Randomized Phase II Study of Fulvestrant With or Without Ganetespib in Patients With Hormone Receptor-Positive, Metastatic Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Dana-Farber Cancer Institute

Status Page 
 
 
 
PROTOCOL 11-477 
 
 
 
 
 
 
                                                             
Closed to New Accrual 
 
              
 
 
 
 
 
 
 
 
 
Closure Effective Date:  01/15/2016 
No new subjects may be enrolled in the study as described above.  
Any questions regarding this closure should be directed to the 
study’s Principal Investigator 
 
 
 

 
 
 
 
 
 
 
Office for Human Research Studies 
 
DANA-FARBER / HARVARD CANCER CENTER 
Version: 10.03.14a 
 
 
Protocol Front Sheet 
DFCI Protocol No.: 11-477  
 
1.  PROTOCOL TITLE AND VERSION  
 
Title: Randomized phase II study of fulvestrant with or without ganetespib in patients with hormone receptor-positive, metastatic breast cancer 
Protocol Version No./ Date: 12/14/2015 
Sponsor Study Number: N/A 
 
2.  DF/HCC STUDY CONTACT INFORMATION 
 
Primary Study Contact: Danielle Gore  
Email:  dgore2partners.org 
Phone:  617-632-4870 
 
INVESTIGATORS:  (List only those under DFCI IRB, i.e., from institutions listed in Section 6 below) 
Overall PI: 
Nancy Lin, MD 
Phone: 617-632-2335 
Institution(s): 
DFCI 
Site Responsible PI: 
Douglas Weckstein, MD 
Phone: 603.622.6484 
Institution(s): 
NHOH 
 
 
3.  DRUG / DEVICE INFORMATION    N/A: 
  
 
 Drug(s), Biologic(s):  Ganetespib (STA-9090) 
 Device(s) Name:        
Provided by: Synta Pharmaceuticals 
IND Exempt: 
        ‐or‐ 
IND#: 115026 Holder Type: DF/HCC Investigator    
IND Holder Name: Nancy Lin, MD  
Provided by:      
IDE Exempt: 
        ‐or‐ 
IDE #:            Holder Type: [pull down]    
IDE Holder Name:        
 
4.  PROTOCOL COORDINATION, FUNDING, PHASE, MODE, TYPE ETC. 
 
Regulatory Sponsor: 
Funding/Support (check all that apply): 
Phase: Phase 2 
DF/HCC Investigator  Nancy Lin, MD      
 Industry: Synta Pharmaceuticals 
 
 
 Federal Organization:       
Multi-Center (i.e., non-DF/HCC site participation): 
Cancer Related:  Yes   If yes: 
      Grant #:       
Yes 
Primary Disease Program: 
 Internal Funding:       
 
Breast Cancer 
 Non-Federal:       
Protocol Type: Therapeutic - Continuation 
or 
 Other: Komen Grant #KG110450 
If Ancillary, provide parent protocol #:       
Primary Discipline Based Program: 
 
 
[pull down] 
CTEP Study: [pull down] 
 
 
 
 
Protocol Involves (check all that apply as listed in the protocol document, even if not part of the research but is mandated by the protocol document): 
 Chemotherapy 
 Hormone Therapy 
 Medical Record Review 
 Immunotherapy 
 Vaccine 
 Questionnaires/Surveys/Interviews 
 Surgery 
 Data Repository 
 Radiological Exams 
 Bone Marrow/Stem Cell Transplant 
 Exercise/Physical Therapy 
 Required Biopsy Study 
 Cell Based Therapy 
 Genetic Studies 
 Human Embryonic Stem Cell 
 Gene Transfer (use of recombinant DNA) 
 Human Material Banking 
 Quality of Life 
 Radiation Therapy 
 Human Material Collection 
 Other:       
 
5.  SUBJECT POPULATION (also applies to medical record review and specimen collection studies) 
 
Total Study-Wide Enrollment Goal: 71 
Greater than 25% of the overall study accrual will be at DF/HCC: 
 Yes   
 No 
Total DF/HCC Estimated Enrollment Goal: 56 
Adult Age Range: 18+ 
Pediatric Age Range: N/A 
Will all subjects be recruited from pediatric clinics?    
 Yes    
 No 
If enrolling both adults and pediatric subjects, anticipated percent of pediatric subjects: N/A 
Retrospective Medical Record Reviews only (Please provide date range): from       to       
 
6.  DF/HCC PARTICIPANTS UNDER DFCI IRB (check all that apply) 
 
 Beth Israel Deaconess Medical Center (BIDMC) 
 DF/BWCC in Clinical Affiliation with South Shore Hospital (DFCI @ SSH) 
 Beth Israel Deaconess Medical Center – Needham (BIDMC-Needham) 
 Dana-Farber at Milford Regional Cancer Center (DFCI @ MRCC) 
 
 Dana-Farber at Steward St. Elizabeth’s Medical Center (DFCI @ SEMC) 
 Boston Children’s Hospital (BCH) 
 Massachusetts General Hospital (MGH) 
 Brigham and Women’s Hospital (BWH) 
 Mass General/North Shore Cancer Center (MGH @ NSCC) 
 Dana-Farber Cancer Institute (DFCI) 
 Mass General at Emerson Hospital – Bethke (MGH @ EH) 
 Dana-Farber/New Hampshire Oncology-Hematology (DFCI @ NHOH) 
 New England Cancer Specialists (NECS) 
 
 
7.  NON-DF/HCC PARTICIPANTS UNDER DFCI IRB (check all that apply) 
 
 
Cape Cod Healthcare (CCH)  
 
Lowell General Hospital (LGH)  
 
New Hampshire Oncology-Hematology-P.A. (NHOH)  
 
Newton-Wellesley Hospital (NWH) 
 Broad Institute 
 Lawrence & Memorial Cancer Center in affiliation with Dana-Farber 
Community Cancer Care (LMCCC) 
 

Protocol Front Sheet 
 
FS Page: 2 
 
8.  DF/HCC INITIATED STUDIES ONLY  - INSTITUTIONAL PARTICIPANTS UNDER OTHER IRB  (N/A: 
) 
 
 
DF/HCC Multi-Center Protocols:  (list institution/location) 
 
DF/PCC Network Affiliates: (list institution/location) 
University of North Carolina at 
Chapel Hill 
Chapel Hill, NC 
     
      
 
 

Page 1 of 2 
 
Protocol Number: 11-477 
 
Approval Date:  
02/28/12 
(IRB meeting date when protocol/consent  
 approved or conditionally approved) 
 
Activation Date:  
05/18/12 
(Date when protocol open to patient entry) 
 
Approval signatures are on file in the Office for Human Research Studies, tel. 617-632-3029. 
Date 
Posted 
Revised Sections 
IRB 
Approval 
Date 
OHRS 
Version 
Date 
6/1/12 
DFCI Nursing Protocol Education Sheet  Updated 
N/A 
- 
6/1/12 
Alert Page Updated Due to Amendment #4 
5/24/12 
- 
09/24/12 
Front Sheet replaced due to Amendment #5 
09/21/12 
N/A 
09/28/12 
Temporary Closure to New Accrual: due to 
Administrative HOLD per DF/HCC DSMC (effective 
date: 09/20/12 ; Amendment # 6) 
09/24/12 
N/A 
10/11/12 
Alert Page, Protocol and Front Sheet replaced due to 
Amendment #7 
10/04/12 
N/A 
10/16/12 
Re-Open to accrual; Amendment #8 (Effective 
10/10/12) 
10/12/12 
N/A 
11/08/12 
Protocol and Front Sheet replaced due to Amendment 
#9 
10/26/12 
N/A 
01/30/13 
Front Sheet replaced due to Amendment #10 
01/29/13 
n/a 
02/22/13 
Study renewal/ Consent Form footer replaced due to 
Continuing Review #1 
02/14/13 
N/A 
02/28/13 
Protocol, Consent Form and Front Sheet replaced, 
Pharmacy Manual added due to Amendment #11 
02/19/13 
02/28/13 
03/25/13 
Correction: alert page removed (AM #11) 
n/a 
n/a 
03/26/13 
Front Sheet replaced due to Amendment #12 
03/25/13 
n/a 
04/02/13 
Protocol and Front Sheet replaced due to Amendment 
#13 
04/01/13 
N/A 
04/26/13 
Front Sheet replaced due to Amendment #14 
04/26/13 
N/A 
06/03/13 
Protocol, Consent Form and Front Sheet replaced due 
to Amendment #15 
05/30/13 
06/03/13 
07/23/13 
Protocol and Front Sheet replaced; Study Medication 
Preparation & Administration (300 mg) and 
Recruitment Materials added due to Amendment #16 
07/11/13 
N/A 
08/05/13 
Alert Page added due to Amendment #17 
07/22/13 
N/A 
08/28/13 
No changes to online documents; Amendment #19 
08/16/13 
N/A 
09/11/13 
BIDMC added as participating site; Consent Form and 
Front Sheet replaced due to Amendment #18  
08/23/13 
09/05/13 
09/17/13 
Site Specific Closure: temporary closing BIDMC site to 
new accrual; remains open at DFCI, DFCI at FH 
(effective 09/16/13; Amendment #20) 
09/17/13 
n/a 
10/02/13 
Re-open to accrual at BIDMC; Amendment #22 
(Effective 09/24/13) 
09/25/13 
N/A 
10/02/13 
Consent Form and Front Sheet replaced due to 
Amendment #21 
10/02/13 
10/02/13 
10/03/13 
Consent Form, Protocol and Front Sheet replaced due 
to Amendment #23 
09/30/13 
10/02/13 
10/09/13 
Correction: Consent Form replaced due to incorrect 
version previously provided w/ Am #23 
09/30/13 
10/08/13 
10/17/13 
Front Sheet replaced due to Amendment #25 
10/15/13 
n/a 
10/24/13 
Protocol and Nursing PES replaced, Alert Page 
removed due to Amendment #24 
10/08/13 
N/A 
11/13/13 
Protocol, Consent Form and Front Sheet replaced due 
to Amendment #26 
11/07/13 
11/13/13 

Page 2 of 2 
 
11/26/13 
Correction: Consent Form replaced due to incorrect 
version previously provided w/ Am #26 
11/07/13 
11/26/13 
01/27/14 
Consent Form replaced due to Continuing Review #2 
01/23/14 
01/24/14 
02/12/14 
Alert Page added due to Amendment #27 
01/23/14 
N/A 
03/18/14 
Consent Form, Protocol and Front Sheet replaced due 
to Amendment #28 (Note: re-consent required) 
02/25/14 
03/18/14 
04/02/14 
Protocol, Pharmacy Manual-300 mg and Front Sheet 
replaced due to Amendment #29 
03/24/14 
N/A 
04/04/14 
Correction AM #29: Alert Page removed 
N/A 
N/A 
04/04/14 
Update: PES replaced 
N/A 
N/A 
04/15/14 
Alert Page added due to Amendment #30 
04/09/14 
n/a 
05/14/14 
Alert Page and Front Sheet replaced due to 
Amendment #31 
05/02/14 
N/A 
06/03/14 
Front Sheet replaced due to Amendment #32 
06/02/14 
n/a 
07/25/14 
New Hampshire Oncology – Hematology site closed to 
new accrual; All other sites remain open to accrual; 
Amendment # 33 (Effective 06/30/14) 
07/01/14 
N/A 
08/14/14 
Administrative Update #1: Pharmacy manuals 400mg 
and 300mg replaced with Pharmacy Manual  
N/A 
N/A 
10/07/14 
Protocol, Front Sheet , Nursing PES replaced due to 
Amendment #34 
09/30/14 
N/A 
10/14/14 
Correction Amendment #34: Alert Page removed 
N/A 
N/A 
11/11/14 
BIDMC removed from the study.  
Consent Form and Front Sheet replaced due to 
Amendment #35 
11/10/14 
N/A 
01/05/14 
Consent Form replaced due to Amendment #36 
12/22/14 
12/23/14 
01/22/15 
Study renewal / Consent Form footer replaced due to 
Continuing Review #3 
01/08/15 
N/A 
05/18/15 
Protocol, Consent Form and Front Sheet replaced due 
to Amendment #37 
05/15/15 
05/18/15 
Date 
Posted 
Revised Sections 
IRB 
Approval 
Date 
OnCore 
Version 
Date 
10/20/15 
Front Sheet replaced due to Amendment #38 
10/16/15 
N/A 
12/28/15 
Study renewal / Consent Form footer replace due to 
Continuing Review #4 
12/17/15 
12/18/15 
01/06/16 
Protocol, Consent Form and Front Sheet replaced due 
to Amendment #39 
12/29/15 
01/05/16 
01/15/16 
Permanent Closure to New Accrual: Slow accrual 
(effective date: 01/15/16; Amendment #40) 
01/08/16 
N/A 
Date 
Posted 
Revised Sections 
 Approved 
Date 
Version 
Date 
(OnCore) 
12/16/16 
Study renewal/Consent Form footer replaced due to 
Continuing Review #5 
12/15/16 
12/16/16 
12/14/2017 
Study renewal/ Consent form footers replaced per 
Continuing Review #6 
10/19/2017 
11/05/2017 
 

 STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015  
_____________________________________________________________________________________________ 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
 
Protocol Version Date: December 14, 2015  
 
Local Protocol #: 11-477 
 
 
Title: Randomized phase II study of fulvestrant with or without ganetespib in patients with 
hormone receptor-positive, metastatic breast cancer 
 
Principal Investigator:  
 
Nancy U. Lin, M.D. 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
YC-1250 
Boston, MA 02215 
Tel: 617-632-2335 
Fax: 617-632-1930 
Email: nlin@partners.org  
 
Coordinating Center:  
Dana-Farber Cancer Institute, Boston, MA 
 
Co-Investigators:  
 
Luke Whitesell, MD 
Whitehead Institute for Biomedical Research 
Nine Cambridge Center 
Cambridge, MA 02142 
Email: whitesell@wi.mit.edu 
 
Ian Krop, MD, PhD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
YC 1250  
Boston, MA 02215 
Tel: 617-632-3800 
Fax: 617-632-1930 
Email: ikrop@partners.org 
 
Sandro Santagata, MD, PhD 
Brigham & Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Tel: 617-732-7352 
Email: santagat@wi.mit.edu 
 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Myles Brown, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
Tel: 617-632-3948 
Fax: 617-632-5417 
Email: myles_brown@dfci.harvard.edu 
 
Eric P. Winer, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
YC-1250 
Boston, MA 02215 
Tel: 617-632-3800 
Fax: 617-632-1930 
Email: ewiner@partners.org 
 
Carey Anders, MD 
Lineberger Cancer Center 
University of North Carolina 
Chapel Hill, NC 
Tel: 919-966-4431 
Fax: 919-966-6735 
Email: carey_anders@med.unc.edu 
 
 
Statistician: DFCI Staff Statistician 
 
Project Manager:  Kathryn (Kasey) Componeschi 
Dana-Farber Cancer Institute 
450 Brookline Ave., LG-GC 
Boston, MA 02215 
Tel:  617-632-5873 
Fax:  617-632-5152 
 
Email: kcomponeschi@partners.org 
 
Study Coordinator:  
 
Danielle Gore 
 
Dana-Farber Cancer Institute  
 
450 Brookline Avenue 
 
Dana Building 157 
 
Boston, MA 02215 
 
Tel: 617-632-4870 
 
Fax: 617-632-3550 
 
Agent(s):  ganetespib – Synta Pharmaceuticals; Fulvestrant (commercial supply) 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 

 STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015  
_____________________________________________________________________________________________ 
 
 
 
SCHEMA 
 
                                                        ER+ metastatic breast cancer 
                                  At least 1 prior endocrine therapy (adjuvant or metastatic) 
 
Stratify: Measurable disease or non-measurable (but evaluable) disease  
(Note: Non-measurable slots filled as of 4/30/14)
*on-study biopsy required for patients with biopsy-accessible disease (Section 3.1.14 and Section 8.1) 
**Central confirmation of PD required PRIOR to cross-over from Arm A to Arm C, or off-study for PD (Arm B).  Patients 
starting on Arm A who cross over to Arm C (fulvestrant + ganetespib) will be restaged every 2 cycles and continue on therapy 
until time of progression. However, patients who have been on-study for >1 year will be restaged every 2-4 cycles. At time of 
off study, CTCs, CPT tube, and optional tumor biopsy will be collected. 
NOTE: Patients who come off protocol treatment for a reason other than progression or death should remain on study and 
continue to be followed per protocol guidelines to assess for progression per Study Calendar D. See Section 5.6 and 5.8 for 
details. 
Collect archival tumor blocks 
Optional baseline research biopsy 
Research blood draw: lavender top, Streck, PBMC, CTCs 
 
Arm A 
Arm B 
C2D8 
--CTCs, PBMC 
C2D9 
--Research biopsy 
(required)* 
--CTCs, PBMC 
RE-STAGE 
CYCLE 1  
(1 cycle = 28 d) 
CYCLE 2  
 
CR,PR,SD 
PD** 
-CTCs 
-Streck tube 
-PBMC 
-Optional tumor 
biopsy 
PD** 
CR, PR, SD 
Randomize 1:2 
N=24 
N=47 
FULVESTRANT                                   FULVESTRANT + GANETESPIB 
Continue 
protocol 
therapy 
Cross-over to 
Arm C** 
Fulvestrant 
      +  
Ganetespib 
Off-study
Continue 
protocol 
therapy 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
Table of Contents  
1. 
OBJECTIVES 
8 
1.1 
Study Design 
8 
1.2 
Primary Clinical Objective 
8 
1.3 
Secondary Clinical Objectives 
8 
1.4 
Correlative Objectives 
8 
2. 
BACKGROUND 
11 
2.1 
Ganetespib (STA-9090) 
11 
2.2 
Fulvestrant 
20 
2.3 
Study Disease 
20 
2.4 
Rationale for Combining Endocrine Therapy with Ganetespib 
21 
2.5 
Summary 
22 
3. 
PARTICIPANT SELECTION 
23 
3.1 
Eligibility Criteria 
23 
3.2 
Exclusion Criteria 
25 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
27 
4. 
REGISTRATION PROCEDURES 
27 
4.1 
General Guidelines for DF/HCC Institutions 
27 
4.2 
Registration Process for DF/HCC Institutions 
27 
4.3 
Registration Process for Other Investigative Sites 
28 
5. 
TREATMENT PLAN 
29 
5.1 
Study Procedures 
35 
5.2 
Agent Administration 
42 
5.3 
Definition of Dose-Limiting Toxicity 
43 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
44 
5.5 
Supportive Care Guidelines 
45 
5.6 
Cardiovascular Guidelines 
48 
5.7 
Duration of Therapy 
49 
5.8 
Duration of Survival and Adverse Event Follow Up 
50 
5.9 
Criteria for Removal from Study 
50 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
51 
6.1 
Anticipated Toxicities 
52 
6.2 
Dose Modifications/Delays 
53 
7. 
DRUG FORMULATION AND ADMINISTRATION 
57 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
7.1 
Ganetespib (STA-9090) 
57 
7.2 
Fulvestrant 
62 
8. 
CORRELATIVE/SPECIAL STUDIES 
64 
9. 
STUDY CALENDAR 
65 
9.1 
STUDY CALENDAR A 
67 
9.2 
STUDY CALENDAR B 
69 
9.3 
STUDY CALENDAR C 
71 
9.4 
STUDY CALENDAR D 
73 
9.5 
SPECIMEN SUBMISSION REQUIREMENTS 
76 
10. 
MEASUREMENT OF EFFECT 
88 
10.1 
Antitumor Effect– Solid Tumors 
88 
10.2 
Guidelines for Following Patients with Non-Measurable but Evaluable Disease 
95 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS 
95 
11.1 
Definitions 
95 
11.2 
Procedures for AE and SAE Recording and Reporting 
97 
11.3 
Reporting Requirements 
98 
11.4 
Reporting to the Study Sponsor 
98 
11.5 
Reporting to the Institutional Review Board (IRB) 
99 
11.6 
Reporting to the Food and Drug Administration (FDA) 
99 
11.7 
Reporting to Synta Pharmaceuticals, the Manufacturer 
100 
11.8 
Reporting to Hospital Risk Management 
100 
11.9 
Monitoring of Adverse Events and Period of Observation 
100 
12. 
DATA AND SAFETY MONITORING 
101 
12.1 
Data Reporting 
101 
12.2 
Safety Meetings 
101 
12.3 
Monitoring 
102 
13. 
REGULATORY CONSIDERATIONS 
103 
13.1 
Protocol Review and Amendments 
103 
13.2 
Informed Consent 
103 
13.3 
Ethics 
103 
13.4 
Study Documentation 
104 
13.5 
Records Retention 
104 
14. 
STATISTICAL CONSIDERATIONS 
104 
14.1 
Background Data for Sample Size Justification 
104 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
14.2 
Primary Clinical Objective and Sample Size Justification 
105 
14.3 
Interim Safety Analysis 
106 
14.4 
Analysis of Secondary Clinical Endpoints 
107 
14.5 
Analysis of Correlative Endpoints 
108 
14.6 
Reporting and Exclusions 
112 
15. 
PUBLICATION PLAN 
113 
16. 
REFERENCES 
114 
17. 
APPENDICES 
116 
 

 STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015  
_____________________________________________________________________________________________ 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
8 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a randomized phase II trial of fulvestrant alone or in combination with ganetespib (STA-
9090) (a novel HSP-90 inhibitor) in patients with hormone receptor-positive, metastatic breast 
cancer. 
 
1.2 
Primary Clinical Objective 
 
The primary objective of this trial is to evaluate the effect of the addition of ganetespib to 
fulvestrant on progression-free survival (PFS), compared to fulvestrant alone. 
 
1.3 
Secondary Clinical Objectives 
 
 To assess the safety and tolerability of ganetespib in combination with fulvestrant 
 
 To describe and compare the objective response rate by RECIST 1.1 between arms, limited 
to patients with measurable disease at baseline.  
 
 To describe and compare the clinical benefit rate, defined as complete response (CR) + 
partial response (PR) + stable disease >/= 6 months between arms 
 
 To describe and compare overall survival (OS) between arms 
1.4 
Correlative Objectives 
1.4.1 
The primary correlative objective is to test whether high nuclear expression of 
HSF1 (as assessed on archival breast tumor samples) is associated with PFS, separately in 
the fulvestrant only arm and the combination arm.   
For this analysis, we will assay existing archival breast tumor specimens.  Metastatic 
specimens will take priority over primary tumor specimens; however both should be 
collected when available.  We hypothesize that high nuclear expression of HSF1 may be 
associated with worse progression-free survival in patients treated with fulvestrant alone.  
In patients treated with the combination of fulvestrant + ganetespib, we hypothesize that 
because high nuclear expression of HSF1 may be indicative of increased dependence on 
the heat shock network, it may be associated with improved PFS. 
1.4.2 
All other correlative objectives are exploratory and hypothesis-generating only.  
They are listed below: 
 We will collect cycle 2 biopsies (required in patients with biopsy-accessible disease, see 
Section 3.1.14 and Section 8.1) to assess the effect of fulvestrant alone versus 
fulvestrant plus ganetespib within tumor specimens.  Using a Nanostring custom code 
set, we will assess a set of genes regulated by HSF1, the major transcriptional 
regulator of inducible expression for the entire heat shock network.  We will also 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015 
 
 
 
 
 
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9 
assess a panel of estrogen and ER-regulated genes, other downstream targets of 
Hsp90, and genes thought to play a role in malignant progression/endocrine 
resistance.   
 
We will compare cycle 2 biopsy specimens between patients treated with fulvestrant 
alone versus those treated with fulvestrant + ganetespib.  We will use a cutoff of 4-
fold increase or decrease relative to standard reference genes to characterize the 
expression of each of the selected genes (upregulated, downregulated, or neutral) for 
comparison between groups.  
 
 We will tabulate the expression of the same set of genes as specified above (by 
Nanostring custom gene set), categorized as above (upregulated, downregulated, 
neutral), in archival specimens (primary and metastatic, as available), cycle 2 tumor 
biopsies, and optional time-of-progression tumor biopsies, in order to describe the 
stability of these markers over time 
 
 Using the cycle 2 biopsies (required in patients with biopsy-accessible disease, see 
Section 3.1.14 and Section 8.1), we will also compare the expression of ER, PR, AR, 
HSF1, HER2, and EGFR by immunohistochemistry and amplification of EGFR and 
HER2 using fluorescence in situ hybridization (FISH) to assess the effect of 
fulvestrant alone versus fulvestrant plus ganetespib within tumor specimens.   
 
