium sativum), ginseng, gingko (ginkgo biloba), 
glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone, prednisone, [pleconaril], primidone, 
quercetin, raltegravir, ritonavir, rufinamide, sorafenib, stribild (combo of elvitegravir, cobicistat, emtricitabine, 
and tenofovir), sulfinpyrazone, telaprevir, terbinafine, ticagleror, ticlopidine, 
topiramate, [troglitazone] , vemurafenib, vicriviroc/ritonavir vinblastine 
Inhibitors 
Strong inhibitors: 
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir / ritonavir, eltegravir/ritonavir, grapefruit juice, 
indinavir, indinavir/ritonavir,  itraconazole, ketoconazole, lopinavir/ritonavir,, mibefradil, nefazodone, nelfinavir, 
posaconazole  ritonavir, saquinavir, saquinavir/ritonavir,  telaprevir, telithromycin, tipranavir/ritonavir, 
troleandamycin, voriconazole 
Moderate inhibitors: 
amprenavir, aprepitant, atazanavir, atazanavir/ritonavir, casopitant, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, 
grapefruit juice (citrus parasidi fruit juice), imatinib, lomitapide, netupitant, nilotinib, schisandra sphenanthera,  
tofisopam, verapamil 
Weak inhibitors: 
almorexant, alprazolam, alprazolam, amiodarone, amlodipine, amlodipine, atorvastatin, azithromycin, berberine, 
bicalutamide, bicalutamide, blueberry juice, cilostazol, cilostazol, cimetidine, clotrimazole, clozoxazone, 
cranberry juice, cyclosporine, delavirdine, everolimus, fluoxetine, fluvoxamine, fosaprepritant, ginkgo, 
goldenseal, isoniazid, isoniazid, ivacaftor, lacipidine, linagliptin, nilotinib, oral contraceptives, pazopanib, 
peppermint oil, propiverine, ranitidine, ranitidine, ranolaxine, ranolazine, resveratrol, roxithromycin, Seville 
orange, simeprevir, sitaxentan, tabimorelin, tacrolimus, teriflunomide, ticagrelor, tipranavir/ritonavir, tolvaptan, 
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Table 9.0 
Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and 
PgP/CYP3A dual inhibitors 
Substrates 
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, aprepitant, atorvastatin acid, 
atorvastatin, azithromycin, boceprevir, bosentan, carvedilol, caspofungin, ceritinib, cerivastatin, citalopram, 
colchicine, CP-481,715, cyclosporine, dabigatran, digoxin, docetaxel, domperidone, doxepin, doxorubicin, 
eribulin, everolimus, fentanyl,fexofenadine, fidaxomicin, fluvastatin, fosamprenavir, gatifloxacin, idelalisib, 
iloperidone, indacaterol, indinavir, , irbesartan, lacosamide, lapatinib, levetiracetam, levofloxacin, linagliptin, 
linezolid, loperamide, losartan, maraviroc, mirabegron, moxifloxacin, naloxegol, nateglinide, nevirapine, 
nintedanib, lodaterol, paclitaxel, pantoprazole, paroxetine, pazopanib, phenytoin, posaconazole, pravastatin, 
proguanil, quinidine, quinine, ranolazine, riociguat, risperidone, ritonavir, rivaroxaban, saquinavir, silodosin, 
simeprevir, simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib, tacrolimus,talinolol, telaprevir, tenofovir, 
ticagrelor, tipranavir, tolvaptan, topotecan, umeclidinium, valsartan, vardenafil, vincristine, voclosporin, 
voriconazoleeverolimus 
Inducers 
avasimibe, carbamazepine, efavirenz, genistein, phenytoin, quercetin, rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
PgP Inhibitors 
alogliptin, canaglifozin, cremophor RH40, curcumin, ketoconazole, lapatinib, lopinavir/ritonavir, mirabegron, 
propafenone, simepravir, valspodar, vandetanib, voclosporin 
PgP/CYP3A Dual Inhibitors 
amiodarone, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, erythromycin, 
felodipine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, indinavir/ritonavir, itraconazole,  mibefradil, milk 
thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, quinidine, ranolazine, 
rifampin, ritonavir, saquinavir/ritonavir, Schisandra chinensis, St John’s wort (hypericum perforatum), talinolol, 
telaprevir telmisartan, ticagrelor, tipranavir /ritonavir, tolvaptan,  verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011, 29-Oct-
2012, which summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the University of Washington’s Drug Interaction Database, and Indiana University School 
of Medicine's Drug Interaction Table. 
 
9    VISIT SCHEDULE AND ASSESSMENTS 
9.1 
Baseline assessment  
 
The following baseline assessments have to be performed at any time  prior to initiation of 
treatment and must include: 
• Determination of Oncotype Dx recurrence score. 
• Determination of tumor HER2, ER and PR status 
The following baseline assessments have to be performed within 4 weeks prior to initiation of 
treatment and must include: 
• Complete history and review of systems including assessment of Eastern 
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review of concomitant medication and documentation of the date of the last dose 
of endocrine or chemotherapy received before entering the study.  
• Complete physical examination including measurements of height, weight, and 
vital signs including oxygen saturation by pulse oximetry.  
• Record  breast tumor and axillary node measurements by physical exam for 
palpable tumors. 
• Bilateral mammogram with clip placement to mark tumor bed 
• MRI of the involved breast (or a unilateral ultrasound of the involved breast if a  
patient is unable to have a breast MRI due to claustrophobia, metal in body, or 
lack of insurance coverage, etc). 
• If suspicious lymph nodes are detected clinically or by imaging, a diagnostic 
image guided fine needle aspiration or biopsy of the suspicious node is required. 
• Complete blood count (CBC) including platelets and differential  
• Comprehensive metabolic profile (CMP) including albumin, calcium, phosphorus, 
BUN, creatinine, total bilirubin, alkaline phosphatase, LDH, AST, ALT, Na, K, 
Cl, CO2 and fasting glucose. 
• Fasting lipid profile 
• Hemoglobin A1C 
• PTT, PT and INR 
• 12-lead ECG 
• Complete microscopic urine analysis. 
• CT scan of the chest and abdomen for clinical stage III or symptomatic stages II 
• Bone scan for clinical stage III or symptomatic stage II.  
• Bone density assessment ( within 12 months). If  results of baseline bone density 
confirm evidence of osteoporosis, treatment for osteoporosis will be left to the 
discretion of the treating physician.  
 
