Clinical trial NCT00810797
Conditions: Breast Cancer
Keywords: recurrent breast cancer stage IV breast cancer
Sponsor: City of Hope Medical Center
Start date: 2008-12-02; Completion date: 2019-06-26
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using exemestane may fight breast cancer by lowering the amount of estrogen the body makes.

PURPOSE: This phase II trial is studying how well exemestane works in treating postmenopausal women with stage IV breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Progression-free survival at 4 months, as measured by Response Evaluation Criteria in Solid Tumors (RECIST).

SECONDARY OBJECTIVES:

I. Objective response rate (complete response \[CR\] and partial response \[PR\]).

II. Clinical benefit (CR, PR, and stable disease \>= 6 months).

III. Assessment of toxicity.

IV. Assessment of compliance with medication adherence.

V. Assessment of quality of life.

VI. Assessment of bone health.

TERTIARY OBJECTIVES:

I. Serial measurements of serum estradiol, estrone, and estrone sulfate.

II. To investigate treatment resistance (e.g., expression of amphiregulin, epidermal growth factor receptor \[EGFR\]), using molecular and immunohistochemical analyses of blood and tumor samples of pre- and post- (when available) treatment tissues. Microarray analyses to quantitate the expression of specific estrogen-responsive genes (e.g. thyroid transcription factor 1 \[TTF1\] and PDZK1) will also be performed.

OUTLINE: Patients receive exemestane orally (PO) once daily (QD) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for 1 year.

Arms: arm 1: Patients receive oral exemestane once daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: exemestane intervention 2: laboratory biomarker analysis intervention 3: quality-of-life assessment intervention 4: immunohistochemistry staining method
Intervention descriptions: intervention 1: Given orally intervention 2: One year after completion of study treatment intervention 3: One year after completion of study treatment intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
IRB #08063 
 
08/12/14 
Version: 13 
CITY OF HOPE 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE: Intermittent Exemestane Therapy for Metastatic Breast Cancer 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB #08063 
 
VERSION: 13 
 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
 
 
Initial Submission (Version, Dated June 18, 2008) 
Version 00 
 
COH Amendment 01 (Version dated April 13, 2009) 
Version 01 
 
COH Amendment 02 (Version dated March 22, 2010) 
Version 02 
 
COH Amendment 03 (Change in PI to T Luu, Protocol Version 6/9/10)  
Version 03 
 
COH Amendment 04 (Title Page Only: Add J Chao and J Portnow) 
                          Version 04 
 
COH Amendment 05 (Title Page Only: Add M Koczywas) 
Version 05 
 
COH Amendment 06 (Version April 9, 2011) 
Version 06 
 
COH Amendment 07 (Add Dr.Tomoko Tagawa) 
Version 07 
COH Amendment 08 (Version December 8, 2011) 
 
 
 
             Version 08 
 
 
COH Amendment 09 (Title Page dated 01/12/2012)                                                             Version 09 
 
 
COH Amendment 10 (Protocol dated 7/9/13) 
 
 
 
                           Version10 
COH Amendment 11 (Protocol dated 10-25-13, DSMP and CBC/CMP)  
 
Version 11 
COH Amendment 12 (Title page only dated 06/19/14) 
 
 
 
 
Version 12 
COH Amendment 13 (Title page only dated 08/12/14) 
 
 
 
 
Version 13 
 
 
SITE: 
Breast 
 
HISTOLOGY: 
Breast Cancer  
 
 
 
STAGE (If applicable): 
 
 
Stage IV 
 
MODALITY:  
 
 
 
Hormone Therapy 
 
 
 
 
TYPE:  
 
 
 
 
Pilot, Phase II 
 
PRINCIPAL INVESTIGATOR: 
 
George Somlo, M.D. 
 
COLLABORATING INVESTIGATORS: 
Shiuan Chen, M.D. 
 
PARTICIPATING CLINICIANS: 
 Medical Oncology:  Joseph Chao, M.D., Arti Hurria, M.D., 
Marianna Koczywas, M.D., Stephen Koehler, M.D., Joanne 
Mortimer, M.D., , Jana Portnow, M.D., Warren Chow, M.D., 
Vincent Chung, M.D., Michaela Cristea, M.D., Lucille Leong, 
M.D., Dean Lim, M.D., Robert Morgan, M.D., Sumanta Pal, M.D., 
Karen Reckamp, M.D., Przemyslaw Twardowski, M.D., James 
Waisman, M.D., Jeffrey Weitzel, M.D., Yun Yen, M.D., Christina 
Yeon, M.D. and Yuan Yuan, M.D., Samuel Chung, M.D. 
 
PARTICIPATING INSTITUTION:        City of Hope National Medical Center 
 
City of Hope-South Pasadena, CA 


CITY OF HOPE  
1500 East Duarte Road 
Duarte, CA 91010 
 
DIVISION OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:  Intermittent Exemestane Therapy for the Treatment of Metastatic Breast Cancer 
 
DISEASE SITE:  Breast 
 
STAGE:  IV 
 
MODALITY: Hormonal Therapy 
 
TYPE:  Pilot, Phase II 
 
VERSION: 
June 18, 2008 
REVISED: 
October 1, 2008, April 13, 2009, March 22, 2010, June 9, 2010, April 9, 2011, 
December 8, 2011, July 9, 2013, October 25, 2013 
 
PRINCIPAL INVESTIGATOR:   Thehang Luu, MD                                                 
                                                           Division of Medical Oncology and 
Experimental Therapeutics 
                                                           City of Hope  
                                                           1500 East Duarte Road, MOB 1002M 
                                                           Duarte, CA 91010 
                                                           Tel: (626) 256-4673, ext 62307 
                                                           Fax: (626) 301-8898 
                                                           Email: tluu@coh.org 
CO-INVESTIGATORS:   
George Somlo, MD 
 
 
 
Shiuan Chen, PhD 
Director, Breast Oncology Program  
Director, Surgical Research 
Division of Medical Oncology and   
City of Hope  
     Experimental Therapeutics 
 
Kaplan CRB, Room 2002C  
 
City of Hope   
 
 
 
Duarte, CA 91010 
1500 E. Duarte Road  
 
 
Tel: (626) 256-4673, ext 63454 
Duarte, CA 91010 
 
 
 
Fax: (626) 301-8393 
Tel: (626) 256-4673, ext 62475 
 
Email: schen@coh.org         
Fax: (626) 301-8898 
Email: GSomlo@coh.org 
 
BIOSTATISTICIAN: 
SATELLITE SITE : 
Paul Frankel, PhD 
Cathie T. Chung, M.D., PhD 
Division of Information Sciences 
The Angeles Clinic and Research Institute 
City of Hope 
2001 Santa Monica Boulevard, Suite 560W 
1500 E. Duarte Rd. 
Santa Monica, CA 90404 
Duarte, CA 91010 
310/582-7900 
Tel: 626/256-673, ext 65265 
cchung@theangelesclinic.org 
Fax: 626/471-7106 
Email: pfrankel@coh.org                                        