For this analysis, each of the markers will be described as “positive” or “negative”.  
For ER, PR, AR, and EGFR, “positive” will include “high positive”, defined as >10% 
nuclear staining, and “low positive” will be defined as 1-10% nuclear staining, and 
“negative” will be defined as no staining or only rare cells positive.  For HSF1, 
“positive” will be defined as 2+ staining, and “low/negative” will include “low-
positive” (1+ staining), and true negatives (no staining or rare cells positive) 
(Santagata et al, manuscript in preparation).  For HER2, we will use the standard 0-3+ 
scale, but will dichotomize with 0, 1+, and 2+ being negative and 3+ positive. 
 
For this analysis, FISH ratio > 2.0 will be considered positive.  FISH ratio < 2.0 will 
be considered negative. 
 
 We will tabulate the expression of ER, PR, AR, HSF1, HER2, and EGFR by 
immunohistochemistry in archival specimens (primary and metastatic, as available), 
cycle 2 tumor biopsies, and optional time-of-progression tumor biopsies, in order to 
describe the stability of these markers over time.   
 
 We will tabulate the amplification status of EGFR and HER2 using fluorescence in situ 
hybridization (FISH) in archival specimens (primary and metastatic, as available), 
cycle 2 tumor biopsies, and optional time-of-progression tumor biopsies, in order to 
describe the stability of these markers over time.   
 
 We will describe ER, PR, AR, and HSF1 expression (using the same cutoffs as above) 
and describe HER2/EGFR amplification (using the same cutoffs as above) in 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer            Protocol version date: 12/14/2015 
 
 
 
 
 
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10 
circulating tumor cells (CTCs) pre-therapy, Cycle 2 Day 8, Cycle 2 Day 9, and at 
time of progression, separately by arm of treatment.   
 
 We will explore the relationship between EGFR and/or HER2 amplification in baseline 
CTCs and PFS, in each arm separately.   
 
 We will compare ER, PR, AR, HSF1 expression, and HER2 and EGFR amplification 
status on cycle 2 Day 9 on-study biopsy and Cycle 2 Day 9 CTCs.  
 
 We will collect peripheral blood mononuclear cells (PBMC) pre-therapy, Cycle 2 Day 
8, Cycle 2 Day 9, and time of progression.  Using a Nanostring custom code set, we 
will assess a set of genes regulated by HSF1, the major transcriptional regulator of 
inducible expression for the entire heat shock network.  We will also assess a panel of 
estrogen and ER-regulated genes, other downstream targets of Hsp90, and genes 
thought to play a role in malignant progression/endocrine resistance.  We do not 
expect changes in estrogen and ER-regulated genes or genes thought to play a role in 
malignant progression/endocrine resistance, but will do this in order to have a 
consistent assay between PBMC samples and tumor samples as described above.  We 
will describe gene expression over time upon exposure to fulvestrant or the 
combination of fulvestrant + ganetespib. 
 
 We will describe the frequency of mutations in PIK3CA, ESR1, and other potential 
genes of interest in archival tumor specimens, cycle 2 Day 9 biopsy specimens, and at 
the time of progression (when available) 
 
 We will explore the relationship between the presence of a PIK3CA and ESR1 
mutations in archival tissue and PFS, in each arm separately 
 
 We will describe mutations in PIK3CA, ESR1, and other potential genes of interest in 
circulating free DNA (cfDNA) at baseline and time of progression. 
 
 We will explore the relationship between baseline mutations in PIK3CA and ESR1 in 
circulating cfDNA and PFS, in each arm separately.   
 
 We will tabulate the PIK3CA and ESR1 mutations detected in cfDNA and tumor tissue 
in order to explore the level of agreement between these two methods 
 
 We will bank any extra materials for future study.  We anticipate that this annotated 
repository will be valuable for future research into the mechanisms of resistance to 
fulvestrant and to ganetespib. 

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2. BACKGROUND 
 
2.1 
Ganetespib (STA-9090) 
 
Mechanism of Action 
 
Ganetespib (STA-9090) is a novel, synthetic small molecule that inhibits heat shock protein 90 
(HSP90), a molecular chaperone protein that modulates cellular homeostasis and responses to 
environmental stress by regulating post-translational folding of client proteins.  Inhibition of 
HSP90 leads to aberrant protein conformations, which targets most clients for ubiquitination and 
subsequent degradation via the proteosome.  Of note, HSP90 client proteins include the steroid 
hormone receptors (ER, PR, AR, etc), BCR-ABL, B-RAF, CDK4, c-KIT, EGFR, HER2, IGF-
1R, hTERT, Src, PI3K, p53, MEK, PDGFR, VEGFR, and AKT.  HSP90 inhibition also has been 
shown to disrupt signaling through the JAK/STAT pathway.  
 
Preclinical Studies 
 
STA-9090 inhibits HSP90 chaperone activity by binding to its N-terminal ATP pocket.  It is a 
novel compound unrelated to geldanamycin, 17-AAG, or IPI-504.   
 
STA-9090 has cytotoxic activity against a broad range of cell lines derived from hematologic 
and solid tumors.  The IC50 values for STA-9090 are in the low nM range and at least 20-fold 
more potent than 17-AAG.  In all but 3 cell lines tested, STA-9090 was more potent than 17-
AAG at inducing cell death.  In BT-474 breast cancer cell lines, STA-9090 induced significantly 
more degradation of HER2.  A 5-minute exposure to STA-9090 was able to depress HER2 
protein levels and maintain this state over the subsequent 3 days.   
 
Animal Studies 
 
In nonclinical studies evaluating absorption, distribution, biotransformation, and elimination, 
STA-9090 peak and total exposure increased in an approximately dose-proportional manner in 
rats and cynomolgus monkeys over the dose ranges tested.  No significant gender differences 
were observed in the pharmacokinetics in either species.  STA-9090 was highly protein-bound 
and highly distributed through tissues, with the exception of the central nervous system.  Fecal 
elimination through bile was the major source of excretion.  STA-9090 was extensively 
metabolized in the liver to mainly glucuronide conjugates.  STA-9090 appears to be an inhibitor 
of CYP2C19 and CYP3A4 (midazolam specific), but does not seem to be an inducer of 
CYP/UDP-UGT enzymes. 
 
Results from safety pharmacology show acceptable cardiac effects, in particular, no evidence of 
QT prolongation.  In genetic toxicity studies, STA-9090 was demonstrated to be non-mutagenic 
and non-clastogenic. 
 
STA-9090 was highly efficacious in the Daudi Burkitt’s non-Hodgkin lymphoma xenograft 
model. Intravenous (i.v.) bolus dosing via the tail vein at a dose of 25 mg/kg STA-9090 on a 

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schedule of 1 time per day, 5 times per week (125mg/kg weekly) resulted in significant tumor 
growth inhibition.  Consistent with the increased in vitro potency of STA-9090 relative to 17-
AAG, a three-fold higher dosage of 75 mg/kg 17-AAG (375 mg/kg weekly) caused only modest 
tumor growth inhibition in this model. 
 
In conjunction with the above study, the tolerability of STA-9090 was evaluated by measuring 
cumulative average body weight changes for each treatment group over the course of the study. 
Both STA-9090 and 17-AAG were well tolerated at these dosages, with only minimal effects on 
body weights. In this and other studies, 25-35 mg/kg STA-9090 or 75-100 mg/kg 17-AAG dosed 
5 times per week (125-175 mg/kg and 375-500 mg/kg weekly, respectively) were the highest 
dosages that were well tolerated based on body weights in Nude and SCID mice. This was based 
on no single animal in a treatment group losing ≥20% of its body weight at any point during a 
study, and no treatment group losing ≥10% cumulative average body weight over the course of a 
study. However, when dosing only 1, 2 or 3 times per week, even higher doses of STA-9090 
were well tolerated. 
 
STA-9090 was also highly efficacious in the SU-DHL-4 GCB-type diffuse large B-cell 
lymphoma (DLBCL) xenograft model. In this study, 100mg/kg STA-9090 dosed only 2 times 
per week (200 mg/kg weekly) resulted in significant tumor growth inhibition, with a %T/C value 
of 2. Again, emphasizing the increased potency of STA-9090, an equivalent dosage of 100 
mg/kg 17-AAG (200 mg/kg weekly) was not significantly efficacious, with a %T/C value of 72.  
 
Both drugs had only minimal effects on cumulative average body weights in this study. 
Treatment with 150 mg/kg STA-9090 dosed only 1 time per week also displayed significant 
efficacy in this tumor model. The STA-9090 dose response was also examined in the SU-DHL-4 
DLBCL xenograft model. Doses of 25, 50, 75 and 100 mg/kg STA-9090 dosed 2 times per week 
were all highly efficacious in this model, with %T/C values of 26, 4, -90 and -93, respectively. 
However, doses 6.25 and 12.5 mg/kg STA-9090 failed to show significant efficacy, with %T/C 
values of 69 and 57, respectively. Seventy five and 100 mg/kg STA-9090 dosed 2 times per 
week for a total of 3 weeks (150 and 200 mg/kg weekly) resulted in 25% and 50% of the animals 
in each group being free of tumors by the end of the study, respectively. 
 
A similar STA-9090 dose response was observed in the RPMI 8226 human multiple myeloma 
xenograft model. Doses of 25, 50, 100 and 150 mg/kg STA-9090 dosed 1 time per week were all 
efficacious in this model, with %T/C values of 38, 11, -19 and -66, respectively. Importantly, 
these results illustrate that dosing STA-9090 only once weekly can still result in significant in 
vivo efficacy. It is likely that the STA-9090 dose and dosing schedule necessary to achieve 
significant efficacy in a xenograft tumor model depends upon the specific HSP90 client proteins 
that are critical for the proliferation and survival of a particular tumor cell line, as well as the 
kinetics of HSP90 client protein degradation and re-synthesis after treatment with a HSP90 
inhibitor. 
 
Although human cancers are typically characterized by a wide variety of genetic alterations that 
collectively contribute to the transformed state, a subset of cancers appears to be particularly 
dependent upon single oncoproteins for their genesis, sustained proliferation and/or survival. In 
such cancers, inactivation of the critical oncoprotein can cause rapid tumor cell growth arrest, 

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differentiation or apoptosis. This phenomenon has been termed “oncogene addiction,” and has 
important implications for the development of targeted cancer therapeutics.  
 
Significantly, a number of such addicting oncoproteins are also HSP90 client proteins. 
Therefore, cancers involving these oncoproteins are particularly promising indications for 
treatment by HSP90 inhibition. To examine this possibility, STA-9090 was tested in several 
xenograft tumor models of cancers that are addicted to specific HSP90 client proteins. The best 
characterized examples of oncogene addiction are in chronic myelogenous leukemia (CML) and 
B-cell acute lymphoblastic leukemia (B-ALL). The vast majority of CML cases and a subset of 
B-ALL cases are associated with a chromosomal translocation resulting in expression of the 
BCR-ABL tyrosine kinase, which is a HSP90 client protein1. STA-9090 was highly efficacious 
in the BCR-ABL+ KU812 CML xenograft model. In this study, 25 mg/kg STA-9090 dosed 5 
times per week (125 mg/kg weekly) resulted in dramatic tumor regression, with a %T/C value of 
-78. In addition, tumors were undetectable in 25% of STA-9090-treated animals by the end of 3 
weeks of dosing.  
 
Another example of oncogene addiction is in acute myeloid leukemia (AML) associated with 
activation of the FLT3 receptor tyrosine kinase, which is a HSP90 client protein. FLT3 
activation, most commonly by an internal tandem duplication mutation (termed FLT3-ITD), is 
the most frequently found genetic alteration associated with AML. STA-9090 was highly 
efficacious in the FLT3-ITD+ Mv 4-11 AML xenograft model. In this study, 25 mg/kg STA-
9090 dosed 5 times per week (125mg/kg weekly) resulted in dramatic tumor regression, with a 
%T/C value of -94. Tumors were undetectable in 63% of STA-9090 treated animals by the end 
of 3 weeks of dosing. In contrast, a three-fold higher dosage of 75 mg/kg 17-AAG (375 mg/kg 
weekly) was substantially less efficacious than STA-9090 in this model, with a %T/C value of 
18. 
 