9.2 
Evaluation During Study 
The following assessments will be performed every 4 weeks ( +/- 3 days) except as noted: 
• Medical history including ECOG performance status, treatment related AE assessment, 
concomitant medication review and study drug compliance assessment including dose and 
any treatment interruption. 
• Physical examination including measurements of weight and vital signs including oxygen 
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• Record  breast tumor and axillary node measurements by physical exam for palpable 
tumors. 
• CBC, including differential and platelets   
• CMP including albumin, calcium, phosphorus, BUN, creatinine, total bilirubin, alkaline 
phosphatase, LDH, AST, ALT, Na, K, Cl, CO2 and fasting glucose. 
• PTT,PT and INR 
• Radiological Assesment: The involved breast, and axilla (in patients with enlarged axillary 
nodes at baseline), will be reimaged by MRI between weeks 12 and 13 and again after 
completing neoadjuvant therapy. If a patient is unable to have a breast MRI (due to 
claustrophobia, metal in body, or lack of insurance coverage, etc) a breast ultrasound will 
be used to replace MRI at baseline, at 12-13 weeks and after completing neoadjuvant 
therapy. Other imaging, such as ultrasonography or MRI, is at the discretion of the treating 
physicians. 
• Breast imaging may be repeated any time during therapy if clinical suspicion of 
progression of disease. 
• Dispense study medication in appropriate supply 
• Accountability and compliance check of returned pill diary and study medication 
• Fasting lipid profile every 2 cycles ( every 8 weeks) 
9.3 
Treatment discontinuation for disease progression 
If any of the following events occur during study treatment, the patient will be considered to 
have failed upfront endocrine therapy and everolimus. She will be removed from the study 
and offered other treatment, which could include immediate surgery - if the patient's tumor is 
resectable - or neoadjuvant chemotherapy; response to any subsequent preoperative therapy 
and findings at surgery will be recorded in these patients. 
 
• If a patient's tumor increases in size over baseline >20% by clinical examination at any 
point during study treatment  
• If a patient’s tumor increases in size over baseline >20%  radiographically on the 12-13 
week breast MRI (or ultrasound when indicated) 
9.4  
Surgical evaluation: 
Surgery will be scheduled 3-8 weeks after completion of last chemotherapy.  
 
A. Patients with evidence of tumor response ( including stable disease) : Patients completing 
26 weeks of neoadjuvant AI plus everolimus who are deemed resectable will undergo 
surgery. The decision regarding lumpectomy or mastectomy will be at the discretion of the 
treating surgeon.  All patients will have axillary lymph node sampling with a technique 
that is deemed appropriate by the treating surgeon:  
• 
For clinically node negative disease at baseline, defined as negative clinical 
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lymph node by imaging, sentinel node sampling is preferred over full axillary 
lymph node dissection. Subsequent full axillary lymph node dissection is at the 
discretion of the treating physicians.   
• 
For patients with clinically positive nodes at baseline – defined as palpable 
nodes or overtly abnormal nodes on imaging or and/or histologically confirmed 
node positive disease at baseline, who are clinically node-negative after 
completion of neoadjuvant therapy, sentinel node sampling is permitted, with 
subsequent full axillary lymph node dissection at the discretion of the treating 
physicians.  
• 
For patients with bulky or matted lymph nodes at baseline or persistently 
clinically positive axillary nodes at the time of surgery, full axillary lymph 
node dissection is preferred. 
   
B. Patients with evidence of disease progression during therapy: Patients who progress 
clinically or by imaging assessment during therapy will be removed from protocol 
treatment and further treatment including immediate referral to surgery or additional 
chemotherapy will be at the discretion of the treating physician. Response to any 
subsequent preoperative therapy and findings at surgery will be recorded.   
A copy of the pathology report is required. The patient's response to treatment will be 
recorded (clinical and at surgery ypT and ypN stage) and a PEPI (Preoperative Endocrine 
Prognostic Index) score calculated, which requires breast and nodal staging as well as repeat 
measurements of tumor ER expression and Ki67 ( APPENDIX B) 
 
9.5  
Post-operative treatment:  
Post-operative treatment is at the discretion of the treating physicians. Participation in 
subsequent adjuvant clinical trials is allowed. 
 
9.6 
Biomarker Assessment:  
Baseline formalin fixed paraffin embedded (FFPE) tissue block will be obtained from the 
diagnostic breast biopsy to collect 4 unstained slides and an additional single tissue core 
(ranging from 0.6mm to 4.0mm in diameter, obtained with a microarray instrument). In 
addition, a tissue block from the residual tumor tissue will be obtained from the surgical 
specimen to collect 10 unstained slides and an additional single tissue core (ranging from 
0.6mm to 4.0mm in diameter, obtained with a microarray instrument).  
 