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                                                         TABLE OF CONTENTS 
 
                                                                                                                            
Page  
 
SCHEMA ................................................................................................................................... 4                             
 
1.0  OBJECTIVES .................................................................................................................. 5 
1.1 Primary ...................................................................................................................... 5 
1.2 Secondary .................................................................................................................. 5 
1.3 Exploratory ............................................................................................................... 5 
 
2.0  BACKGROUND AND RATIONALE ………………………………………………...5 
 
3.0  TREATMENT PLAN ...................................................................................................... 7 
            3.1 Study Design ............................................................................................................. 7 
3.2 Treatment Dosage and Schedule ............................................................................... 8 
3.3 Concurrent Treatment ............................................................................................... 8 
3.4. Number of Subjects.................................................................................................. 8 
3.5 Treatment Duration and Follow-Up.......................................................................... 8 
 
4.0 SUBJECT ELIGIBILITY ............................................................................................... 9 
4.1 Inclusion Criteria ...................................................................................................... 9 
4.2 Exclusion Criteria ..................................................................................................... 9 
4.3 Minorities and Women Statement .......................................................................... 10 
 
5.0 STUDY PROCEDURES ............................................................................................... 10 
            5.1 Screening………………………………………………………………………….10 
5.2 Tumor Assessments ................................................................................................ 11 
5.3 Toxicity Assessments.............................................................................................. 15 
5.4 Quality of Life Assessments ................................................................................... 15 
5.5 Exemestane Drug Diary .......................................................................................... 15 
 
6.0  STATISTICAL CONSIDERATIONS ......................................................................... 17 
            6.1 Maximum Accrual .................................................................................................. 17 
            6.2 Correlative Analysis................................................................................................ 18 
 
6.3 Reporting of Results ............................................................................................... 18 
 
7.0  DATA AMD SAFETY MONITORING ...................................................................... 18 
7.1 Definition of Risk Level ......................................................................................... 18 
            7.2 Monitoring and Personnel Responsible for Monitoring ......................................... 18 
            7.3 7.4 Reporting of Unanticipated Problems and Adverse Events .............................. 19 
                 7.3.2 Definitions....................................................................................................... 19 
 
8.0  DRUG INFORMATION ............................................................................................... 20 
                 8.1 Description ......................................................................................................... 20 
                 8.2 Toxicology ......................................................................................................... 21 
                 8.3 Pharmacology .................................................................................................... 21 


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9.0  REGULATORY OBLIGATIONS ............................................................................... 22 
9.1 Informed Consent.................................................................................................... 22 
9.2 Confidentiality of Records ...................................................................................... 22 
9.3 Registration Process  ............................................................................................... 22 
9.4 Data Collection Forms and Submission Schedule .................................................. 23 
 
10.0  STUDY CALENDAR…………………… .............................................................. 24-25 
 
11.0  REFERENCES ......................................................................................................... 26-27 
 
12.0  APPENDICES 
 
       Appendix A:   Health Assessment Questionnaire (HAQ DI©) ................................. 28-30 
 
 
Appendix B: Performance Status Criteria ..................................................................... 31 
 
         Appendix C :  EORTC QLQ-C30....................................................................................32 
 
 
 
 


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SCHEMA 
 
N=36 
 
- Postmenopausal Women 
- Biopsy proven Metastatic Breast Cancer (MBC) 
- ER and/or PR Positive Breast Cancer 
- Two prior chemotherapy regimens for MBC allowed 
- Disease recurrence while on adjuvant hormonal 
   therapy (as long as treatment was taken for at  
    least six months) or after discontinuation/completion of adjuvant 
    hormonal therapy. 
- Disease progression following either 0, 1 or 2 
   prior hormonal therapies for MBC 
- No prior exposure to exemestane (EXE) 
- Measurable or non-measurable (but evaluable) 
  disease 
- ECOG performance status 0-1 
- Adequate hematologic, renal and hepatic functions 
       
   
   
 
 
 
 
 
 
 
R 
E
G 
 I 
S 
T 
E 
R 
Protocol Treatment 
 
Exemestane 
25 mg daily X 14 days then 
 7 days off treatment, for each 
 21-day cycle of treatment 
  
Study Endpoints: 
  
Measurements of: 
Efficacy 
Toxicity 
Compliance 
Quality of Life 
 
 
 
 


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1.0  
OBJECTIVES 
 
1.1. 
Primary Objective:  
 
- Progression free survival (PFS) at 4 months, as measured by Response Evaluation   
  Criteria in Solid Tumors (RECIST). 
 
1.2  
Secondary Objectives:  
      
- Objective response rate [compete response (CR), partial response (PR)] 
- Clinical benefit [CR +PR + Stable disease≥ 6 months] 
- Assessment of toxicity 
- Assessment of compliance with medication adherence 
- Assessment of quality of life 
- Assessment of bone health 
 
1.3  
Exploratory Objectives: 
      
       
- Serial measurement of serum estradiol, estrone and estrone sulfate. 
      
- To investigate treatment resistance (e.g. expression of amphiregulin, EGFR), using 
molecular  
           and immunohistochemical analyses of blood and tumor samples of pre- 
           and post- (when available) treatment tissues. Microarraay analyses to  
           quantitate the expression of specific estrogen-responsive genes (e.g. TTF1 and  
           (PDZk1) will also be performed. 
 
 
2.0  
BACKGROUND AND RATIONALE 
       
The efficacy of aromatase inhibitors (AI) in the treatment of postmenopausal women with 
hormone receptor positive, metastatic breast cancer (MBC) is undisputed. In this regard, 
prior randomized clinical trials have documented the superiority of exemestane (EXE) 
over tamoxifen, as first line therapy [1] and the superiority of EXE over megestrol 
acetate, as second line therapy after tamoxifen failure [2]. Prior phase II studies have also 
documented the efficacy of EXE in the treatment of MBC after failure of several lines of 
prior hormonal therapies [3], including prior exposure to nonsteroidal AIs [4, 5]. While 
the utility of EXE has been proven with respect to several important clinical indicators 
(e.g. response rate, time to progression, median survival time and median duration of 
response), eventually all patients will develop disease progression due to the development 
of acquired resistance to further treatment. In addition, as has recently been reported, 
some patients with breast cancer may derive less than maximal benefit from AI therapy 
due to noncompliance because of musculoskeletal-related adverse effects [6, 7]. The aim 
of this research proposal, therefore, is to determine whether there may be an effective 
strategy to delay the time to development of resistance to EXE in the treatment of MBC, 
while minimizing potential toxicities and ensuring patient compliance with treatment. 
 