Another example of oncogene addiction is in gastric carcinoma associated with amplification of 
the c-MET receptor tyrosine kinase, which is a HSP90 client protein. Amplification of the c-
MET locus occurs in up to 20% of gastric carcinomas, and inhibition of c-MET activity rapidly 
induces apoptosis in these cells. STA-9090 was highly efficacious in the c-MET-amplified 
MKN45 gastric carcinoma xenograft model. In this study, 50 mg/kg STA-9090 dosed 3 times per 
week (150 mg/kg weekly) resulted in significant tumor growth inhibition, with a %T/C value of 
8. 
 
All of the above in vivo studies in xenograft tumor models employed STA-9090 solublized in a 
formulation consisting of 10% DMSO, 18% Cremophor RH40 and 3.6% dextrose in sterile water 
(DRD). This DRD formulation is well tolerated in mice when i.v. bolus dosed via the tail vein at 
5-20 mL/kg. In order to demonstrate that STA-9090 is efficacious when using non-DRD 
formulations, more representative of that used in the clinic, an in vivo efficacy study was 
conducted with STA-9090 formulated in 45% PEG 400, 55% 50 mM carbonate buffer pH 10.0 
in sterile water (45 PEG), which is a formulation that is well tolerated in mice. STA-9090 
formulated in 45 PEG was still highly efficacious in the FLT3-ITD+ Mv 4-11 AML xenograft 
model. In this study, doses of 12.5, 18, 25 and 35 mg/kg STA-9090 dosed 1 time per week were 
all efficacious, with %T/C values of 42, 30, 11 and -50, respectively. This result indicates that 

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the in vivo activity of STA-9090 in xenograft tumor models is not dependent upon the use of the 
DRD formulation. 
 
Human Pharmacokinetics 
 
The pharmacokinetics of ganetespib administered at various doses to subjects with solid tumors 
on a weekly or twice-weekly schedule is under investigation in 2 Phase I trials. Preliminary data 
and calculated parameters are available in subjects with solid tumors for doses up to 259 mg/m2. 
Cmax and AUC increase in approximate proportion to dose irrespective of dosing day with 
virtually identical dose-exposure ratios for Day 1 and Day 15, indicating linear 
pharmacokinetics.  Distribution and elimination phases of ganetespib show maximum 
concentration at the end of the infusion declining by approximately 10-fold within the first hour 
and nearly 100-fold within 10 hours following infusion termination.  Mean terminal half-lives 
have ranged from approximately 5.2 to 14 hours.  Ganetespib plasma concentrations on Day 1 
and 15 are comparable following either once or twice weekly dosing, indicating the lack of drug 
accumulation.  Ganetespib exhibits biphasic pharmacokinetics with concentrations declining by 
greater than 10-fold within the first few hours following infusion termination. Mean terminal 
half-lives have ranged from 10.4 to 14.3 hours. STA-9090 plasma concentrations on Day 1 and 
15 are comparable, indicating the lack of drug accumulation when dosed either once or twice 
weekly.  
 
In the dose-escalation 9090-02 trial, blood samples were obtained on C1D1 and C1D15 to 
quantitate HSP70 RNA levels.  Maximum induction occurred in the sample acquired 1.5 to 2 
hours after the start of infusion but reached a plateau at low ganetespib levels, suggesting that 
this may be an overly sensitive biomarker of ganetespib activity. 
 
Drug Interactions 
 
Inhibition and induction potentials of STA-9090 were investigated in human liver microsomes 
and human hepatocytes.  STA-9090 was an inhibitor of CYP2C19 and CYP3A4 (midazolam-
specific) but was not an inducer of CYP or UGT isozymes. 
 
At clinically relevant concentrations, STA-9090 inhibited UGT-mediated metabolism to some 
extent, but not CYP2C9 or CYP3A4-mediated metabolism of potential co-medications in human 
hepatocytes.  STA-9090 did not significantly affect the CYP3A4-mediated metabolism of 
atorvastatin, dexamethasone, fentanyl, and warfarin, or CYP2C9-mediated metabolism of 
warfarin.  Inhibition of CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (testosterone-specific) were 
less than 50% at concentrations up to 10 M. 
 
Based on the Caco-2 permeability assay, STA-9090 is a potential P-gp substrate. 
As per Chouinard, et.al, fulvestrant is glucuronidated by UGT1A1, 1A3, 1A4 and 1A8 and 
ganetespib has been shown to inhibit UGT-mediated metabolism of furosemide (UGT1As); 
however, laboratory work completed at Synta specifically addressing possible UGT-mediated 
interactions with ganetespib indicates that an alteration of fulvestrant metabolism by ganetespib 
is unlikely. Fulvestrant metabolism is unaffected by the presence of ganetespib at ganetespib 
concentrations of 1, 10, and 20 M in human hepatocytes in vitro.  For reference, at 216 

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mg/m2 ganetespib, Cmax is approximately 16 M. At 150 mg/m2 it is approximately 11 M 
(9090-02) 
 
Synta also addressed DDI potential from the perspective of a possible effect of fulvestrant on 
ganetespib in vitro. There was no alteration of ganetespib metabolism by fulvestrant.  
Concentrations of 0.3 and 3 M fulvestrant and 1, 10, and 20 M of ganetespib were used. 
 
Safety 
 
Data available as of 20 September 2013 for Synta-sponsored studies of single-agent ganetespib 
in patients with solid tumors and hematologic malignancies.  
 
The MTD for once-weekly dosing in solid tumors was established at 216 mg/m2 ganetespib 
based on DLTs of asthenia and diarrhea at the highest tested dose level, 259 mg/m2. The 
recommended once-weekly dose administered 3 consecutive weeks of a 4-week cycle is 200 
mg/m2. The recommended dose for twice-weekly dosing (72-hour interval between doses) in 
patients with solid tumors is 150 mg/m2 administered 3 consecutive weeks of a 4-week cycle 
and is based on current safety, tolerability, and preliminary activity data.  The doses selected for 
further study in patients with hematologic malignancies were 200 mg/m2 once weekly and 90 
mg/m2 twice weekly administered 4 consecutive weeks without a rest week.  
 
Approximately 99% of the patients in the largest pooled data set (single-agent studies, n=378) 
experienced at least 1 AE; 92% experienced at least 1 treatment-related event. The most 
frequently reported AEs were related to GI toxicity, and included diarrhea (79%), nausea (42%), 
decreased appetite (30%), vomiting (25%), constipation (21%), and abdominal pain (19%). Non-
GI related events that occurred frequently have included fatigue (54%), headache (19%), and 
anemia (21%). Two-thirds (66%) of these patients experienced an event that was a Grade ≥3; 
31% experienced a Grade ≥3 treatment-related event. Thirty-nine percent experienced at least 1 
serious adverse event (SAE); 8% of patients had at least 1 treatment-related SAE.  
 
In the Phase 2b study in patients treated with ganetespib in combination with docetaxel, Study 
9090-08, preliminary findings show a similar safety profile with 53% reduction in the incidence 
of diarrhea. This was due to implementation of antidiarrheal prophylactic medication for patients 
receiving ganetespib. In the integrated data from patients treated with ganetespib in combination 
with docetaxel (Studies 9090-07 and 9090-08), 97% of patients experienced at least 1 AE, 77% 
at least 1 treatment-related event. The most frequently reported AEs were related to GI toxicity 
and included diarrhea (48%), nausea (25%), decreased appetite (17%), vomiting (14%), 
constipation (10%), Non-GI related events that occurred frequently include neutropenia (46%), 
consistent with known toxicity related to docetaxel treatment, fatigue (30%), and anemia (26%).  
 
Of the 223 patients treated with ganetespib in combination with docetaxel, 57% had treatment-
emergent AEs that were Grade 3 or Grade 4. Thirty-seven percent had at least 1 SAE and 18%, 
at least 1 treatment-related SAE. The most common Grade 3 or 4 event in patients receiving the 
combination treatment was neutropenia (17% and 24%, respectively). In patients treated with 
docetaxel only, 19% of patients experienced a Grade 3 event of neutropenia and 17% 
experienced a Grade 4 event. Severe neutropenia was balanced in the study arms and it is a 

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known toxicity of docetaxel. Febrile neutropenia was experienced by 8% of those receiving the 
combination treatment compared to 4% of patients treated with docetaxel only  
 
Events of Special Interest 
 
Events that may be a class effect of Hsp90 inhibition include diarrhea, ocular toxicities, and 
elevations in liver enzymes.  
 
Diarrhea is the most significant and frequently reported AE associated with the use of 
ganetespib. In integrated data from Studies 9090-07 and 9090-08, 48% of patients treated with 
both ganetespib and docetaxel experienced at least 1 AE of diarrhea compared to 15% of patients 
treated with docetaxel alone. In single-agent studies, approximately 78% of ganetespib patients 
experienced this event. The postulated mechanism of action is inhibition of EGFR in cells that 
line the GI tract, leading to a transient secretory diarrhea, limited to 24 to 48 hours following 
ganetespib infusion. This AE is manageable with loperamide or Lomotil® (atropine 
diphenoxylate). Prophylactic use of loperamide can reduce the occurrence of diarrhea from 
>80% to approximately 40%.  
 
Ocular toxicity, manifested as visual disturbances, has been reported for several Hsp90 
inhibitors. Of the 601 patients treated with ganetespib (single-agent and combination-treatment 
studies) as of 20 September 2013, 6 (1%) patients experienced an event of blurred vision and 4 
(<1%) experienced an event of visual impairment that was assessed as related. In patients treated 
with single-agent ganetespib (N=378), 4 patients (1%) experienced treatment-related blurred 
vision and 3 patients (<1%) experienced treatment-related visual impairment. In patients treated 
with ganetespib in combination with docetaxel in Studies 9090-07 and 9090-08, a treatment-
related visual disturbance of blurred vision was experienced by 2 (<1%) patients and a treatment-
related visual disturbance of visual impairment was experienced by 1 patient. There were no 
such treatment-emergent events in the patients treated with docetaxel alone.  
 
In studies using single-agent ganetespib, visual disturbances regardless of relationship to 
treatment included: blurred vision (5%), visual impairment (2%), and eye pain, vitreous floaters, 
cataract, conjunctival hemorrhage, conjunctivitis, dry eye, eyelid edema, periorbital edema, 
visual acuity reduced, chromatopsia, conjunctival hyperemia, eye swelling, eyelid ptosis, 
glaucoma, night blindness, ocular hyperemia, photopsia, and scotoma (all <1%).  
In studies using ganetespib in combination with docetaxel, visual disturbances regardless of 
relationship to treatment included; lacrimation increased, dry eye, vision blurred (all 2%) and 
conjunctivitis, abnormal sensation in eye, blepharospasm, and cataract (all <1%).  
In patients treated with 17-DMAG or AUY922 who experience visual disturbances, the 
mechanism of visual disturbances is linked to induction of apoptosis in cells in the outer nuclear 
layer of the retina [Zhou, J Clin Oncol, 2012]. In contrast, ganetespib did not elicit induction of 
apoptosis in preclinical studies using rodent models, consistent with the very low number of 
reported visual disturbance cases in the clinic.  
 
Hepatocellular injuries are usually detected by enzyme elevations in serum aminotransferases 
(ATs), total bilirubin, and alkaline phosphatase. In the combination treatment arm of Studies 
9090-07 and 9090-08, AEs of elevated aspartate aminotransferase (AST) and alanine 

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aminotransferase (ALT) were reported in 6% and 4%, of patients, respectively. An AE of 
elevated alkaline phosphatase was reported in 2% of patients and an AE of elevated bilirubin was 
reported in <1% of patients. Grade 3 elevations of AST and ALT were each reported in 1% of 
patients. In the pooled data from 378 patients who received single-agent ganetespib, AEs of 
elevated AST and ALT were reported in 15% and 14% of patients, respectively. An AE of 
elevated alkaline phosphatase was reported in 16% of these patients and an AE of elevated 
bilirubin was reported in 6%. Grade ≥3 elevations of AST and alkaline phosphatase were 
reported in 5% of patients and Grade ≥3 elevations of ALT and bilirubin in 3% of patients. None 
of the patients experienced concomitant elevations of ATs ≥3× the upper limit of normal (ULN) 
and bilirubin ≥2× ULN.  
 