Specimens collected at Yale University Cancer Center will be shipped to the following 
address: 
 
ATTN: Lawrence Rispoli 
300 George Street, Suite 120 
New Haven, CT 06511 
 
Speciments collected at Thomas Jefferson University Sidney Kimmel Cancer Center will be 
shipped to the following address: 


 
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ATTN: Angela Pallotto 
Main Building 
132 South 10th Street, Room 1170 
Philadelphia, PA 19107 
 
All samples collected as part of this study will be sent to the address above at Thomas 
Jefferson University for storage at the end of the study.The samples from the baseline biopsies 
and the surgical specimens will be used (when feasible) for measurement of Ki67 and 
research analyses.  Ki67 analysis will be performed at any Clinical Laboratory Improvement 
Amendments  (CLIA) certified laboratory including the Yale Specialized Translational 
Services (STS) laboratory. ER expression will be repeated on the surgical specimen for PEPI 
score calculation. The planned molecular analysis of these tissues may include gene 
expression profiling, and PI3K pathway biomarkers by Automated Quantitative Analysis  to 
develop an assay that may predict response or resistance to an everolimus and aromatase 
inhibitor combination.  Candidate markers include pS6, mTOR, p4E-BP1, pAKT and APC.  
 
9.7 
End of Study Evaluation 
Once post-operative therapy is completed, the final study follow up visit will be within 4-6 
weeks after completion of surgery and will include: 
• Complete review of systems and medical history including ECOG performance status 
assessment,  endocrine therapy related AE assessment and record concomitant 
medications 
• Physical examination including measurement of weight and vital signs including oxygen 
saturation by pulse oximetry. 
• CBC, including differential and platelets, serum albumin, calcium, phosphorus, BUN, 
creatinine, total bilirubin, alkaline phosphatase, LDH, AST, ALT, Na, K, Cl, CO2 
assessment and fasting glucose. 
• Complete microscopic urine analysis 
• PTT, PT and INR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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10 STUDY CALENDAR 
 
Baseline 
W1 
W5 
W9 
W13 
W17 
W21 W25 W26 
Surgery 
End of Study 
Evaluation 
within 4 weeks 
prior* 
Assessments every 4 wks (+/- 3 Days) 
3-8 wks post 
chemo 
4-6 wks after surgery 
Informed Consent 
X 
HER2, ER, PR Assessment1 
X 
Oncotype Dx Recurrence 
Score2 
X 
Physical 
Complete Medical History3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Tumor 
Assessment5 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Assessment 
X 
X 
X 
X 
X 
X 
X 
Study Drug Compliance6 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
CBC Complete w/Diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
PTT, PT & INR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Micro Urinalysis 
X 
X 
Fasting Lipid Profile 
X 
 
X 
 
X 
 
X 
 
 
 
 
Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B & C screening7 
X 
 
 
 
 
 
 
 
 
 
 


 
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Baseline 
W1 W5 W9 W13 W17 W21 W25 W26 
Surgery 
End of Study 
Evaluation 
Pathology 
 
 
 
 
 
 
 
 
 
 
 
FFPE Tissue8 
X 
 
 
 
 
 
 
 
 
X 
 
Imaging 
Bilateral Mammogram9 
X 
MRI of Involved Breast10,11 
X 
X9 
X9 
12-lead ECG 
X 
CT scan chest/abd12 
X 
Bone scan12 
X 
Bone Density Assessment13 
X 
Treatment 
Aromatase Inhibiters14 
X 
X 
X 
X 
X 
X 
X 
X 
Everolimus 
X 
X 
X 
X 
X 
X 
X 
X 
Surgery15,16 
X 
Post-operative treatment17 
X 
*Study subjects who come off treatment for progression or toxicity, should be followed through surgery and end of study visit. For study subjects who 
come off treatment for toxicity, continue to follow for up to 4 weeks or until resolution of toxicity.  
1. ER/PR/HER2 receptor from diagnositic biopsy results will be collected. Receptor status can be performed at any time prior to 
starting study treatment. 
2. Oncotype Dx recurrence score from diagnostic biopsy will be collected. Oncotype Dx analysis can be performed at any time prior to 
starting study treatment.  
3. Complete history and review of systems and documentation of the date of the last dose of endocrine or chemotherapy received 
before entering the study (baseline).  
4. Complete physical examination including measurements of height (only at baseline), weight, and vital signs including oxygen 
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5. Record breast tumor and axillary node measurements by physical exam for palpable tumors. If suspicious lymph nodes are detected 
clinically or by imaging, a diagnostic image guided fine needle aspiration or biopsy of the suspicious node is required. 
6. Study drug compliance assessment including dose and any treatment interruption. 
7. For high risks subjects only. See exclusion criteria # 10.  
8. Baseline fresh frozen formalin fixed paraffin embedded (FFPE) tissue block will be obtained from the diagnostic breast biopsy to 
collect 4 unstained slides and an additional single tissue core (ranging from 0.6mm to 4.0mm in diameter, obtained with a microarray 
instrument). In addition, a tissue block from the residual tumor tissue will be obtained from the surgical specimen to collect 10 
unstained slides and an additional single tissue core (ranging from 0.6mm to 4.0mm in diameter, obtained with a microarray 
instrument). 
9. Mammogram should be done within 4 weeks prior to start of treatment. Mammogram is to be done with clip placement to mark 
tumor bed. Breast imaging may be repeated any time during therapy if clinical suspicion of progression of disease. 
10. Or a unilateral ultrasound of the involved breast if a patient is unable to have a breast MRI due to claustrophobia, metal in body, or 
lack of insurance coverage, etc. Breast imaging may be repeated any time during therapy if clinical suspicion of progression of 
disease. 
11. The involved breast, and axilla (in patients with enlarged axillary nodes at baseline), will be reimaged by MRI between weeks 12 and 
13 and again after completing neoadjuvant therapy. If a patient is unable to have a breast MRI, a breast ultrasound will be used to 
replace MRI at baseline, at 12-13 weeks and after completing neoadjuvant therapy. Other imaging, such as ultrasonography or MRI, 
is at the discretion of the treating physicians. 
12. For clinical stage III or symptomatic stages II 
13. Bone density assessment (within 12 months). If results of baseline bone density confirm evidence of osteoporosis, treatment for 
osteoporosis will be left to the discretion of the treating physician.  
14. Standard dose of one of the following aromatase inhibitors (physician’s choice): Anastrozole 1 mg, Letrozole 2.5 mg, Exemestane 
25 mg. 
15. Surgery will be scheduled 3-8 weeks after completion of last dose of aromatase inhibitor and everolimus. Patients with evidence of 
tumor response (including stable disease): Patients completing 26 weeks of neoadjuvant AI plus everolimus who are deemed 
resectable will undergo surgery. The decision regarding lumpectomy or mastectomy will be at the discretion of the treating surgeon.  
All patients will have axillary lymph node sampling with a technique that is deemed appropriate by the treating surgeon (refer to 
protocol).  
16. B) Patients with evidence of disease progression during therapy: Patients who progress clinically or by imaging assessment during 
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chemotherapy will be at the discretion of the treating physician. Response to any subsequent preoperative therapy and findings at 
surgery will be recorded (refer to protocol).   
17. Post-operative treatment is at the discretion of the treating physicians. Participation in subsequent adjuvant clinical trials is allowed.  
 