In order to achieve our study objectives, we propose a phase II pilot, 
translational trial incorporating the use of intermittent EXE therapy in the 


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treatment of postmenopausal women with hormone receptor positive MBC. The 
rationale for this trial stems from preclinical data derived at the City of Hope, in 
the laboratory of our collaborator, Dr. Shiuan Chen (Figure 1). As Dr. Chen’s 
research interests have been in identifying mechanisms of AI resistance, he has 
generated a unique research tool, MCF-7aro, an estrogen receptor positive 
breast cancer cell line in which aromatase is over-expressed [8,9]. Using this 
cell line, it was demonstrated that continuous exposure to EXE initially 
inhibited cell growth, indicative of the sensitivity of this cell line to treatment. 
With prolonged, continuous exposure to EXE, however, cells eventually 
resumed growth after 6-8 weeks of treatment, reflecting the gradual 
development of acquired resistance to further treatment. In contrast, in cells 
exposed to intermittent treatment with EXE, either on a schedule of 1 week 
on/1week off, 2 weeks on/1 week off or 3 weeks on/1 week off, sensitivity to 
growth inhibition by EXE was maintained beyond 12 weeks. These data suggest 
that the scheduling of EXE therapy may influence the clinical efficacy of this AI 
in the treatment of MBC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
While molecular mechanisms underlying this observation of delayed resistance 
are not yet fully elucidated,  a clinical trial of intermittent EXE therapy in the 
treatment of MBC, is supported by both anecdotal clinical reports, as well as 
data derived from other laboratories. Clinical case reports have documented, for 
example, that patients with MBC can demonstrate regression of disease in 
response to withdrawal of antiestrogen treatments [10, 11]. This effect is 
presumed to result from of an adaptive hypersensitivity to low estrogen levels 
which over time, can lead to a paradoxical inhibitory effect of estrogen on 
breast cancer cell growth. A similar phenomenon has also been observed in 
vitro in that in LTED cells (i.e., MCF-7 breast cancer cells cultured under 
conditions of long-term estrogen deprivation), exposure to estrogen results in 
growth inhibition and induction of apoptosis [12]. In this regard, the current 
standard method of continuous daily dosing of EXE may not be as effective in 
inhibiting breast cancer cell growth, as sequencing intermittent periods of EXE 
Effect of EXE on MCF-7aro Cells
0.0E+00
2.0E+07
4.0E+07
6.0E+07
8.0E+07
1.0E+08
1.2E+08
1.4E+08
1.6E+08
0
2
4
6
8
10
12
14*
16
18
20
22
24
26*
28
Week
Average Cell Number
Continuous
1 week on + 1 week off
2 weeks on + 1 week off
3 weeks on + 1 weeks off
Figure 1.Effect 
of continuous 
and intermittent 
schedules of 
EXE (1μM) 
treatment on 
the growth of 
MCF-7aro cells 
in the presence 
of testosterone 
(T, 1nM). 
(Unpublished 
data) 


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withdrawal. Moreover, in vitro and mouse xenograft  models have shown that  
reversal of resistance to tamoxifen can be achieved with the administration of  
estrogen [13,14], suggesting that  in patients with advanced, hormone receptor 
positive breast cancer, resistance to anti-estrogen therapy may possibly be 
delayed by allowing intermittent periods of exposure to low levels of estrogen. 
An alternative hypothesis to account for the development of acquired resistance 
to EXE is the recent finding of elevated expression of the epidermal growth 
factor (EGF)-like protein, amphiregulin (AREG), in MCF-7 aro cells treated 
continuously with 1μmol/L of EXE. As AREG binds to the EGF receptor, it is 
postulated that AREG may mediate the development of acquired resistance to 
EXE via activation of EGFR and MAPK, leading to cell proliferation. As such, 
it is possible that intermittent withdrawal of EXE may also delay the 
development of acquired endocrine resistance due to diminished expression of 
AREG [15]. In addition to the potential beneficial effects of intermittent EXE 
therapy in terms of prolongation of time to drug resistance, this new method of 
drug scheduling may also allow improvements of other clinically important 
endpoints, such as better quality of life due to reduced exposure to drug-related 
toxicities. 
  
To correlate with observations obtained in cell culture (i.e. that intermittent 
EXE therapy delays the time to re-growth of MCF-7aro breast cancer cells), the 
selected primary endpoint of this study will be progression free survival (PFS), 
although other clinically meaningful endpoints, such as objective response rates 
and clinical benefit will also be measured. That PFS correlates with acquired 
resistance to treatment is exemplified by prior clinical trials in which it was 
shown that as first line therapy, median duration of response to EXE was 
reported as 10 months [1]. However, as second [2] and third [3] line therapies, 
time to tumor progression was reported as 20.3 weeks and 2 months, 
respectively. In other clinical trials in which EXE was used after multiple lines 
of prior endocrine therapy (≥ 2), including use of prior non-steroidal AIs, time 
to tumor progression ranged between 14.7 weeks  to 3.7 months [4,5,16]. In 
view of these previously reported data and in consideration of the desire to be 
able to complete this study in a timely manner, we have chosen to measure PFS 
at 4 months as a benchmark for comparison (10 months  for first line patients, 
see statistical considerations) and as such, have incorporated eligibility criteria 
to reflect the patient population from which these historical data were obtained 
[5,16]. The rationale for inclusion of this study population was also derived in 
consideration of the hypothesis that after long-term estrogen deprivation of 
hormone receptor positive breast cancer cells in vitro, (presumed to be clinically 
equivalent to long-term exposure to anti-estrogens), estrogen may actually 
induce apoptosis [12]. 
 
 
3.0  
TREATMENT PLAN 
 
3.1  
Study Design 
 


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In order to test the study hypothesis that intermittent EXE may delay the time to 
development of acquired resistance, a pilot, phase II  clinical trial will be 
conducted in which all study participants will receive treatment with  EXE.   
 
3.2 
Treatment Dosage and Schedule 
 
As is currently recommended, the standard approved dose of EXE is 25 mg 
orally per day, after a meal. Absorption of EXE is rapid, and after peak plasma 
levels are reached, plasma levels of EXE decline in a polyexponential manner, 
resulting in a terminal half life of approximately 24 hours. Given these 
pharmacokinetic properties and in consideration of convenience/ease of dosing, 
a 21-day treatment cycle, consisting of a schedule of 2 weeks on (consecutive 
daily dosing of 25 mg of EXE from Days 1-14), followed by 1 week off 
(cessation of dosing from Days 15-21), will be used. 
 
 
3.3 
Concurrent Treatment 
 
 
Bisphosphonates 
 
 
Concurrent bisphosphonates for the treatment of bone metastases will be  
permitted. In addition, throughout the study, concomitant medications deemed 
necessary for the supportive care of patients will be given at physician 
discretion. 
 
 
Radiation 
 
 
Subjects with measurable disease per RECIST criteria, who require palliative 
radiation to a non-target lesion, will be permitted to receive treatment without 
being considered as having disease progression. However, patients with 
measurable disease who require radiation to a target lesion will be considered as 
having disease progression and will be removed from study. 
 
Subjects with non-measurable disease by RECIST criteria, who require 
palliative radiation to a single site, will be permitted to receive treatment and 
remain on study. However, subjects with non-measurable disease who required 
palliative radiation to more than one site will be considered as having disease 
progression and will be taken off study. 
 