Liver toxicity in the 1st-generation geldanamycin-derivative Hsp90 inhibitors is an off-target 
effect. According to a study by Cysyk, the presence of benzoquinone moiety in the molecule is 
the suspected cause of liver toxicity [Cysyk, Chem Res Toxicol, 2006]. Ganetespib does not 
contain the benzoquinone moiety and, therefore, liver toxicity is not expected. This correlates 
with the safety information collected to date. 
 
ECG Findings 
 
A thorough QT study examining ECG intervals and morphology was conducted in accordance 
with ICH E14. The study was conducted as a sequence-randomized three-period three-way 
complete crossover study in healthy male volunteers. Each subject was assigned to one of six 
sequence groups. Each subject received 200 mg/m2 ganetespib IV over 1 hour, 400 mg 
moxifloxacin PO concomitantly with placebo vehicle IV over 1 hour (positive control), and 
placebo vehicle IV over 1 hour (negative control). Regimens were separated by 7 days. ECGs 
were recorded continuously over 25 hours starting 1 hour prior to infusion (active or placebo). 
ECGs were extracted in up to 10 replicates from each timepoint at the following times: 45, 30, 
and 15 minutes pre-dose, and at 0.5, 1 (immediately before infusion termination), 1.5, 2, 3, 4, 6, 
8, and 24 hours post-infusion initiation. In all periods, loperamide 2 mg was administered 
prophylactically starting approximately 1 hour prior to drug or placebo administration, and then 
every 4 hours for 12 hours. The study was conducted in healthy male volunteers. Forty-five 
subjects received ganetespib. The dose of 200 mg/m2 was selected as this approximates the 
MTD, is the monotherapy dose being studied, and exceeds the combination therapy dose being 
studied by 33% in many studies. Intervals assessed as placebo-corrected change from baseline 
are denoted as “ΔΔinterval name,” whereas those that are pre dose baseline corrected but not 
placebo corrected are denoted as “Δinterval name.”  
 
A mild heart rate increase was observed. A maximum change in heart rate of +9 bpm was 
observed at 6 hours post dose that returned to baseline (± 2 bpm) at 12 and 24 hours. A ΔΔQTcF 
(QT interval corrected by Fridericia’s equation) shortening of -14 msec was observed at 6 to 8 
hours post dose. At 24 hours post dose, the maximum ΔΔQTcF of 21.5 msec, with a 90% 
confidence interval upper bound of 23.5 msec, was observed. ΔΔQTcF returned to baseline 7 
days after ganetespib dose, which was the next measurement timepoint, immediately prior to the 
placebo or positive control dose in the crossover. One subject exhibited QTcF > 450 msec and 
none exhibited greater than 480 msec after ganetespib administration. Two subjects exhibited 
ΔQTcF >30 msec and none exhibited ΔQTcF greater than 60 msec after ganetespib 

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administration. A mild prolongation in the PR interval was observed. ΔΔPR was prolonged by 
11 msec at 8 and 12 hours and by 6.7 msec at 24 hours. Ganetespib did not have an effect on the 
QRS interval, with ΔΔQRS smaller than 0.65 msec at all post-dosing timepoints. No T-wave 
morphology changes were seen in subjects due to ganetespib.  
 
These results were reviewed by an independent cardiologist who provided the following 
assessment:  
The maximum mean ΔΔQTcF of 21.5 ms at 24 h with ganetespib places this compound in a zone 
of clinical ambiguity; it is not clear that this finding confers a substantial increased risk of 
torsades de pointes in patients who are being treated with ganetespib for cancer. The late 
occurrence of the increase in QTcF (at 24 h) is, however, unexpected. The modest increases in 
ΔΔHR and ΔΔPR are not likely to have clinical importance. In the clinical development program 
there have been 362 patients exposed to ganetespib as a single agent and 218 exposed to 
ganetespib plus docetaxel (total 580 patients). Only 7 subjects had prolonged QT reported as an 
AE, and none had torsades de pointes recorded on any ECG. Eight potential deaths resulting 
from cardiovascular SAEs have been reported and were described by investigators as cardiac 
arrest (n=3), sudden cardiac death (n=2) sudden death (n=1), cardiopulmonary failure (n=1) and 
cardiovascular insufficiency (n=1). A total of 4 of these deaths were reported among 191 
subjects who received ganetespib plus docetaxel in study 9090-08. In this same study, the death 
of 5 of 192 subjects receiving docetaxel alone in the comparator arm was described by 
investigators as the result of cardiovascular SAEs. The incidence of deaths on ganetespib due to 
cardiovascular SAEs does not seem excessive. Risk can be minimized by appropriate patient 
selection, attention to electrolyte balance and ECG recording in early cycles to identify the 
unusual patient who may have particular sensitivity to drugs that prolong cardiac repolarization. 
 
The results from a thorough QT study conducted in healthy volunteers (Study 9090-13) reported 
a modest increase in QT interval 24 hours post ganetespib dose. The mean ΔΔQTcF reached 21.5 
msec. ΔΔQTcF was back to baseline 7 days after ganetespib dose. One (2%) subject exhibited 
QTcF > 450 msec and none greater than 480 msec after ganetespib administration. Two (4%) 
subjects exhibited ΔΔQTcF > 30 msec and none greater than 60 msec after ganetespib 
administration. To date, clinical experience with ganetespib does not support an evidence of a 
clinical safety risk for QTc interval prolongation and Torsade de Pointes or other uncontrolled 
arrhythmias. However, until the effect of ganetespib on QT interval is completely characterized, 
all study protocols with ganetespib single agent or combination treatment must implement 
updated inclusion /exclusion criteria for the cardiovascular system. ECG monitoring has also 
been incorporated.  
 
Infusion Reactions 
 
Ganetespib contains a surfactant (polysorbate 80) that has been associated with hypersensitivity 
reactions in other medications administered by infusion. Symptoms have included pruritus, 
flushing, shortness of breath, chest tightness, dizziness, headache, increased systolic BP and HR. 
Therefore, premedication is required prior to administration of ganetespib. 
 
Updated guidelines for prophylaxis and management of infusion reactions have been 
incorporated into the protocol, based on IB Edition 9.  

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Preliminary Clinical Activity 
 
Preliminary signals of clinical activity have been observed in all of the ongoing Phase 1 and 
Phase 1/2 clinical studies, at different dose levels and schedules. 
Two subjects have achieved a Partial Response (PR) as assessed by RECIST criteria.  One 
subject with metastatic melanoma achieved a PR after the fourth cycle of therapy and received a 
total of 12 cycles of treatment (48 weeks).   One subject with rectal cancer achieved a PR after 
the second cycle of therapy and progressed after cycle 8 (total of 32 weeks of treatment).  This 
subject had a local recurrence which was surgically removed and the subject continued on 
treatment at a higher dose of ganetespib.   
Minor responses have also been observed.  One subject with bronchoalveolar carcinoma, 
refractory to three previous lines of systemic therapy, had a 26% reduction in the size of the 
target lesions after cycle 4 and has completed a total of 13 cycles of treatment with ganetespib.  
One GIST subject with a known PDGFRA mutation, refractory to all standard available 
treatments, had an 18% reduction in tumor burden after 2 cycles and completed 8 cycles on 
study.  Several subjects treated at higher doses (≥150 mg/m2) once weekly achieved disease 
stabilization for at least 4 cycles (16 weeks) of treatment. 
 
In the phase I trial exploring weekly dosing in patients with solid tumors, 16/42 patients achieved 
stable disease for more than sixteen weeks and follow up is ongoing. 
 
For the ongoing Phase 2 studies, there has been one subject (EGFR/Kras wild-type) on the 9090-
06 trial who has achieved a confirmed PR as assessed by RECIST criteria, and several subjects 
have achieved shrinkage of baseline target and non-target lesions for ≥ 4 cycles of treatment.   
 
Results of a randomized phase 2 study of docetaxel with or without ganetespib in patients with 
NSCLC who have progressed on first-line therapy have recently been presented in abstract form 
(Ramalingam et al, ASCO 2013).  The study enrolled 252 patients with stage IIIB/IV NSCLC.  
The combination was well-tolerated. Mild to moderate diarrhea was observed but was 
manageable with antidiarrheal medications. .  Grade ¾ adverse events included neutropenia, 
fatigue, anemia, and febrile neutropenia, which occurred with similar incidence in both arms.  
Patients who received the combination experienced improved overall survival (medians 7.4 
versus 9.8 months).  The difference was particularly pronounced in the subset of patients who 
were more than 6 months from initial diagnosis (medians 6.4 versus 10.7 months, p<0.01).   
 
Rationale for Initial Dose 
 
The maximum tolerated dose in the once weekly phase 1 study in solid tumor subjects (protocol 
9090-02) has been determined at 216 mg/m2.  The dose to be used in this study is 200 mg/m2.  
This dose level has been selected based on the expectation that there will be no pharmacological 
differences between 200 and 216 mg/m2.  In addition, a 200 mg/m2 dose is within the predicted 
efficacious dose range based on pre-clinical models when adjusted for the human equivalent 
dose and would facilitate an accurate drug preparation for infusion.      
 

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2.2 
Fulvestrant 
 
Fulvestrant is a pure anti-estrogen which is thought to act by downregulating ER expression.  In 
the United States, fulvestrant is approved for the treatment of hormone receptor-positive, 
metastatic breast cancer in postmenopausal women with disease progression after antiestrogen 
therapy.2 
 
In two phase III randomized trials conducted in patients with hormone receptor-positive, 
metastatic breast cancer, who had progressed on either adjuvant or metastatic endocrine therapy, 
fulvestrant was associated with an objective response rate of 17-19%, not significantly different 
in comparison to the aromatase inhibitor anastrozole, where the response rate was 15-17%.3  
Median time to progression (TTP) was 5.5 months.  In the EFECT trial, which enrolled patients 
who had previously progressed on a nonsteroidal aromatase inhibitor, fulvestrant appeared 
equally active compared to exemestane, and was associated with a median TTP of 3.7 months, 
and objective response rate of 7%.4. Similar results were observed in the fulvestrant control arm 
of CALGB 40302, with a median TTP of 4.0 months.5 
 
More recently, the CONFIRM trial evaluated a different dose and schedule of fulvestrant, given 
as a 500 mg IM injection on days 1 and 15 of Cycle 1, followed by 500 mg IM injections on day 
1 of each subsequent cycle.6 Compared to the 250 mg once monthly schedule, there was a 1 
month improvement in median PFS, leading to U.S. FDA approval of the 500 mg dose with 
loading schedule. 
 
In postmenopausal women with ER-positive tumors, aromatase inhibitors (AI) are now routinely 
used as part of adjuvant systemic therapy.  Based upon data in several phase III trials (conducted 
prior to the widespread use of aromatase inhibitors in the adjuvant setting), aromatase inhibitors 
are also widely used in the first-line metastatic setting.  After progression on a nonsteroidal AI, a 
number of strategies are typically used in clinical practice, including a steroidal AI, fulvestrant, 
estradiol, and tamoxifen (Chia et al, J Clin Oncol 2008; Ellis et al, J Am Med Assoc 2009).  
There are no prospective trials comparing endocrine strategies in patients after AI failure, and the 
optimal sequencing of endocrine agents in the metastatic setting is not known.  However, the 
2010 National Comprehensive Cancer Center guidelines suggest that AIs, fulvestrant, tamoxifen, 
megestrol acetate, fluoxymesterone, and ethinyl estradiol are all reasonable options as 
subsequent endocrine therapy after progression on first-line endocrine therapy.   
 