 
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11 Evaluation of Safety 
 
Information about all adverse events, whether volunteered by the subject, discovered 
by investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
 
11.1 Specification of Safety Parameters 
11.1.1 
Unanticipated Problems 
Unanticipated problems (UAPs) include, in general, any incident, experience, or outcome that 
meets the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
UAPs are considered to pose risk to participants or others when they suggest that the research 
places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
11.1.2 
Adverse Event 
An adverse event is any untoward or unfavorable medical occurrence in a human participant, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participant’s participation in the research, 
whether or not considered related to the participant’s participation in the research. 
11.1.3 
Laboratory test abnormalities 
 
Laboratory abnormalities that constitute an Adverse event in their own right (are 
considered clinically significant, induce clinical signs or symptoms, require concomitant 
therapy or require changes in study treatment), should be recorded on the Adverse Events 
CRF. Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
 
Laboratory abnormalities, that do not meet the definition of an adverse event, should 
not be reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
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as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol and is still, by definition, an adverse event. 
 
11.1.4 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the participant at immediate risk of death from the event as 
it occurred) 
• Is disabling or incapacitating 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect  
• An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the participant or may require intervention to 
prevent one of the outcomes listed in this definition. 
 
11.2 Safety Assessment and Follow-Up 
The PI will follow adverse events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator (or designee) will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome information 
until resolution or stabilization. 
11.3 Recording Adverse Events 
The following subsections detail what information must be documented for each adverse 
event occurring during the time period specified in Section 11.4. 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF). All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should be recorded in the source document, though 
should be grouped under one diagnosis.  
 
All adverse events occurring during the study period must be recorded.  


 
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The clinical course of each event should be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause. Serious adverse 
events that are still ongoing at the end of the study period must be followed up to determine 
the final outcome. Any serious adverse event that occurs after the study period and is 
considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately.  
11.3.1 
Relationship to Study Intevention 
The relationship to study intervention or study participation must be assessed and documented 
for all adverse events. Evaluation of relatedness must consider etiologies such as natural 
history of the underlying disease, concurrent illness, concomitant therapy, study-related 
procedures, accidents, and other external factors.  
The following guidelines are used to assess relationship of an event to study intervention: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
11.3.2 
Expectedness 
The PI is responsible for determining whether an AE is expected or unexpected. An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the intervention. Risk information to assess 
expectedness can be obtained from preclinical studies, the investigator’s brochure, published 
medical literature, the protocol, or the informed consent document. 
11.3.3 
Severity of Event 
Adverse events will be graded for severity according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 
11.3.4 
Intervention 
Any intervention implemented to treat the adverse event must be documented for all adverse 
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11.4 
Safety Reporting 
The study period during which adverse events must be reported is normally defined as the 
period from the initiation of any study procedures to the end of the study treatment follow-up.  
For this study, the study treatment follow-up is defined as 30 days following the last 
administration of study treatment. 
 
For patients whose Oncotype Dx recurrence score is unknown and who sign the molecular 
pre-screening ICF, AEs which occur after signature of this consent will only be captured if 
they meet the definition of serious as outlined in Section 11.1.2 and are reported to be causally 
related with study procedures (e.g. an invasive procedure such as biopsy). Once the main 
study ICF is signed, all AEs per the descriptions below will be captured in the Adverse Event 
CRF. 
Patients whose Oncotype Dx recurrence score is known will sign the main study ICF. 
 
For patients with unknown Oncotype Dx Recurrence Scores and who sign the molecular pre-
screening ICF, SAE collection will start upon signing the molecular pre-screening ICF. SAEs 
will only be reported if the event is suspected to be causally related to a study procedure as 
assessed by the investigator (e.g. an invasive procedure such as biopsy). SAEs will be 
followed until resolution or until clinically relevant improvement or stabilization. If the main 
ICF is not signed (molecular screen failure), SAE collection ends 30 days after the last study 
related procedure. 
 
For patients with known Oncotype Dx Recurrence Scores who sign the main study ICF, SAE 
collection starts at time of main study informed consent whether the patient is a screen failure 
or not. 
11.4.1 
Reporting to IRB 
11.4.1.1 Unanticipated Problems 
All incidents or events that meet criteria for unanticipated problems (UAPs) as defined in 
Section 11.1.1 require the creation and completion of an unanticipated problem report form 
(OHR-20).  
UAPs that pose risk to participants or others, and that are not AEs, will be submitted to the 
TJU IRB on an OHR-20 form via the eazUP system within 10 working days of the 
investigator becoming aware of the event.  
UAPs that do not pose risk to participants or others will be submitted to the TJU IRB at the 
next continuing review.  
Participating sites will submit UAPs to their local IRB per local institutional requirements. 
Participating sites will provide TJU with a copy of all UAP reports. 