3.4  
Number of Subjects 
 
 
This trial will entail enrollment of a maximum of 36 patients for treatment, as 
discussed in section 6.0. The target accrual goal will be 18 subjects/year. 
 
3.5  
Treatment Duration and Follow-Up 
 
 
Study subjects will remain on treatment until disease progression, the development 


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of unacceptable toxicities, consent withdrawal, PI discretion (in cases where further 
treatment on protocol would not be in the best interest of the study participant) or death. 
Study participants will be followed for one year after completion of study treatment. 
 
 
 
4.0  
SUBJECT ELIGIBILITY 
 
4.1  
Inclusion Criteria 
  
 
4.1.1  Histologically or cytologically confirmed metastatic carcinoma of the breast. 
 
 
4.1.2  Hormone receptor (ER and/or PR) positive disease [defined as: ER and/or PR 
positivity as ≥ 5% staining], as confirmed by immunohistochemistry (IHC) based 
on primary breast tissue or metastatic tissue. 
          
 
4.1.3  Females ≥ 18 years old and determined to be postmenopausal, as defined by  
any of the following: 
 
- Natural menopause, with at least one year since last menses. 
 
- Chemotherapy-induced menopause with at least 1 year from last menses and 
serum LH/FSH and estradiol levels within the postmenopausal range. 
- History of surgical or radiation-induced ovarian ablation. 
 For women ≤ 56 years old and with a history of hysterectomy but at least 
  one ovary intact, serum LH/FSH and estradiol levels must be within the  
 postmenopausal range.         
 
4.1.4   Postmenopausal women with disease recurrence while receiving either tamoxifen 
or a non-steroidal AI as adjuvant therapy (as long a adjuvant hormonal therapy 
was taken for 6 months before disease progression)  or with disease recurrence 
following the discontinuation/ completion of adjuvant hormonal therapy. 
 
4.1.5  Postmenopausal women with disease progression following either 0, 1 or 2 
               prior hormonal therapies for metastatic breast cancer, as long as subject 
               has had no prior exposure to EXE. 
  
     
4.1.6  Measurable or non-measurable (but evaluable) disease, as defined by        
  
RECIST criteria. 
 
    
4.1.7  ECOG performance status (Appendix B) of 0-1 and adequate hematologic 
            
 
(neutrophil count ≥ 1.5X109 cells/L; platelet count ≥ 100 X 109 cells/L), renal 
 
      (serum creatinine ≤ 1.5 times the upper limit of normal) and hepatic (total serum 
              
 
bilirubin ≤ 1.5 times the upper limit of normal; AST/ALT levels ≤ 2.5 times the 
             
 
upper limit of normal in patients without liver metastases or ≤ 5 times the upper 
                   
limit of normal in patients with liver metastases; alkaline phosphatase ≤ 2.5 times  
                   
the upper limit of normal for patients without bone or liver metastasis) function. 
 
        4.1.8  Subjects must have an estimated life expectancy of greater than 6 months. 
 


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4.2  
Exclusion Criteria 
  
          4.2.1    Prior exposure to EXE, whether in the adjuvant or metastatic setting. 
  
          4.2.2    Prior history of any other cancer with the exception of non-melanoma skin 
                     cancer and treated in situ carcinoma of the cervix. 
 
          4.2.3    Active or symptomatic CNS metastasis (stable or treated brain metastasis 
                     allowed but patients must be off decadron, if given for CNS disease). 
 
            4.2.4  Hormone receptor negative or unknown breast cancer. 
 
            4.2.5  More than two prior chemotherapy regimen for treatment of metastatic disease 
(any prior chemotherapy given in the adjuvant setting is permitted). 
 
            4.2.6  Administration of any other anti-cancer therapy within 2 weeks of initiating 
                      study treatment. Use of bisphosphonates, however, are permitted for patients 
                      with known bone metastases. 
 
        4.2.7   Treatment with any other concurrent investigational agent or anti- 
                   tumor drug (chemotherapy, antibody therapy or other biologic agents), will 
                   not be permitted. 
 
 
 4.2.8  Any uncontrolled medical co-morbidity or psychiatric disorder which  
                 
interferes with the ability to provide informed consent or comply with 
                 
study procedures. 
 
4.3 Minorities and Women Statement 
  
          Female subjects of all racial/ethnic groups are eligible for this study if they meet 
        the eligibility criteria specified in sections 4.1 and 4.2. To address disparities 
        in healthcare and breast cancer treatment among women from underserved 
        populations, all efforts will be made to accrue subjects from ethnically diverse, 
        underserved and minority populations. In order to achieve this goal, this study will  
       
be conducted with the collaboration of Dr. Kimlin Ashing-Giwa who has established  
        the City of Hope Center of Community Alliance for Research and Education  
        (CCARE), an organization charged with increasing the awareness of cancer clinical         
        trials among underserved populations.    
  
 
5.0  
STUDY PROCEDURES 
 
 5.1  
Screening 
 
            A signed and dated IRB approved protocol consent form must be obtained 
          before any study specific procedures can be performed. Procedures that are  
          considered part of routine care are not considered study specific procedures but may 


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          be used to determine eligibility during screening. The following assessments must  
          be performed within 28 days of initiation of treatment: 
 
            -  Review of inclusion and exclusion criteria. 
            -  Recording of concomitant mediation, including date of last use of prior therapy 
               for treatment of breast cancer. 
            - Complete review of medical history (documentation of diagnosis, hormone 
               receptor status of tumor, most recent radiologic assessment of disease status and 
               prior treatment history) 
            - Complete physical examination, including assessment of ECOG performance 
               status. 
            -  Laboratory assessment for hematologic, renal and hepatic function. 
            -  Disease assessment according to RECIST criteria. All baseline radiologic scans 
               (CT, MRI, bone scans) must be performed within 28 days of study initiation. 
[Note: PET/CT Scan may be used in lieu of Bone Scan when patient is symptomatic] 
            -  If available, submission of archival paraffin-embedded or fresh frozen tumor 
               tissue samples. 
         
5.2  
Tumor Assessments 
 
Radiologic assessment of disease must include computed tomography (CT) or magnetic 
resonance imaging (MRI) of the chest, abdomen and pelvis and the imaging modality 
selected should remain consistent throughout the entire study. All subjects will 
additionally undergo a bone scan at baseline [Note: PET/CT Scan may be used in lieu of 
Bone Scan when patient is symptomatic]. Subjects with a positive bone scan at baseline 
will continue to have bone scans as part of their radiologic assessments throughout the 
study period. Subjects with a negative bone scan at baseline, will not be required to 
continue with further bone scans during the study period, unless clinically indicated. All 
imaging studies will be required at baseline and will be repeated every 3 cycles (i.e. day 
15-21 of every 3rd cycle). Tumor response assessments will be performed according to 
RECIST criteria: 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference 
 
Eligibility 
Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
             Measurable lesions - lesions that can be accurately measured in at least one dimension 
with longest diameter 20 mm using conventional techniques or 10 mm with spiral CT 
scan. 
            Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 
mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 


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lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques. 
 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 and never more than 4 weeks before the beginning of the 
treatment.  
 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.  
 Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes). For the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Methods of Measurement 
 
 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 
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. 
 
 Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 
 When the primary endpoint of the study is objective response evaluation, ultrasound 
(US) 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. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
 
 The utilization of endoscopy and laparoscopy for objective tumor evaluation has not 
yet been fully and widely validated. Their uses in this specific context require 
sophisticated equipment and a high level of expertise that may only be available in 
some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, 
such techniques can be useful in confirming complete pathological response when 
biopsies are obtained. 
 
 Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response when all lesions have disappeared. 
 


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 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). 
Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of five lesions per organ and 10 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) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  
 A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference by 
which to characterize the objective tumor. 
 All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up.  
 
Response Criteria 
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 LD of target lesions, taking as 
reference the baseline sum LD 
* Progressive Disease 
(PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
Evaluation of non-target lesions 
* Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
* Incomplete 
Response/          
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits 
* Progressive Disease 
Appearance of one or more new lesions and/or unequivocal 


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(PD): 
progression of existing non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is exceptional. In such 
circumstances, the opinion of the treating physician should prevail and the 
progression status should be confirmed later on by the review panel (or study 
chair). 
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 PD 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  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  
 In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
Confirmation 
 The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed.  In cases where confirmation of response is not feasible, it 
should be made clear when reporting the outcome of such studies that the responses 
are not confirmed. 


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 To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after 
the criteria for response are first met. Longer intervals as determined by the study 
protocol may also be appropriate.  
 In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval (in general, not less than 6-8 weeks) that 
is defined in the study protocol  
 
Duration of overall response 
 The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever status is recorded first) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started. 
 
Duration of stable disease 
 SD is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
  
5.3  
Toxicity Assessments 
 
To protect against and minimize potential risks, assessments of treatment-related    
toxicities will be performed by the study nurse every three weeks (via telephone). The 
NCI, Common Toxicity Criteria for Adverse Events (CTCAE, version  
3.0, available at http://ctep.cancer.gov//forms/CTAEv3.pdf)), will be used as a guide to    
assess severity. To assess musculoskeletal adverse effects associated with EXE use, all  
subjects will complete modified Health Assessment Questionnaires (HAQ DI©) 
(Appendix A) at the start of each cycle of treatment, as previously validated [7, 17].  
 
5.4  
Quality of Life Assessment (Appendix C) 
      
          For determination of quality of life associated with EXE use, the European         
 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
          Questionnaire (QLQ-C30) will be used. This instrument consists of a 30-item,   
          cancer-specific tool which encompasses measures of physical, emotional, cognitive        
          and social well being, in addition to measures of symptoms and overall quality of  
          life. Questionnaires will be completed at the start of every new cycle of treatment. 
       
5.5  
Exemestane Drug Diary 
      
           To assess compliance with treatment, all patients will be supplied with a           
 
calendar of the treatment schedule at the start of each new cycle and will be  
         instructed to track their daily consumption of EXE at home. Completed calendars  
          will be collected at the end of each cycle of treatment. 
      
 
 
 


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6.0   
STATISTICAL CONSIDERATIONS  
 
6.1  
Maximum Accrual: 36 Subjects 
 
While toxicity is safely assumed to be reduced, the improvement in PFS is less clear and 
interim stopping conditions in case the PFS is dramatically worse than historical data [5], 
are incorporated in the design. The following design operating characteristics were 
calculated by the method of Simon, but the specific design chosen differs slightly from 
the Optimum or Minimax design to take into consideration the sawtooth nature of the 
power function [18, 19].  Patients will be defined as a “success” or “failure” based on 
whether they have obtained the appropriate benchmark for median PFS (see below). An 
interim analysis will be performed at 21 subjects.  If fewer than six of the first 21 subjects 
are a “success”, the study will be stopped for futility.  If fewer than fourteen patients out 
of the 36 subjects are a success this will also be suggestive that this regimen does not 
warrant further study.  This design discriminates between an encouraging “success” rate 
of 50% and a discouraging “success” rate of 30%.  The probability of early stopping if 
the true success rate is 50%, is 1% whereas the probability of early stopping if the true 
success  rate is 30%, is 36%.The overall type II error for the decision on whether or not 
the treatment is promising is 7%, whereas the type I error is less than 17%, when 
comparing a discouraging success rate of 30% to an encouraging rate of 50%. 
 
For second or third line patients (as was done prior to the amendment to include first line 
patients) if patients are progression-free at the 4 month evaluation this will be considered 
a success. Based on recent publication (e.g. Paridaens, et al , Vol 26, No. 30, pp-4883-
4890, JCO 2008) the median PFS for first line patients on EXE is approximately 10 
months. As a result, we will view a “success” for first line patients if they are 
progression-free at 10 months.  
 
Patients who are not first line will be assigned to Treatment Arm 1. Patients who are first 
line will be accrued to treatment Arm 2. These arms are used simply as a convenience for 
easier determination of the primary endpoint, and no specific accrual goals are made for 
each treatment arm, with a total goal of 36 subjects. 
 
While it is assumed that reduced exposure to EXE results in fewer and less severe drug-
related toxicities, a sufficient sample size must be accrued in order to obtain a reasonable 
estimate of the frequency of treatment related toxicities. One benchmark will look at the 
incidence of joint disorders,reported by Gradishar [5], at approximately 30%. A one-
sided exact binomial test with a nominal 10% significance level, will have 81% power to 
detect a difference from a historical 30% complication rate, to a 15% complication rate 
with 36 subjects. Generally, however, if the PFS is equivalent to historical data, this will 
be considered successful, based on the assumption that reduced drug exposure will result 
in less toxicity. While progression free survival (time to progression or death) at 4 
months (and 10 months)  is calculated as a binomial (all treated patients will count and 


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patients lost to follow-up before 4 months (10 months for first line) will count as a 
failure), progression-free survival will also be reported using the method of Kaplan-
Meier. 
 
 
6.2  
Correlative Analysis 
   
With 36 patients, correlative analysis will be exploratory in nature. No attempt will be   
made to adjust for multiple comparisons (except as part of standard microarray analysis) 
and this will be noted in any report. Changes from baseline and comparison between 
responders and non-responders, will be summarized. We will also do a more refined 
analysis of 1st line, second line and third-line patients to explore the potential impact of 
EXE in these different patient populations. 
6.3  
Reporting of results 
 All patients included in this study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are later determined to be 
ineligible.  Each patient will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death 
from malignant disease, 6) early death from toxicity, 7) early death because of other 
cause, or 9) unknown (not assessable, insufficient data). 
 
7.0  
DATA AND SAFETY MONITORING 
  
7.1  
Definition of Risk Level 
 
This is a Risk Level 3 study, as defined in the “City of Hope Data and Safety Monitoring 
Plan”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx because it is a pilot, 
Phase II clinical trial where the risks are at least balanced by the potential benefit to 
subjects and the importance of the knowledge that may result. 
 