2.3 
Study Disease 
 
With over 200,000 new cases per year, breast cancer accounts for nearly one-third of all new 
cancer diagnoses among women in the United States.7  Approximately 40,000 women will die of 
breast cancer in the U.S. alone.7  Worldwide, breast cancer is a major cause of cancer mortality, 
and was responsible for approximately 458,000 deaths in the year 2008.8   
 
There is increasing recognition that breast cancer is comprised of several subtypes, each with 
distinct features.9 The majority of invasive breast cancers express the estrogen receptor (ER) 
and/or progesterone receptor (PR), and are HER2-negative.  Patients with ER and/or PR-
positive/HER2-negative (hereafter, designated as ER-positive) tumors tend to have a somewhat 

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better prognosis than patients with other tumor subtypes.  However, in the metastatic setting, 
median survival is approximately 3 years and long-term remissions are relatively uncommon.   
 
Initial treatment of ER-positive, metastatic breast cancer typically consists of endocrine therapy.  
Standard endocrine therapy options include tamoxifen, aromatase inhibitors, ovarian 
suppression, and fulvestrant.  The choice of agent(s) varies depending on prior therapy, patient 
age and menopausal status, and anticipated tolerability.  Although endocrine therapies can often 
be very effective, resistance almost invariably develops.  While some patients may be salvaged 
with further lines of endocrine therapy, virtually all patients eventually progress through the 
available endocrine agents and require treatment with cytotoxic chemotherapy.  For these 
reasons, in the metastatic setting, strategies to overcome or delay the emergence of endocrine 
resistance, particularly with treatments that are associated with a favorable toxicity profile in 
relation to standard cytotoxic agents, would be of great clinical value.  Successful strategies 
could then be evaluated in the adjuvant setting.  On average, among women with early-stage, 
ER-positive/HER2-negative tumors, the relative and absolute benefits of endocrine therapy far 
exceed that of chemotherapy.10  Thus, efforts to improve responsiveness to endocrine agents 
could ultimately have a substantial impact on overall breast cancer outcomes in patients with all 
stages of breast cancer. 
 
2.4 
Rationale for Combining Endocrine Therapy with Ganetespib 
 
Estrogen Receptor expression is typically conserved in metastatic lesions, compared to matched 
primaries.11 Furthermore, patients who have progressed on a single line of endocrine therapy 
may subsequently respond to additional lines of endocrine therapy.4,12 Thus, ER likely continues 
to drive a subset of metastatic breast cancers, even after progression.  Hormonal therapies for 
ER-positive breast cancer comprise the earliest and perhaps most efficacious “molecularly 
targeted” approach to cancer therapy to date.  Approaches to augment the efficacy of endocrine 
therapy and to delay the emergence of resistance have great potential to improve disease 
outcomes for the most common subtype of breast cancer. 
 
While it is clear that a functional ER contributes to the growth of both hormone-sensitive and 
refractory tumors, further hormonal manipulation using a range of ligand-dependent therapies 
only manages to delay tumor progression in the vast majority of cases.  Ligand-independent 
approaches to disrupt ER function may offer greater potential for long-term disease control. 
 
Steroid hormone receptors such as the ER require the molecular chaperone HSP90 to achieve a 
mature conformation that is capable of high-affinity ligand binding and subsequent activation.  These 
interactions are ATP-dependent, and classical HSP90 inhibitors disrupt formation of mature ER-
HSP complexes by blocking ATP binding to the ATP/ADP binding pocket of HSP90.  In the 
presence of the prototypical HSP90 inhibitor geldanamycin (GA), the ER accumulates in an 
intermediate complex containing a cohort of HSP that target the ER protein for degradation via 
the ubiquitin-proteasome pathway. As a result, receptor half-life is shortened and cellular levels 
profoundly decreased.  
 
In addition, Hsp90 inhibitors deplete cellular levels of many signaling proteins, including EGFR, 
HER2, IGF-1R, VEGF, RAF, and AKT, which have been implicated in the development of 

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endocrine resistance.  A number of efforts to combine endocrine therapy with a molecularly 
targeted agent have yielded disappointing results.  For example, despite promising phase II data, 
the phase III study of letrozole with or without the mTOR inhibitor CCI-779 was closed early 
due to lack of efficacy.  More recently, CALGB 40302, a randomized trial of fulvestrant with or 
without the dual EGFR/HER2 inhibitor lapatinib was also closed early due to lack of efficacy.5 
We hypothesize that this may be the result of selective pressure for escape pathways beyond the 
specific pathway targeted.  The ability of HSP90 inhibitors to simultaneously deplete multiple 
proteins and destabilize the entire network of signaling pathways that enable endocrine resistance 
could overcome endocrine resistance and/or delay the emergence of endocrine resistance.  
Indeed, the first HSP90 inhibitor to be developed clinically, 17-AAG, has already shown promise 
in patients with HER2-positive breast cancer that have become resistant to trastuzumab.13   
 
In preclinical models, 17-AAG markedly disrupts ER transcriptional activity in both tamoxifen-
sensitive and tamoxifen-resistant MCF-7 cells.14 Tumor progression in mice bearing xenografts 
established using MCF-7 cells that demonstrate tamoxifen dependence for growth in vivo was 
significantly inhibited by 17-AAG administered on a standard dose and schedule.  Further work 
has demonstrated that geldanamycin, at concentrations with no single agent anti-tumor activity, 
can virtually eradicate the outgrowth of tamoxifen-resistant MCF-7 cells in culture.    
 
In comparison to 17-AAG, ganetespib is a potent, second-generation, small-molecule HSP90 
inhibitor with a chemical structure unrelated to the ansamycin family of first-generation HSP90 
inhibitors (e.g. 17-AAG or IPI-504).  In preclinical studies, STA-9090 has shown potency up to 
100 times greater than the first generation HSP90 inhibitors as well as potency across a wider 
range of kinases.  STA-9090 has activity against a wider range of cancer types.  Work by 
Whitesell et al (personal communication) has demonstrated more potent anti-proliferative 
activity against MCF-7 breast cancer cells than 17-AAG (IC50 ~25 nM versus 250-500 nM).  
Furthermore, it was more effective at limiting the emergence of tamoxifen-resistant clones and in 
cultures of MCF-7 cells and was synergistic with tamoxifen in a xenograft model.15 More 
recently, preliminary evidence of synergistic activity of fulvestrant and STA-9090 has been 
demonstrated in cell lines, and xenograft studies are underway. 
2.5 
Summary 
 
This is a randomized phase II trial evaluating fulvestrant with or without ganetespib, a potent, 
novel HSP90 inhibitor.  The primary clinical objective is progression-free survival.  We 
hypothesize that ganetespib will augment the efficacy of fulvestrant and be associated with an 
improvement in progression-free survival. 
Secondary clinical endpoints include objective response rate (among patients with measurable 
disease at baseline), safety/tolerability, clinical benefit rate (CR + PR + SD >/= 6 months), and 
overall survival.   
The correlative objectives of this study include evaluation of the relationship between HSF1 and 
clinical outcome, alterations in heat-shock network function, ER expression and transcriptional 
activity, and alterations in other relevant downstream targets.  Patients who enroll on this trial 
will also be approached regarding an 18FES-PET companion study (which will be written as an 
entirely separate, IRB-approved protocol) when it is available.  
 

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3. PARTICIPANT SELECTION 
Laboratory tests required for eligibility must be completed within 14 days prior to 
randomization. Baseline measurements must be documented from tests within 28 days prior 
to randomization.  QTc must be documented by 12-lead ECG within 28 days prior to 
randomization.  Other non-laboratory tests must be performed with the timeframe specified. 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1 
Participants must have histologically confirmed invasive breast cancer that is 
metastatic or unresectable locally advanced.  Histological documentation of 
metastatic/recurrent breast cancer is not required if there is unequivocal evidence for 
recurrence of the breast cancer. 
3.1.2 
Estrogen and/or progesterone receptor positive breast cancer, as determined by 
pathology from either primary or metastatic site(s).  Central confirmation is not required. 
3.1.3 
HER2 negative, defined as 0-1+ by immunohistochemistry or FISH-negative 
(ratio < 2.2). Central confirmation is not required. 
3.1.4 
Postmenopausal women are eligible. Postmenopausal is defined as any of the 
following: 
 Age > 60 years 
 Age > 45 with intact uterus and amenorrhea for 12 months or more 
 Follicle stimulating hormone (FSH) levels within postmenopausal range according 
the ranges established by the testing facility 
 Premenopausal women who have been on a GnRH agonist for at least 3 consecutive 
months prior to study entry are eligible.  Women in this group MUST remain on the 
GnRH agonist for the duration of protocol treatment. 
 Status-post bilateral oophorectomy-After adequate healing post surgery. 
3.1.5 
Women and men, age > 18 years of age 
3.1.6 
Measurable disease is required.  Measurable disease is defined as at least one 
lesion that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan.  
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses identified by physical exam 
that are not measurable by reproducible imaging techniques, and cystic lesions are all 
considered non-measurable.  See section 10 for details. As of 4/30/14, the evaluable/non-
measurable cohort has been filled and only patients with measurable disease are 
allowed moving forward.  Prior to 4/30/14, up to 20% of patients entered on this trial 
(i.e. 14 patients) were entered with evaluable but nonmeasurable disease. 

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3.1.7 
Endocrine resistant breast cancer, defined as either: 
 
Relapsed while on adjuvant endocrine therapy or within 1 year of completion of 
adjuvant endocrine therapy 
 
-OR- 
 
 
Progression through at least one line of endocrine therapy for metastatic or locally 
advanced breast cancer.  There is no limit on the number of prior endocrine therapies 
received. 
3.1.8 
Patients may have received up to one prior line of chemotherapy for metastatic or 
unresectable locally advanced breast cancer. 
3.1.9 
Patients may have initiated bisphosphonate therapy prior to start of protocol 
therapy.  Bisphosphonate therapy may continue during protocol treatment.  Such patients 
will have bone lesions considered evaluable for progression. 
3.1.10 
Patients must be at least 2 weeks from prior chemotherapy or radiotherapy, or any 
investigational drug product, with adequate recovery of toxicity to baseline, or grade <1, 
with the exception of alopecia and hot flashes. There is no washout period for prior 
endocrine therapy.  
3.1.11 
ECOG Performance Status 0-1 (Appendix A) 
3.1.12 
Availability of a tissue block from initial breast cancer diagnosis and/or 
metastatic recurrence.  If a tissue block is not available, 10-20 unstained slides may be 
provided as an alternative.  If unstained slides will be provided, they should not be sent 
until specifically requested by the DFCI study coordinator. 
3.1.13 
For patients with biopsy-accessible disease, patients must be willing to undergo a 
required on-treatment research biopsy.  This biopsy will occur on ~Cycle 2 Day 9. 
3.1.14 
Biopsies may be done with local anesthesia or intravenous conscious sedation, 
according to standard institutional guidelines. 
3.1.15 
Research biopsies requiring general anesthesia are not allowed on this protocol 
unless a biopsy is being obtained simultaneously for clinical reasons, in the judgment of the 
patients’ treating physician. 
3.1.16 
Patients who undergo an attempted on-treatment research biopsy and in whom 
inadequate tissue is obtained are still eligible to continue protocol therapy.  They will not 
be required to undergo a repeat biopsy attempt. 