 
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11.4.1.2 Adverse Events 
Grade 1 AEs will be reported to the IRB at continuing review.  
Grade 2 AEs will be reported to the IRB at the time of continuing review.  
11.4.1.3 Serious Adverse Events 
SAEs will be reported to the IRB on OHR-10 forms via the electronic reporting system 
(eSAEy) according to the required time frames described below. 
Grade 3-4 AEs that are unexpected and deemed to be at least possibly related to the study will 
be reported to the IRB within 2 working days of knowledge of the event. 
Grade 3-4 AEs that are deemed unrelated to the study will be reported to the IRB within 5 
working days.  
Grade 5 AEs will be reported to the IRB within one working day of knowledge of the event. 
All SAEs will be submitted to the IRB at continuing review, including those that were 
reported previously. 
11.4.2 
Reporting to SKCC DSMC 
On a quarterly basis, all AEs and SAEs, safety and toxicity data, and any corrective actions 
will be submitted to the DSMC per the DSMP. The quarterly report to DSMC will also 
include any unanticipated problems that in the opinion of the PI should be reported to the 
DSMC. 
For expedited reporting requirements, see Appendix C: DSMC AE/SAE Reporting 
Requirements. 
11.4.3 
Reporting to Drug Supplier 
The principal investigator has the obligation to report all serious adverse events to the IRB 
and the Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after 
the patient has provided informed consent and until at least 30 days after the patient has 
stopped study treatment/participation , must be reported to Novartis within 24 hours of 
learning of its occurrence. Information about all SAEs is collected and recorded on a Serious 
Adverse Event Report Form.  The investigator must assess and record the relationship of each 
SAE to each specific study treatment (if there is more than one study treatment), complete the 
SAE Report Form in English, and send the completed, signed form along with the Novartis 
provided fax cover sheet to the Novartis Oncology Drug Safety and Epidemiology 
(DS&E) department by fax (fax: 877-778-9739) within 24 hours.  
Any additional information for the SAE including complications, progression of the 
initial SAE, and recurrent episodes must be reported as follow-up to the original episode 
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a different time interval or otherwise considered completely unrelated to a previously reported 
one should be reported separately as a new event. 
 
Any SAEs experienced after this 30 days period should only be reported to Novartis if 
the investigator suspects a causal relationship to the study drug. Follow-up information is 
submitted in the same way as the original SAE Report.  Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.  
 
If the SAE is not previously documented in the Everolimus Investigator Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study drug, a 
DS&E associate may urgently require further information from the investigator for Health 
Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform 
all investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
11.1 
   Reporting for Subsites 
 
All SAEs occurring at a participating site  must be reported to the Thomas Jefferson 
University clinical study coordinator and Novartis (per section 11.4.3)  within 24 hours of 
notification. The initial notification can take place via email, followed by the submission of a 
formal report. 
 
SAEs should be reported to  Thomas Jefferson University s The Off-site OHR-10 form (or 
On-site OHR-10 for Network site or sites using the TJU IRB) located in Appendix D, and 
should comprise a full written summary, detailing relevant aspects of the adverse events in 
question, including grading and attribution to study drug. Where applicable, information from 
relevant hospital case records and autopsy reports should be included.  
 
SAE reports should be signed by the sub-site PI, and then faxed to the Thomas Jefferson 
University coordinator within 24 hours at: 215-923-9974 attention: Noelle Sowers.   
 
The TJU coordinator will notify the TJU PI and obtain the TJU PI signature, and report these 
events to the TJU Medical Monitor/IRB appropriately (within 5 working days if it deems an 
amendment, or in a spreadsheet at the time of annual review if no amendment is necessary). 
Any non-reportable AE must be kept by the sub-site on an ongoing tracking log to be 
reviewed by TJU quarterly (see Appendix E). 
 
Unanticipated problems (UAPs) occurring at participating sites that pose risk to subjects or 
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form OHR-20 and should be faxed to the Thomas Jefferson University coordinator within 5 
days at: 215-923-9974 attention: Noelle Sowers.  
11.2 
Coordinating Site 
All reportable AEs/SAEs occurring at the coordinating site must be reported to TJU 
IRB/Medical Monitor using the On-site OHR-10 Form, and should comprise a full written 
summary detailing relevant aspects of the adverse events in question, including grading and 
attribution to study drug. Where applicable, information from relevant hospital case records 
and autopsy reports should be included. 
 
Reportable AE/SAEs from TJU will then also be faxed to the Participating Site coordinator 
per same guidelines as outlined above. 
 
All unexpected AE./SAEs that are probably or definitively related to the study procedures 
from either the participating site or the coordinating site must be reported to the TJU IRB 
within 48 hours of the TJU Principal Investigator being notified of the event.  
 
Any on-study death (regardless of relationship) and any unforeseen death, that indicates that 
the participant or others may be at increased risk of harm, must be submitted to the TJU 
IRB/Medical Monitor within 24 hours of notification. Any unrelated SAE should be reported 
within 5 working days. The TJU study team will notify the TJU IRB appropriately. 
 
Additional follow-up SAE reports should be submitted when available. 
 