7.2  
Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT), consisting of the PI, Collaborating Investigator, 
CRA/protocol nurse and statistician, is responsible for monitoring the data and safety of 
this study, including implementation of any stopping rules for safety and efficacy.  
 
Data and safety will be reported to the COH DSMC using the PMT report and submitted 
according to the timelines in Table 1 below.  Protocol specific data collection will include 
the following items: summary of accrual, adverse events, and treatment related mortality. 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 


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3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
. 
 
 7.3  
Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change 
of an existing condition that occurs during or after treatment, whether or not it is 
considered to be related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it 
is not listed in the investigator’s brochure and/or package insert; is not listed at the 
specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the 
adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or unexpected 
adverse event that results in any of the following outcomes: 
 Death 
 Is life-threatening experience (places the subject at immediate risk of death from 
the event as it occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary Malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasisas of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 


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Unanticipated problem (UP) – Any incident, experience, or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
 
7.4 Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that 
occurs during the study conduct will be reported to the DSMC and IRB by submitting 
electronically in iRIS (http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by 
the physician, nurse, or reported by the patient, will be reported according to 
definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and 
Table 2 below.  Those SAEs that require expedited reporting will be submitted 
electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the protocol continuation reports and PMT report (see Table 2 below). 
 
 
 
 
 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 


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Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 


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Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days 
of last day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations 
Director. The DSMC will review the case and make a determination as to whether the 
study will be suspended, terminated, amended, or allowed to continue without 
amendment. 
 
 
 
 
 
 
 
 
 


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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Additional Reporting Criteria 
 
Pfizer 
               
In addition to requirements of reporting of adverse events to the COH DSMB and 
IRB, serious adverse events resulting in death or considered life threatening will 
be submitted to Pfizer within 24 hours of awareness, via FDA MedWatch Form 
3500A-Mandatory 
Reporting, 
obtained 
from 
the 
FDA 
website 
(http://www.fda.gov/medwatch/report/hcp.htm). The period that serious adverse 
events will be reported to Pfizer will be from the occurrence after the first dose of 
EXE, through 28 days after discontinuation of study treatment. 
 
 
Fax FDA MedWatch Form 3500A to: 
                         
                        Pfizer U.S. Clinical Safety 
                        Fax: 1-866-997-8322 
                  
 
 
 
 
8.0  
DRUG INFORMATION 
 
8.1  
Description 
 
EXE is an oral, irreversible, steroidal aromatase inactivator, structurally similar to   the 
natural substrate, androstenedione. In postmenopausal women, estrogens are produced 
primarily by the conversions of androgens into estrogens through the aromatase enzyme 
in peripheral tissues. By acting as a false substrate and irreversibly binding to the active 
site of the aromatase enzyme, EXE causes inactivation of the aromatase enzyme, 


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resulting in significant inhibition of circulating estrogen concentrations in 
postmenopausal women, but has no detectable effect on adrenal biosynthesis of 
corticosteroids or aldosterone. In postmenopausal breast cancer patients treated with 25 
mg of EXE daily, whole body aromatization was suppressed by greater 
than 90%. EXE is currently approved by the FDA for use in the treatment  
of postmenopausal women with advanced breast cancer, whose disease has progressed 
following tamoxifen therapy. EXE is also approved for use as adjuvant therapy  
for postmenopausal women with estrogen receptor positive breast cancer. 
      The recommended dose of EXE is 25 mg orally once daily after a meal.  
       
 8.2  
Toxicology 
  
      In clinical trials of 1058 postmenopausal women with advanced breast cancer, daily 
      doses of EXE consisting of 25 mg, was generally well tolerated and adverse events 
      were usually mild to moderate. Adverse effects of EXE which have been reported  
      among postmenopausal women receiving this therapy in either the adjuvant or 
      metastatic setting, include: 
 
      More Common 
        
           Endocrine/metabolic: diaphoresis (6-17.8%), hot sweats (13-32.9%) 
           Gastrointestinal: nausea (8.5-18%), diarrhea (4-9.6%), vomiting (7%) 
            
           Musculoskeletal:  arthralgia (14.6-28.8%), myalgia (5.5%), osteoporosis (4.6%), 
                                        pain in limb (9%), osteoarthritis (5.9%) 
           Neurologic: headache (6.9-13.1%), insomnia (11-13.7%), dizziness (8-9.7%) 
           Constitutional: fatigue (11-22%), asthenia (6%) 
           Dermatologic: alopecia (15.1%), dermatitis (8.2%) 
           Psychiatric: depression (6.2-13%), anxiety (4.1-11%) 
   
           Severe 
 
           Cardiovascular: heart failure (0.4%), myocardial infarction (1.6%) 
           Musculoskeletal: fracture of bone (4.2%) 
           Neurologic: cerebrovascular accident (6 deaths due to stroke, N=2252) 
           Hematologic: thromboembolic event (0.9%)     
               
   8.3  Pharmacology 
 
           Kinetics:  EXE is rapidly absorbed after oral administration and high-fat food 
           increases plasma levels. It is metabolized hepatically via the CYP3A4 pathway and 
           converted into an active 17-dihydro metabolite. Routes of systemic excretion 
           of EXE consist of fecal (42%) and renal (42%), with < 1% of drug remaining 
     unchanged. Elimination half life is 24 hours. Based on experience with 
     EXE in multiple doses up to 200 mg daily, the manufacturer does not  
     recommend dosage adjustment in patients with renal or hepatic impairment. 
           In postmenopausal women, suppression of plasma estrogen was observed 
           8-24 h after single oral doses of EXE [20].  


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            Formulation:  EXE is supplied as a 25 mg tablet. 
 
           Storage and Stability:  Store at controlled room temperature, 250 C. 
 
           Administration: Oral 
      
           Supplier:  This study will supply all study participants with EXE, as provided by the  
                           manufacturer (Pfizer). 
 
                 
9.0  
REGULATORY OBLIGATIONS 
 
9.1  
Informed Consent 
 
      All patients will have signed an informed consent for participation in research 
activities, according to all institutional, NCI and federal regulations and will 
have been given a copy of the Experimental Subject’s Bill of Rights. 
The original signed consent form will be placed in the medical record. A 
copy will be given to the subject and a copy will be filed in the research record. 
 
9.2  
Confidentiality of Records 
 
     The study protocol will strictly adhere to all HIPAA and COH IRB regulations. 
Confidentiality of subjects will be strictly maintained. All research records and 
data collection forms will be stored in secured cabinets at the data coordinating 
center at COH.  
 
9.3  
Registration Process  
 
9.3.1 Registrations for this protocol must be made through the CRIM office at the City 
of Hope between the hours of 8:30 a.m. to 4:30 p.m., Monday through Friday 
(except holidays).  
 
9.3.2 Patients must be registered within 2 weeks prior to initiation of protocol therapy. 
 
9.3.3 A patient failing to meet all protocol requirements may not be registered.  If you 
have any questions regarding eligibility, contact (626) 256-4673 ext. 62468 and 
ask for the CRA in charge of this study. 
 