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3.1.17 
Participants must have normal organ and marrow function as defined below: 
 Absolute neutrophil count > 1,500/mcL 
 Platelets > 100,000/mcL 
 Hgb > 9 mg/dL(which may be post transfusion) 
 Total bilirubin < 1.5 X institutional upper limit of normal (patients with 
documented Gilbert’s disease are allowed total bilirubin up to 3X ULN) 
 AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of if no liver 
metastases; and < 5 X institutional upper limit if liver metastases are present 
 Creatinine < 2X institutional upper limit of normal 
3.1.18 
Adequate IV access  
3.1.19 
Fulvestrant is contraindicated in pregnancy (category D).  The effects of 
ganetespib on the developing human fetus are unknown. For these reasons, women of 
child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately.  
Premenopausal women who have been on a GnRH agonist for at least 3 consecutive 
months prior to study entry are eligible.  Women in this group MUST remain on the GnRH 
agonist for the duration of protocol treatment.  Such patients should be counseled that 
GnRH agonists alone may not be adequate contraception and that adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation should be employed. 
3.1.20 
Ability to understand and the willingness to sign a written informed consent 
document. 
3.1.21 
Patients on therapeutic dose anti-coagulation with warfarin, LMWH, or other 
anti-coagulants will be allowed to participate in the study. However, the anti-coagulants 
should be held pre- and post- research biopsy (when applicable) as per institutional 
standards. The risks of a temporary hold of anti-coagulation should be carefully considered 
and explained to the patient as part of the informed consent process. If it is not felt to be in 
the best interest of the patient to have anti-coagulation held, the patient may still enter the 
study, but should not undergo a research biopsy. 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 

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3.2.1 
Prior treatment with an HSP90 inhibitor (e.g. 17-AAG, IPI-504, AUY922,    
STA-9090 (ganetespib) etc.) 
3.2.2 
Prior treatment with fulvestrant. 
3.2.3 
Participants may not be receiving any other investigational agents. 
3.2.4 
Concurrent treatment with commercial agents or other agents with the intent to 
treat the participant’s malignancy, including endocrine therapy, chemotherapy, and/or 
targeted therapy, with the exception of bisphosphonates and GnRH agonists, as detailed in 
Section 3.1.8 and 3.1.10. 
3.2.5 
Untreated or progressive brain metastases.  Patients with treated brain metastases 
not requiring chronic corticosteroids for symptom control are eligible. 
3.2.6 
Pending visceral crisis, in the opinion of the treating investigator. 
3.2.7 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to fulvestrant or ganetespib. 
3.2.8 
Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.2.9 
Serious cardiac illness, defined as follows: 
 Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic 
bradycardia, unstable congestive heart failure, active myocardial ischemia, or 
indwelling temporary pacemaker 
 Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a 
Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class 
III antiarrhythmic drug (e.g. sotalol, amiodarone, dofetilide). Use of other 
antiarrhythmic drugs is permissible. 
 Use of medications that have been linked to the occurrence of torsades de pointes (see 
Appendix I for a list of such medications). Investigators should note that Zofran 
(ondansetron) has been linked to QTc prolongation and the occurrence of torsades de 
pointes. Therefore it should not be used in patients being treated with ganetespib. The 
use of all other serotonin 5 HT3 antagonists is acceptable (e.g., palonsetron, 
granisetron, tropisetron). 
 Second-or third degree atrioventricular block (AV block) unless treated with a 
permanent pacemaker. 
 Complete left bundle branch block (LBBB) 
 History of long QT syndrome or a family member with this condition 
 
3.2.10 
Corrected QTc>470msec. The corrected QTc may be corrected using either 
Bazett’s or Friderica’s formula. In general QTcf is the preferred correction method. 

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3.2.11 
Pregnant women are excluded from this study because fulvestrant is 
contraindicated in pregnancy (category D) and ganetespib is an agent with the potential for 
teratogenic or abortifacient effects. Because there is an unknown but potential risk of 
adverse events in nursing infants secondary to treatment of the mother with fulvestrant or 
ganetespib, breastfeeding should be discontinued if the mother is treated on either arm of 
the trial.  
3.2.12 
Individuals with the following cancers are eligible if diagnosed and definitively 
treated prior to study entry: cervical cancer in situ, basal cell or squamous cell carcinoma of 
the skin.  Individuals with a history of other malignancy are ineligible unless disease-free 
for at least 3 years or deemed by the investigator to be at low risk (<10%) for recurrence of 
that malignancy.  
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Both men and women are eligible for this protocol.  Every effort will be made to include patients 
from minority populations.  Because breast cancer predominantly affects females, it is 
anticipated that male enrollment will be <5% of the overall study population. 
 
 
4. REGISTRATION PROCEDURES 
   
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registration must occur prior to the initiation 
of therapy. Any participant not registered to the protocol before treatment begins will be 
considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a 
participant does not receive protocol therapy following registration, the participant’s registration 
on the study may be cancelled. Notify the QACT Registrar of registration cancellations as soon 
as possible.  
4.2 
Registration Process for DF/HCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time.  
   
The registration procedures are as follows: 
 

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1. Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments. 
 
2. Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical and/or research chart. To be 
eligible for registration to the protocol, the participant must meet all inclusion and 
exclusion criterion as described in the protocol and reflected on the eligibility 
checklist. 
  
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for 
the treatment study. Registration to both treatment and ancillary studies will not be 
completed if eligibility requirements are not met for all studies. (Note—there are 
currently no active ancillary studies associated with this trial.) 
  
3. Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 
617-632-2295. 
  
4. The QACT Registrar will (a) review the eligibility checklist, (b) register the 
participant on the protocol, and (c) randomize the participant when applicable. 
  
5. An email confirmation of the registration and/or randomization will be sent to the 
Overall PI, study coordinator(s) from the Lead Site, treating investigator and 
registering person immediately following the registration and/or randomization. 
 
4.3 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the Participating 
Institution and faxed or e-mailed to the Coordinating Center at CTOPM@dfci.harvard.edu or 
by fax at 617-632-5152: 
 
 Signed informed consent form 
 HIPAA authorization form (if separate from the informed consent document) 
 Completed QACT Eligibility Checklist 
 Copy of required laboratory tests including: Hematology (CBC w/differential), Serum 
Chemistries (potassium, BUN, creatinine, magnesium, total bilirubin, SGOT (AST), 
SGPT (ALT), and Alkaline Phosphatase, tumor markers (CEA and CA27-29), and 
pregnancy test (for women of child-bearing potential only). 
 
 EKG report 
  Confirmation of archival tissue availability (primary and/or metastatic sites) 
  Radiologic imaging report including bone scan 
 Pathology report and documentation of ER/PR and HER2 status 

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 Clinic visit note documenting history and physical exam 
 
The Coordinating Center will review the submitted documents in order to verify eligibility and 
consent. To complete the registration process, the Coordinating Center will: 
 
 Register the participant on the study with the DF/HCC QACT 
 Upon receiving confirmation of registration by the QACT, the Coordinating Center will 
inform the Participating Institution and provide the study specific participant case 
number, and if applicable the dose treatment level.  
 
Registration and randomization with the QACT can only be conducted during the business hours 
of 8:00 AM and 5:00 PM Eastern Standard Time Monday through Friday. Same day treatment 
registrations will only be accepted with prior notice and discussion with the DF/HCC Lead 
Institution. 
 
Treatment may not begin without confirmation from the Coordinating Center that the participant 
has been registered.  
 
 
5. TREATMENT PLAN  
 
Treatment must begin within 7 days of randomization.  Treatment will be administered on an 
outpatient basis. Expected toxicities and potential risks as well as dose modifications for 
fulvestrant and ganetespib are described in Section 6 (Expected Toxicities and Dosing 
Delays/Dose Modification). No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant’s malignancy.   
 
Patients who enter the study and who are postmenopausal on the basis of GnRH agonist 
treatment must continue that treatment throughout the duration of the study. 
 
A total of 71 patients will be enrolled in the study.  Patients will be stratified according to 
whether or not they have measurable disease (by RECIST 1.1) at baseline and then randomized 
1:2 to the two treatment arms: 
 
Arm A: Fulvestrant (n=24) 
Arm B: Fulvestrant plus Ganetespib (n=47) 
 
Patients who are randomized to Arm A may cross over to Arm C (Fulvestrant plus ganetespib) at 
the time of centrally confirmed progression. 
 
In both Arms A and B, each cycle will be ~28 days in length.  Treatment will continue until 
disease progression (possibly the second progression on the combination therapy, if the patient 
was originally randomized to Arm A fulvestrant), unacceptable toxicity, withdrawal of consent, 
or death, whichever comes first.  Follow up (specifically, tumor measurements as scheduled in 

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the protocol) will continue until disease progression, withdrawal of consent, death, or the start of 
other anti-neoplastic therapy, whichever comes first. 
 
Minor schedule changes owing to observed holidays, inclement weather, etc. are permitted. 
Patients may interrupt therapy for protocol-directed reasons (i.e. toxicity).  From Cycle 3 
forward, patients may also interrupt therapy for personal preferences (e.g., holidays, vacations).  
Treatment should resume according to protocol guidelines.  Patients may not voluntarily omit 
fulvestrant at any time.  From Cycle 3 forward, patients may not voluntarily omit more than 2 
doses of ganetespib in a single cycle, except as detailed below.  See Section 9.0 Study Calendar 
for additional details.  
 
It is anticipated that some patients in Arm B or Arm C may either choose or be taken off of 
ganetespib for reasons other than disease progression (i.e., for toxicity or patient preference).  
The following guidelines apply: 
 
 Patients who are taken off of ganetespib for toxicity at any time should remain on study 
and continue fulvestrant.  Restaging evaluations and clinic visits should continue on the 
protocol mandated schedule until either disease progression, intercurrent illness that 
prevents further administration of treatment, unacceptable adverse event(s), the 
participant decides to withdraw from the study, or general or specific changes in the 
participant's condition render the participant unacceptable for further treatment in the 
opinion of the treating investigator. 
 
 Patients being treated with fulvestrant + ganetespib whose disease remains stable or in 
response for at least 6 cycles may elect to discontinue ganetespib.  Once ganetespib is 
discontinued, it will not be restarted.  Patients who discontinue ganetespib should remain 
on study and continue fulvestrant.  Restaging evaluations and clinic visits should 
continue on the protocol mandated schedule until either disease progression, intercurrent 
illness that prevents further administration of treatment, unacceptable adverse 
event(s), the participant decides to withdraw from the study, or general or specific 
changes in the participant's condition render the participant unacceptable for further 
treatment in the opinion of the treating investigator. 
 
As part of the clinical trial, ganetespib will be provided free of charge to study participants by 
Synta Pharmaceuticals.  Patients and/or their insurance companies will be billed for the cost of 
fulvestrant, which will come from commercial supply.   
 
 
Arm A 
Agent 
Pre-medications 
Dose 
Route 
Schedule 
Cycle 
Length 

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31 
Fulvestrant 
None 
500 mg 
Intramuscular 
injection 
C1: D1, D15 
C2: D1 
Then on Day 
1 of each 
subsequent 
cycle 
 28 days 
(4 weeks) 
 

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Arm B: Dose Level 1 
Agent 
Pre-medications* 
Dose 
Route 
Schedule 
Cycle 
Length 
Fulvestrant 
None 
500 
mg 
Intramuscular 
injection 
C1: D1, 
D15 
C2: D1 
Then on 
Day 1 of 
each 
subseque
nt cycle 
28 days 
(4 weeks) 
Ganetespib 
 Suggest 2 mg 
Loperimide 1-2 hrs 
before infusion. 
 Dexamethasone 10 
mg IV, or therapeutic 
equivalents 
 Diphenhydramine 
HCL 25-50 mg,  or 
therapeutic 
equivalents (dose of 
diphenhydramine may 
be reduced per 
investigator 
discretion if patient  
had previous 
problems with 25mg 
or higher) 
 
200 
mg/m2 
Intravenous (see 
section 5.2.1 for 
vascular access 
device 
restrictions) 
D 1,8,15 
*See section 5.2 for management of diarrhea and hypersensitivity reactions. For patients who 
have successfully tolerated at least 2 cycles of ganetespib without a hypersensitivity reaction, 
routine premedication with dexamethasone and diphenhydramine prior to subsequent 
ganetespib infusions is not required and is left to the discretion of the treating provider.   
 

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At the time of initial protocol design, it was decided that if more than 2 DLTs were observed 
within the first 10 patients randomized to Arm B, study accrual would be temporarily suspended, 
pending review by the Study PI and the Synta medical monitor (Section 14.2).  If the DLTs were 
confirmed, the study would re-open at Dose Level -1 (i.e., 175 mg/m2); if the DLTs were not 
confirmed (i.e. the events did not meet the definition of DLT), the study would re-open at Dose 
Level 1 (i.e., 200 mg/m2).  This DLT rule was not triggered for the first 10 patients randomized 
to Arm B and enrollment has continued at Arm B Dose Level 1.   
 