Unanticipated problems that pose risk to subjects or others, and that are not AEs/SAEs should 
be reported to TJU IRB within 10 working days using form OHR-20 and should be faxed to 
the Participating Site coordinator within 24 hours.  
12 
Study Oversight 
In addition to the PI’s responsibility for oversight, study oversight will be under the direction 
of the SKCC’s Data and Safety Monitoring Committee (DSMC). The DSMC operates in 
compliance with a Data and Safety Monitoring Plan (DSMP) that is approved by the Clinical 
Trials Oversight Committee (CTOC).  
13 
Clinical Site Monitoring and Auditing 
Clinical site monitoring and auditing is conducted to ensure that the rights of human 
participants are protected, that the study is implemented in accordance with the protocol 
and/or other operating procedures, and that the quality and integrity of study data and data 
collection methods are maintained. Monitoring and auditing for this study will be performed 
in accordance with the SKCC’s Data and Safety Monitoring Plan (DSMP) developed by the 
SKCC Data and Safety Monitoring Committee (DSMC). The DSMP specifies the frequency 
of monitoring, monitoring procedures, the level of clinical site monitoring activities (e.g., the 
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reports. Some monitoring activities may be performed remotely, while others will take place 
at the study site(s). Appropriate staff will conduct monitoring activities and provide reports of 
the findings and associated action items in accordance with the details described in the DSMP. 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
funding sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related docuemnts (e.g. source documents, regulatory 
documents, data collection instruments, study data etc). The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc).  
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliabce and quality assurance 
offices.  
Representatives from the Thomas Jefferson University study team will monitor on site at the 
participating site (or virtually if geographically impossible) within 4 weeks of the first subject 
enrolling, and every 4-6 weeks thereafter as outlined in the TJU Monitoring Policy. 
Additional study monitoring by an independent auditing agency will be conducted at 10% and 
50% of site accrual per the TJU Data and Safety Monitoring Plan. This will either occur on-
site, if feasible, or will require participating sites to send TJU all source documents, patient 
charts, etc to TJU for audit.  
Teleconferences with the PIs, research nurses/coordinators, and regulatory staff will occur 
quarterly. This will be a forum to discuss study related issues including accrual. SAE/AEs 
experienced, stud response, deviations/violations and study management issues. Minutes of 
these discussions will be taken to document the date of these meetings, the participants and 
the issues that were discussed. Copies of these minutes will be maintained in the Regulatory 
Binders at all participating sites.  
14 
STATISTICAL CONSIDERATION 
 
14.1 
Primary Endpoint  
The primary study endpoint is  PEPI score 0 as defined in Appendix B.  These results will be 
retrieved from the routine pathology report. The PEPI score will be reported using descriptive 
statistics and 95% confidence intervals.  
 
14.2 
Secondary Endpoint  
1. Clinical and radiographic response rate will be assessed by two measures. 
Radiographic tumor size measurements by MRI (or ultrasound when MRI not feasible) 
and physical examination after completion of all chemotherapy compared to baseline.  
Response will be categorized following RECIST criteria (Appendix A). The results 
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2. Toxicity will be recorded using the standard NCI Common Toxicity Criteria as per 
http://ctep.cancer.gov/forms/CTCAEv4.pdf.and . Results will be reported in a tabular 
format by worst grade and occurrence per patient over the entire study period  
3. Measurements of Ki67 at baseline and after completion of neoadjuvant therapy.  
4. Baseline and residual cancer tissue will be collected for future biomarker analysis. 
Considering the small sample size of the study the biomarker results will be 
exploratory and hypothesis generating. The planned molecular analysis of these tissues 
may include gene expression profiling, and PI3K pathway markers. 
14.3 
Sample Size calculation  
This is  a single arm phase II study to evaluate neoadjuvant endocrine therapy with everolimus 
in postmenopausal women with ER+/HER2 – breast cancers with low and intermediate risk 
( < 25) Recurrence Scores. The primary endpoint will be response defined as a PEPI-0 rate. A 
treatment with minimal activity would be expected to have PEPI-0 rate of 25%. Alternatively, 
a treatment will be considered worthy of further study if its true PEPI-0 rate is 45% or better.  
Simon’s optimal two-stage design is employed for this single-arm phase II trial and a total of 
27 eligible patients will be enrolled. First, 15 eligible patients will be enrolled in the study. if 
5 or more of 15 eligible patients achieve a PEPI score of 0, we will enroll another 12 patients 
into the study. If 10 or more of the 27 eligible patients achieve a PEPI score of 0, we will 
conclude that the regimen warrants further study. This design has a power of 80% and a one-
sided significance level of 0.1. The probability of stopping early if the treatment is ineffective 
(true PEPI-0 rate of < 25%) is 69%. Assuming that 10-20% of enrolled patients will be 
inevaluable, we plan to enroll  up to 33 in total. 
Protocol amendments, or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Novartis and the investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB at each study center.  A 
copy of the written approval of the IRB must be provided to Novartis. Examples of 
amendments requiring such approval are: 
1. 
increases in drug dose or duration of exposure of subjects, 
2. 
significant changes in the study design (e.g. addition or deletion of a control group), 
3. 
increases in the number of invasive procedures, 
4. 
addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients 
included in the trial.  If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons Novartis must be notified and the IRB at 
the center must be informed immediately.   Amendments affecting only administrative aspects 
of the study do not require formal protocol amendments or IRB approval but the IRB must be 


 
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kept informed of such administrative changes. Examples of administrative changes not 
requiring formal protocol amendments and IRB approval include: 
1. 
changes in the staff used to monitor trials  
2. 
minor changes in the packaging or labeling of study drug. 
  