9.3.4 Pre-study laboratory tests, scans and x-rays must be completed prior to 
registration according to study calendar. 
 
9.3.5 Patients must sign an informed consent prior to registration. 
 
9.3.6 Confirm that the patient meets all inclusion and exclusion eligibility criteria for 
this  protocol. 
 


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9.3.7 Complete the eligibility checklist. 
 
9.3.8 Verify that all required pre-study tests were performed. 
 
9.3.9 Fax the completed eligibility checklist and the signed, dated informed consent to 
CRIM.  The FAX number is (626) 301-8393.  
 
9.3.10 Call the CRA at (626) 256-4673 x 62468 to confirm the FAX arrival. If the 
coordinator is not in the office, have her paged. 
 
9.3.11 If the patient qualifies, the City of Hope coordinator will assign the patient's study 
ID number.   
 
9.3.12 Once a patient has been registered, the CRA will confirm registration of the 
 
patient.  
 
 
 
 
9.4  
Data Collection Forms and Submission Schedule 
  
      All data will be collected using COH Biostatistics Information Tracking System 
 
(BITS) data collection forms.  Forms to be completed include: 
 
Eligibility Checklist:  This form will be completed at the time of registration. 
 
On-Study Form:  
To be completed within two weeks of registration. 
 
Treatment Form:  
To be completed within four weeks of completion of one  
 
cycle of treatment. 
 
Flow Sheets:  
Protocol specific flow sheets are to be submitted along with each 
       
treatment form. 
 
Response/Off-Study/ 
Follow-Up:  
Form F/U is to be submitted each time a patient 
is evaluated for response and/or new follow-up information is 
obtained. 
Supplemental  
Data Form:  
The timeline for submission of the supplemental data form 
 
will be protocol specific, if applicable. 
                                    
Additionally, Health Assessment Questionnaires (Appendix A), EORTC Quality of Life 
Questionnaires (Appendix C) and treatment diaries will be collected per study calendar 
(section 10). 


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10. STUDY CALENDAR  
STUDY CALENDAR 
  
Screen 
Study Treatment 
Study 
Termination 
Cycle 
  
1 
2 
3 
4 
5 
6 
  
  
Cycle Days5 
  
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
Continue Assessments Until PD, Unacceptable Toxicity, Consent 
Withdrawal,  PI Discretion or Death  
  
Study Week 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
  
Treatment Schedule5 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Exemestane 
  
X 
X 
OFF 
X 
X 
OFF 
X 
X 
OFF 
X 
X 
OFF 
X 
X 
OFF 
X 
X 
OFF 
  
GENERAL ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Review of Eligibility 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History/Clincal Evaluation1 
X 
 
  
  
 
  
  
X 
  
  
 
  
  
 
  
  
X 
  
  
  
Weight/Height/Vitals 
X 
 
  
  
 
  
  
X 
  
  
 
  
  
 
  
  
X 
  
  
  
Prior & Current Medication List 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Assessment of Compliance/Toxicity 
  
 
  
  
 
  
  
X 
  
  
 
  
  
 
  
  
X 
  
  
  
LABORATORY ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood Chemistry6 
X 
X 
  
  
X 
  
  
 X 
  
  
 X 
  
  
 X 
  
  
 X 
  
  
  
Hematology6 
X 
X 
  
  
X 
  
  
 X 
  
  
 X 
  
  
X  
  
  
 X 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TUMOR RELATED ASSESSMENTS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone Scan2 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
  
Radiologic Assessments3 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life (Appendix C) 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Tumor Sample4 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 HAQ Questionnaire (Appendix A) 
  
X    
  
X 
  
  
X 
  
  
 X 
  
  
 X 
  
  
 X 
  
  
  
  


IRB #08063  
 
 
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Version: 11 
27
 
1Clinical evaluation including physical examination and assessment of performance status (ECOG Score) 
 
  
 
  
 
  
2Patients with a positive bone scan at screening [note: PET/CT Scan may be used in lieu of Bone Scan when patient is symptomatic] will continue to have bone 
scans performed every 9 weeks while on study. Subjects with a negative bone scan at the start of study will not be required to continue with follow-up bone scans, 
unless clinically indicated.  
 
  
3Radiologic assessments may be performed by CT or MRI but the same modality used at the time of screening must be used throughout the study. Studies will be 
repeated every 9 weeks. 
 
  
4Tumor samples of primary and metastatic sites (archived block, slides or fresh tissue collected for clinical care purposes), will be collected at study initiation. If 
possible, pre- and post-treatment biopsy specimens will also be obtained. 
  
5  All tests,  procedures and treatment will have +/- 3 day window. 
 
6 Research Patient Numbers (RPNs) will be used as identifiers for blood samples collected. 
  After Cycle 6, Blood Chemistry and Hematology will be done per MD discretion. 
 
 
 
 
    
 
 
 
 
 


IRB #08063  
 
 
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Version: 11 
28
REFERENCES 
 
1.  Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J 
and Therasse, P. Phase III study comparing exemestane with tamoxifen as first-line 
hormonal treatment of metastatic breast cancer in postmenopausal women: The European 
Organisation for Research and Treatment of Cancer Breast Group. J Clin Oncol  
2008;26:4883-4890. 
2.  Kaufmann M, Bajetta E, Dirix LY, et al. Exemestane is superior to megestrol acetate  
     after tamoxifen failure in postmenopausal women with advanced breast cancer: 
     results of a phase III randomized double-blind trial. J Clin Oncol 2000;18:1399- 
     1411. 
 3. Jones S, Vogel C, Fehrenbacher AL, et al. Multicenter, phase II trial of exemestane as 
     third-line hormonal therapy of postmenopausal women with metastatic breast cancer. 
     J Clin Oncol 1999;17:3418-3425. 
 4. Lφnning PE, Bajetta E, Murray R, et al. Activity of exemestane in metastatic breast  
     cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. 
     J Clin Oncol 2000;18:2234-2244. 
 5.  Gradishar W, Chia S, Piccart M, et al. Fulvestrant versus exemestane following prior 
      nonsteroidal aromatase inhibitor therapy: first results from EFECT, a randomized 
      phase III trial in postmenopausal women with advanced breast cancer. 
      Breast Cancer Res Treat 2006;100(suppl 1):abstract 12. 
 6.  Crew KD, Greenlee H, Capodice J, et al. Prevalence of joint symptoms in post- 
      menopausal women taking aromatase inhibitors for early-stage breast cancer.  
      J Clin Oncol 2007;25:3877-3883. 
 7.  Henry NL, Giles JT, Ang D, et al. Prospective characterization of musculoskeletal 
      Symptoms in early stage breast cancer patients treated with aromatase inhibitors. 
      Breast Cancer Res Treat October 6 2007 (Epub ahead of print). 
 8.  Zhou DJ, Pompon D and Chen S. Stable expression of human aromatase 
      complementary DNA in mammalian cells: a useful system for aromatase inhibitor 
      screening. Cancer Res 1990;50:6949-6954. 
 9.  Sun XZ, Zhou D and Chen S. Autocrine and paracrine actions of breast tumor 
      Aromatase, a three-dimensional cell culture study involving aromatase transfected 
      MCF-7 and T-47D cells. J Steroid Biochem Mol Biol 1997;63:29-36. 
10. Cigler T and Goss PE. Aromatase inhibitor withdrawal response in metastatic breast  
      Cancer. J Clin Oncol 2006;24:1955-1956. 
11. Bhide SA and Rea DW. Metastatic breast cancer after exemestane withdrawal: a 
      case report. The Breast 2004;13:66-68. 
12. Song RXD, Mor G, Naftolin F, et al. Effect of long-term estrogen deprivation on  
      apoptotic responses of breast cancer cells to 17β-estradiol. J Natl Cancer Inst 
      2001;93:1714-1723. 
13. Osipo C, Gajdos C, Chen D, et al. Reversal of tamoxifen resistant breast cancer by low 
      dose estrogen therapy. J Steroid Biochem Mol Biol 2005;93:249-256. 
14. Yao K, Lee E-S, Bentrem DJ, et al. Antitumor action of physiological estradiol on 
      tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 2000;6:   
      2028-2036. 
15. Wang X, Masri S, Phung S and Chen S. The role of amphiregulin in exemestane- 