15 
Source Documents and Access to Source Data/Documents 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, and regulatory and institutional requirements for the protection of 
confidentiality of participant information. Study staff will permit authorized representatives of 
SKCC and regulatory agencies to examine (and when required by applicable law, to copy) 
research records for the purposes of quality assurance reviews, audits, and evaluation of the 
study safety, progress and data validity.  
16 
Ethics/Protection of Human Participants 
16.1 
Ethical Standard 
The investigator will ensure that this study is conducted at all participating sites in full 
conformity with the principles set forth in The Belmont Report: Ethical Principles and 
Guidelines for the Protection of Human Subjects of Research, as drafted by the US National 
Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 
(April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6.  
16.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to a properly constituted independent Institutional Review Board (IRB), in 
agreement with local legal prescriptions, for review and approval. Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes 
are implemented in the study.  
16.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in 
the study and continues throughout study participation. Extensive discussion of risks and 
possible benefits of study participation will be provided to participants and their families, if 
applicable. A consent form describing in detail the study procedures and risks will be given to 
the participant. Consent forms will be IRB-approved, and the participant is required to read 
and review the document or have the document read to him or her. The investigator or 
designee will explain the research study to the participant and answer any questions that may 
arise. The participant will sign the informed consent document prior to any study-related 
assessments or procedures. Participants will be given the opportunity to discuss the study with 
their surrogates or think about it prior to agreeing to participate. They may withdraw consent 


 
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at any time throughout the course of the study. A copy of the signed informed consent 
document will be given to participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their clinical care will 
not be adversely affected if they decline to participate in this study. The consent process will 
be documented in the clinical or research record.  
16.4 
Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the drug 
supplier and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to any study information relating to participants. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all study 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) for the study participants. The clinical study 
site will permit access to such records. 
17 
Data Handling and Record Keeping 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The investigators will maintain adequate case 
histories of study participants, including accurate case report forms (CRFs), and source 
documentation. 
17.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents and laboratory reports must be reviewed 
by the study team and data entry staff, who will ensure that they are accurate and complete. 
Unanticipated problems and adverse events must be reviewed by the investigator or designee.  
17.2 
Study Records Retention 
Study records will be maintained for at least three years from the date that the grant federal 
financial report (FFR) is submitted to the NIH. 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by local regulations. No records 
will be destroyed without the written consent of the sponsor, if applicable. It is the 


 
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responsibility of the sponsor to inform the investigator when these documents no longer need 
to be retained. 
17.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements. The noncompliance may be on the part of the 
participant, the investigator, or study staff. As a result of deviations, corrective actions are to 
be developed by the study staff and implemented promptly. 
All deviations from the protocol must be addressed in study participant source documents and 
promptly reported to the IRB and other regulatory bodies according to their requirements.  
18 
Study Finances 
18.1 
Funding Source 
Novartis Pharmaceuticals is providing the investigational product, everolimus (Afinitor), for 
this study.  
18.2 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
sponsor prior to participation in this study. All Jefferson University Investigators will follow 
the TJU Conflicts of Interest Policy for Employees (107.03). 
18.3 
Participant Stipends or Payments 
Participants will not be paid as part of this study.  
19 
Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical trials registration policy as a condition for publication. The ICMJE defines a 
clinical trial as any research project that prospectively assigns human participants to 
intervention or concurrent comparison or control groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome. Medical interventions 
include drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, 
and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE 


 
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policy requires that all clinical trials be registered in a public trials registry such 
as ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other 
biomedical journals are considering adopting similar policies. The ICMJE does not review 
specific studies to determine whether registration is necessary; instead, the committee 
recommends that researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish. 
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or 
FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or 
designated principal investigator) register and report results of certain "applicable clinical 
trials:"  
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation;  
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA 
regulation (other than small feasibility studies) and pediatric postmarket surveillance studies. 
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA. 
 
20 
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Skoog L, Stal O: PIK3CA mutations and PTEN loss correlate with similar 
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receptor-positive advanced breast cancer. The New England journal of medicine 
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Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, 
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APPENDIX A 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 
 
The baseline longest diameter of the primary breast cancer assessed by mammogram (or 
ultrasonogram or MRI at physicians discretion) will be used as the reference by which to 
characterize objective tumor response in the breast. 
• 
Complete response (CR) 
Disappearance of all evidence of tumor for at least two cycles of therapy. 
• 
Partial response 
At least a 30% decrease in the sum of the longest diameter of target lesions, taking a reference 
the baseline sum longest diameter. 
• 
Stable disease (SD)  
Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify 
for progressive disease, taking as reference the smallest sum longest diameter since the 
treatment started. 
• 
Progressive disease (PD) 
At least a 20% increase in the sum of the longest diameter of target lesions, taking as 
reference the smallest sum longest diameter recorded since the beginning of treatment or the 
appearance of one or more new lesions Clinical progressive disease 
Subjects, who in the opinion of the treating physician investigator have had a substantial 
decline in their performance status and have clinical evidence of progressive disease may be 
classified as having progressive disease. 
1.  Definitions 
Every patient who completed at least one cycle (4 weeks) of therapy may be assessed for 
response. Response and progression will be evaluated in this trial using the RECIST 
Version 1.1.  Lesions are either measurable or non-measurable using the criteria provided 
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Measurable Disease: 
Tumor lesions:  Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to 
be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater 
than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions 
that cannot be accurately measured with calipers should 
be recorded as non-measurable). 
• 20 mm by chest x-ray. 
 
Skin lesions:  Documentation by color photography, 
including a ruler to estimate the size of the lesion, is 
recommended. 
 
Malignant lymph nodes:  To be considered pathologically 
enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan.  At baseline and in 
follow-up, only the short axis will be measured and followed.  
Non-Measurable Evaluable 
Disease: 
All other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with >10- to <15-mm 
short axis) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, 
abdominal masses, abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging 
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Target Lesions: 
The most reproducible measurable lesions, up to a maximum 
of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs should be identified as target lesions and 
recorded and measured at baseline.   
Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), should be representative 
of all involved organs, and in addition should be those that 
lend themselves to reproducible repeated measurements.  
Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion or a 
short axis of >15 mm by CT scan. 
A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.   If lymph nodes 
are to be included in the sum, then as noted above, only the 
short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective 
tumor response. 
Non-Target Lesions: 
All other lesions should be identified as non-target lesions 
at baseline.  Measurements of these lesions are not 
required, but the presence or absence of each should be 
noted throughout follow-up. 
 
i. 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment, as per protocol screening requirements. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of a treatment. 
 
Clinical Lesions: 
Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes).  
In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the 
lesion, is recommended. 
Chest X-ray: 
Lesions on chest X-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
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Conventional CT and MRI: CT and MRI are the best currently available and reproducible 
methods to measure target lesions selected for response 
assessment.  Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness, contiguously.  
Spiral CT scan should be performed using a 5-mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, 
abdomen, and pelvis.  Head and neck tumors and those of 
extremities usually require specific protocols. 
Ultrasound: 
When the primary trial endpoint is objective response, 
ultrasound should not be used to measure tumor lesions.  It is, 
however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions, and 
thyroid nodules.  Ultrasound may also be useful to confirm 
the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
Endoscopy and 
Laparoscopy: 
Use of endoscopy and laparoscopy for objective tumor 
evaluation has not yet been fully and widely validated.  
Therefore, use of these techniques for objective tumor 
response should be restricted to validation purposes in 
specialized centers.  Such techniques can be useful in 
confirming complete pathological response when biopsies are 
obtained. 
Tumor Markers: 
Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper limit of normal, they 
must normalize for a patient to be considered in complete 
clinical response when all lesions have disappeared. 
Cytology and Histology: 
Cytology and histology can be used to differentiate between 
PR and CR in rare cases (e.g., after treatment to differentiate 
between residual benign lesions and residual malignant 
lesions in tumor types such as germ cell tumors). 
 
ii. 
Response Criteria 


 
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Evaluation of Target Lesions 
Complete Response (CR):  
Disappearance of all target lesions.   
Partial Response (PR):  
 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD. 
Stable Disease (SD):   
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
(nadir) sum LD since the treatment started. 
Progressive Disease (PD):   
 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest (nadir) sum since the 
treatment started, or the appearance of one or more new 
lesions.  Requires not only 20% increase, but absolute 
increase of a minimum of 5 mm over sum. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor markers.  All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
Stable Disease (SD):    
 
Persistence of one or more non-target lesions and/or 
persistence of tumor marker level above the normal limits. 
Progressive Disease (PD):  
 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  When the patient 
also has measurable disease, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in the target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  In general, the patient’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria.   
Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is 
required for trials in which response rate is the primary endpoint, but is not required in 
randomized trials or trials with primary survival endpoints (i.e., where response is not a 
primary endpoint). 
 


 
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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
NO 
CR 
CR 
SD 
NO 
PR 
CR 
NE 
NO 
PR 
PR 
SD OR NE 
NO 
PR 
SD 
SD OR NE 
NO 
SD 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by fine needle aspirate or biopsy to confirm the CR status.  
When nodal disease is included in the sum of target lesions, and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression, should it be based on increase in size of the nodes.  As noted earlier, this means 
that patients with CR may not have a total sum of “zero” on the Case Report Form (CRF). 
Non-Measurable Disease Only 
When a patient only has non-measurable disease:  this circumstance arises in some trials when 
it is not a criterion of study entry to have measurable disease.  The same general concepts 
apply here as noted above, however, in this instance; there is no measureable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, 
the patient should be considered to have had overall PD at that point.  While it would be ideal 
to have objective criteria to apply non-measureable disease, the very nature of that disease 
makes it impossible to do so; therefore the increase must be substantial. 
 
 


 
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2.   Response Duration 
Response duration is measured from the time of first response (either CR or PR whichever is 
recorded first) until there is clinically or radiologically documented evidence of disease 
progression. Response duration, by definition, is only assessed in patients who experience 
objective tumor response (CR or PR).  Duration of stable disease is measured from the start of 
the treatment until the criteria for disease progression is met.  The reference measurement 
used should be the smallest measurements recorded since the treatment started. 
 
 
3.   Time to Progression  
Time to progression is measured from the beginning of treatment (day 1 of cycle 1) until 
objective clinical and/or radiological evidence of tumor progression, as outlined above, is 
documented. Every patient who completes at least 1 course (4 weeks) of treatment will be 
evaluated for time to progression.  
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX B 
The preoperative endocrine prognostic index 
 
*To obtain the preoperative endocrine prognostic index (PEPI) score, risk points for relapse-
free survival (RFS) and breast cancer–specific survival (BCSS) were assigned depending on 
the hazard ratio (HR) given in Table 3. The points scale was adapted from the cardiovascular 
literature on predicting outcomes for myocardial infarction (11). The total PEPI score 
assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, 
Ki67 level, and estrogen receptor (ER) status of the surgical specimen. An HR in the range of 
1–2 receives one risk point; a HR in the 2–2.5 range, two risk points; a HR greater than 2.5, 
three risk points. The total risk point score for each patient is the sum of all the risk points 
accumulated from the four factors in the model. For example, a patient with a T1N0 tumor, a 
Ki67 staining percentage of 1 and an ER Allred score of 6 will have no risk points assigned. 
In contrast, a patient with a T3N1 tumor, a Ki67 staining percentage of 25, and an ER Allred 
score of 2 will have a total relapse score of 3 + 3 + 2 + 3 = 11. 
†The natural logarithm interval corresponding to the percent Ki67 values on the original 
percentage scale 


 
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Appendix C 
SKCC DSMP’s AE/SAE Reporting Requirements 


 
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.Appendix D 
 


 
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Appendix E 
Adverse Events Log