IRB #08063  
 
 
October 25, 2013 
Version: 11 
29
      resistant breast cancer cells: evidence of an autocrine loop. Cancer Res 2008; 
      68:1-7. 
16. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled 
      trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase 
      inhibitor therapy in postmenopausal women with hormone receptor-positive, 
      advanced breast cancer: results from EFECT. J Clin Oncol 2008;26:1-8. 
17. Bruce B and Fries JF. The Stanford Health Assessment Questionnaire: a review of 
      its history, issues, progress and documentation. J Rheumatol 2003;30:167-178. 
18. Chernick MR and Liu CY. The saw-toothed behavior of power versus sample size 
      and software solution: single binomial proportion using exact methods. The 
      American Statistician 2002;56:149-155. 
19. Longmate JA. The saw-toothed behavior of power versus sample size and software 
      solution: single binomial proportion using exact methods (Letters to the Editor). 
      The American Statistician 2003;57:148-151. 
20. Evan TRJ, Di Salle E, Ornati G et al. Phase I and endocrine study of exemestane 
      (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res; 
      1992;52:5933-5939. 


ENGLISH 
 
IRB #08063  
 
 
October 25, 2013 
Version: 11 
1
APPENDIX A:  HEALTH ASSESSMENT QUESTIONNAIRE (HAQ DI©) 
 
Name:_____________________________                                          Date_______________ 
 
Please place and “x” in the box which best describes your abilities OVER THE PAST WEEK: 
 
                                                                     WITHOUT ANY         WITH SOME        WITH MUCH         UNABLE  
                                                                                                        DIFFICULTY              DIFFICULTY       DIFFICULTY        T0 DO 
ARE YOU ABLE TO: 
 
DRESSING AND GROOMING                     
 
Dress yourself, including shoelaces 
and buttons? 
 
Shampoo your hair? 
 
ARISING 
 
Stand up from a straight chair? 
 
Get in and out of bed? 
 
EATING 
 
Cut your own meat? 
 
Lift a full cup or glass to your mouth? 
 
Open a new milk carton? 
 
WALKING 
 
Walk outdoors on flat ground? 
 
Climb up five steps? 
 
 
Please check any AIDS OR DEVICES that you usually use for any of the above activities: 
 
             Devices used for Dressing                Built up or special utensils                Crutches 
            (button hook, zipper pull, etc.)  
 
             Special or built up chair                     Cane                   Walker                 Wheelchair                        
 
 
   


ENGLISH 
 
IRB #08063  
 
 
October 25, 2013 
Version: 11 
2
Please check any categories for which you usually need HELP FROM ANOTHER PERSON: 
 
          Dressing and grooming               Arising                     Eating                  Walking   
 
 
 
Please place an “x” in the box which best describes your abilities OVER THE PAST WEEK: 
 
                                                                                                            WITHOUT ANY        WITH SOME           WITH MUCH        UNABLE  
                                                                                                            DIFFICULTY             DIFFICULTY           DIFFICULT           TO DO 
ARE YOU ABLE TO: 
 
HYGIENE  
 
Wash and dry your body? 
 
Take a tub bath? 
 
Get on and off the toilet?  
 
REACH 
 
Reach and get down a 5 pound object 
(such as a bag of sugar) from above 
your head? 
 
Bend down to pick up clothing from 
the floor? 
 
GRIP 
 
Open car doors? 
 
Open previously opened jars? 
 
Turn faucets on and off? 
 
ACTIVITIES  
 
Run errands and shop? 
 
Get in and out of a car? 
 
Do chores such as vacuuming or  
yard work? 


ENGLISH 
 
IRB #08063  
 
 
October 25, 2013 
Version: 11 
3
Please check any AIDS OR DEVICES that you usually use for any of the above activities: 
 
         Raised toilet seat                      Bathtub bar                       Long-handled applicances for reach 
 
 
         Bathtub seat                              Long-handled appliances                  Jar opener 
                                                           in bathroom                                       (for jars previously opened) 
 
 
Please check any categories for which you usually need HELP FROM ANOTHER PERSON: 
 
       Hygiene                Reach                 Gripping and opening things               Errands and chores 
 
 
 
 
Your ACTIVITIES: To what extent are you able to carry out your everyday physical activities 
such as walking, climbing stairs, carrying groceries or moving a chair? 
 
       Completely               Mostly               Moderately               A Little               Not at All 
 
 
 
 
Your PAIN: How much pain have you had IN THE PAST WEEK? 
On a scale of 0 to 100 (where zero represents “no pain” and 100 represents “severe pain”), please 
record the number below. 
 
 
 
 
 
Your HEALTH: Please rate how well you are doing on a scale of 0 to 100 (zero represents 
“very well” and 100 represents “very poor” health), please record the number below. 
 
          
 
 


ENGLISH 
 
IRB #08063  
 
 
October 25, 2013 
Version: 11 
4
 
   APPENDIX B:  PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


ENGLISH 
 
IRB #08063  
 
 
October 25, 2013 
Version: 11 
5
 
 
 
EORTC QLQ-C30 (version 3) 
 


ENGLISH 
 
IRB #08063  
 
 
October 25, 2013 
Version: 11 
6
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you 
provide will remain strictly confidential. 
 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year):  
 
 
 
Not at 
A 
Quite Very 
 
All 
Little 
a Bit Much 
 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week:  
Not at 
A 
Quite Very 
 
  
All 
Little  a Bit Much 
6. 
Were you limited in doing either your work or other daily activities? 1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


ENGLISH 
 
IRB #08063  
 
 
October 25, 2013 
Version: 11 
7
During the past week:  
Not at 
A Quite Very 
 
All 
Little 
a Bit Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0