Arm B: Dose Level -1 
Agent 
Pre-medications* 
Dose 
Route 
Schedule 
Cycle 
Length 
Fulvestrant 
None 
500 mg 
Intramuscu
lar 
injection 
C1: D1, 
D15 
C2: D1 
Then on 
Day 1 of 
each 
subsequent 
cycle 
28 days 
(4 weeks) 
Ganetespib 
 Suggest 2 mg 
Loperimide 1-2 hrs 
before infusion. 
 Dexamethasone 10 
mg IV, or therapeutic 
equivalents 
 Diphenhydramine 
HCL 25-50 mg, or 
therapeutic equivalents 
(dose of 
diphenhydramine may 
be reduced per 
investigator discretion 
if patient had previous 
problems with 25mg 
or higher) 
 
175 
mg/m2 
Intravenous 
(see section 
5.2.1 for 
vascular 
access 
device 
restrictions) 
D 1,8,15 
* See section 5.2 for management of diarrhea and hypersensitivity reactions. For patients who 
have successfully tolerated at least 2 cycles of ganetespib without a hypersensitivity reaction, 
routine premedication with dexamethasone and diphenhydramine prior to subsequent 
ganetespib infusions is not required and is left to the discretion of the treating provider.   
 
 

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Patients who are randomized to Arm A may cross over to Arm C (Fulvestrant plus ganetespib) at 
the time of centrally confirmed progression.  Patients in Arm C will start at Dose Level 1, as 
shown below.  At the time of initial protocol design, it was decided that if the Arm B starting 
dose was dropped to Dose Level -1, as detailed above, then the Arm C starting dose would also 
be dropped to Dose Level -1.  Since the DLT rule was not triggered for the first 10 patients 
randomized to Arm B, the Arm C starting dose has continued at Arm B Dose Level 1.   
 
Arm C: Dose Level 1 
Agent 
Pre-medications* 
Dose 
Route 
Schedule 
Cycle 
Length 
Fulvestrant 
None 
500 mg 
Intramuscular 
injection 
C1: D1,  
C2: D1 
Then on 
Day 1 of 
each 
subsequent 
cycle 
28 days 
(4 weeks) 
Ganetespib 
 Suggest 2 mg 
Loperimide 1-2 
hrs before 
infusion. 
 Dexamethasone 
10 mg IV, or 
therapeutic 
equivalents 
 Diphenhydramine 
HCL 25-50 mg, or 
therapeutic 
equivalents (dose of 
diphenhydramine 
may be reduced per 
investigator 
discretion if patient  
had previous 
problems with 25mg 
or higher) 
 
200 
mg/m2 
Intravenous 
(see section 
5.2.1 for 
vascular 
access device 
restrictions) 
D 1,8,15 
* See section 5.2 for management of diarrhea and hypersensitivity reactions. For patients who 
have successfully tolerated at least 2 cycles of ganetespib without a hypersensitivity reaction, 
routine premedication with dexamethasone and diphenhydramine prior to subsequent 
ganetespib infusions is not required and is left to the discretion of the treating provider.   
 

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Arm C: Dose Level -1 
Agent 
Pre-medications* 
Dose 
Route 
Schedule 
Cycle 
Length 
Fulvestrant 
None 
500 mg 
Intramuscular 
injection 
C1: D1, \ 
C2: D1 
Then on 
Day 1 of 
each 
subsequent 
cycle 
28 days 
(4 weeks) 
Ganetespib 
 Suggest 2 mg 
Loperimide 1-2 
hrs before 
infusion. 
 Dexamethasone 
10 mg IV, or 
therapeutic 
equivalents 
 Diphenhydramine 
HCL 25-50 mg, or 
therapeutic 
equivalents (dose of 
diphenhydramine 
may be reduced per 
investigator 
discretion if patient  
had previous 
problems with 25mg 
or higher) 
 
175 
mg/m2 
Intravenous 
(see section 
5.2.1 for 
vascular 
access device 
restrictions) 
D 1,8,15 
* See section 5.2 for management of diarrhea and hypersensitivity reactions. For patients who 
have successfully tolerated at least 2 cycles of ganetespib without a hypersensitivity reaction, 
routine premedication with dexamethasone and diphenhydramine prior to subsequent 
ganetespib infusions is not required and is left to the discretion of the treating provider.   
 
 
5.1 
Study Procedures 
 
At the time of registration, the eligibility checklist and supporting documentation to verify 
eligibility must be provided prior to randomization.  Data will be collected and maintained on 
study specific case report forms.  See Section 9.0 Study Calendar for additional details.  
   

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5.1.1 
Screening 
All subjects must sign an informed consent document prior to initiation of any study 
related procedures.  The informed consent document must be signed within 30 days of 
randomization.  Baseline laboratory evaluations must be completed within 14 days of 
randomization.  Baseline measurements including scans must be completed within 28 
days of randomization.  QTc must be documented by 12-lead ECG within 28 days of 
randomization.  The remaining screening procedures must be conducted within 28 days 
of randomization. 
 Review of study eligibility criteria 
 Medical history 
 Breast cancer history 
 Record concomitant medications 
 ECOG performance status 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
o Serum HCG, in women of childbearing potential 
 12-lead ECG 
 Review of baseline symptoms 
 Radiologic imaging studies to evaluate tumor status.  Contrast computed tomography 
(CT) (or without contrast if contraindicated) of chest and abdomen is preferred.  
Magnetic resonance imaging (MRI) of chest and abdomen is an acceptable 
alternative.  Note: PET-CT scans are not allowed per protocol for primary assessment 
of response.  PET-CT scans may be done according to clinical judgment to 
supplement CT or MRI scans in cases where results of the PET-CT may clarify or 
resolve a clinical question. 
 Measurements of palpable/visible lesions, if used as a target lesion (for example, chest 
wall nodule) 
 Bone scan 
 Request and collect blocks from initial breast cancer diagnosis and/or 
recurrent/metastatic lesion(s). See section 9.5. If unstained slides will be provided as 
an alternative, they should not be cut or sent until specifically requested by the DFCI 
Study Coordinator. 
 Consider optional baseline research biopsy for patients with easily accessible disease. 
See section 9.5. 
5.1.2 
Cycle 1, Day 1 
 Clinic visit 

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 Record concomitant medications 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Physical examination 
 Height and weight 
 ECOG performance status 
 Record baseline symptoms (using CTCAE grading criteria) 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with 
differential, platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
o CA 27-29, CEA 
 12-lead ECG 
 Research blood draw for whole blood, PBMC, Streck tube, and CTC collection. See 
Section 9.5. 
 Fulvestrant administration via intramuscular injection 
 Ganetespib i.v. administration via silicone VADs (Arm B only) 
5.1.3 
Cycle 1, Day 2 (Arms B and C only) 
 12-lead ECG required 24 hours after Ganetespib infusion.  See section 5.6.  
5.1.4 
Cycle 1, Day 8 (Arm B only) 
 Clinic visit 
 Record concomitant medications 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Physical examination 
 Weight 
 ECOG performance status 
 Record AEs (using CTCAE v4 grading criteria) 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
 Ganetespib administration via silicone VADS 
5.1.5 
Cycle 1, Day 15 
 Clinic visit 
 Record concomitant medications 

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 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Physical examination 
 Weight (Arm B only) 
 ECOG performance status 
 Record AEs (using CTCAE v4grading criteria) 
 Laboratory assessments (Arm B only) 
o Hematology: hemoglobin, hematocrit, white blood cell count with 
differential, platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
 Fulvestrant administration via intramuscular injection 
 Ganetespib administration via silicone VADS (Arm B only) 
5.1.6 
Cycle 2, Day 1 
 Clinic visit 
 Record concomitant medications 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Physical examination 
 Weight (Arm B only) 
 ECOG performance status 
 Record AEs (using CTCAE v4.0 grading criteria) 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
 12-lead ECG (Arms B and C only).  If pre-dose QTc >470 ms a repeat ECG is required 
approximately 24 hours after the Ganetespib dose.  
 Fulvestrant administration via intramuscular injection 
 Ganetespib administration via silicone only VADS (Arm B only) 
5.1.7 
Cycle 2, Day 8 
 Research blood draw for PBMC and CTC analysis. See Section 9.5 and Appendix C for 
details. 
 
For patients randomized to Arm B, Cycle 2 Day 8 draw research blood between 2-4 
hours after the Day 8 dose of ganetespib.  If the Day 8 dose is held for any reason (e.g., 
for toxicity), draw research blood between 2-4 hours after the Day 15 dose of 
ganetespib. 

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5.1.8 
Cycle 2, Day 9 
 Research blood draws for PBMC and CTC analysis. See Section 9.5 and Appendix C 
for details. 
 Tissue biopsy for patients with biopsy-accessible disease.  See Section 9.5 and 
Appendices B and C for details. 
 
For patients randomized to Arm A:, Cycle 2 Day 9 biopsy may be performed +/- 3 days 
and on the same day as the Cycle 2 Day 9 research blood draw (1st research blood draw to 
occur on Cycle 2 Day 8 +/- 3 days).  Draw the Cycle 2 Day 9 research blood samples 18-
48 hours after the Cycle 2 Day 8 research blood draw.  Patients on Arm A who do not 
undergo the Cycle 2 Day 9 research biopsy are not required to undergo the Cycle 2 day 9 
research blood draw. 
 
For patients randomized to Arm B, collect Cycle 2 Day 9 biopsy sample and research 
blood draw between 18-48 hours after the Cycle 2 Day 8 dose of ganetespib. If the Day 
8 dose is held for any reason (e.g., for toxicity), collect the biopsy sample and research 
blood draw between 18-48 hours after the Cycle 2 Day 15 dose of ganetespib.    
5.1.9 
Cycle 2, Days 8 and 15 (Arm B only) 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Weight 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
 Ganetespib administration via silicone VADS 
5.1.10 
Cycle 3 Day 1, and Day 1 of Subsequent Cycles 
 Clinic visit 
 Record concomitant medications 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Physical examination 
 Weight (Arm B only) 
 ECOG performance status 
 Record AEs (using CTCAE v4 grading criteria) 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 

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o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
o CEA, CA27-29, if elevated at baseline.  In patients with elevated markers at 
baseline, tumor markers should subsequently be drawn once every 2 cycles. 
 12-lead ECG (Arms B and C only).  If pre-dose QTc >470 ms a repeat ECG is required 
approximately 24 hours after the Ganetespib dose.  See section 5.6 for additional 
ECG requirements for patient at moderate to high risk of torsades de pointes. 
 Radiologic imaging studies to evaluate tumor status.  Contrast computed tomography 
(CT) (or without contrast if contraindicated) of chest and abdomen is preferred.  
Magnetic resonance imaging (MRI) of chest and abdomen is an acceptable 
alternative.  Note: PET-CT scans are not allowed per protocol for primary assessment 
of response.  PET-CT scans may be done according to clinical judgment to 
supplement CT or MRI scans in cases where results of the PET-CT may clarify or 
resolve a clinical question. 
 Measurements of palpable/visible lesions, if used as a target lesion (for example, chest 
wall nodule) 
 Follow-up imaging and measurements should be done every 2 cycles (8 weeks) and 
every 2-4 cycles (8-16 weeks) for patients who have been on study for >1 year.  
Imaging can be done +/- 1 week from targeted date but before start of the subsequent 
cycle. 
5.1.11 
Days 8 and 15 of Cycle 3 and Subsequent Cycles (Arm B only) 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Weight 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
 Ganetespib administration via silicone VADS 
5.1.12 
Time of Crossover from Arm A to Arm C (applies only to patients initially 
randomized to Arm A) 
 Clinic visit 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Physical exam 
 Weight 
 ECOG performance status 
 Record AEs (using CTCAE v4.0 grading criteria) 
 Record concomitant medications 

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 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
o CEA, CA 27-29 
 12-lead ECG 
 Research blood draw for CTCs, Streck tube, PBMCs. See section 9.5. 
 Optional research biopsy. See section 9.5. 
 Bone scan 
 Measurements of palpable/visible lesions, if used as a target lesion (for example, chest 
wall nodule) 
 Review of films by central radiology reviewer (DF/HCC Tumor Imaging Metrics Core) 
and confirmation of progression by overall study PI (REQUIRED before patient 
receives first dose of ganetespib) 
5.1.13 
Prior to Removal from Protocol Treatment (applies to Arms A, B, and C) 
 Review of films by central radiology reviewer (DF/HCC Tumor Imaging Metrics Core) 
and confirmation of progression by overall study PI is REQUIRED for patient to be 
taken off protocol treatment in either arm, if off-treatment reason is progression. 
 “Real-time” central review for progression is not required if the off-study reason is 
other than progression (i.e. for toxicity, etc.); however, central review will be 
performed at a later time in order to adjudicate the primary endpoint (PFS) 
5.1.14 
End of Protocol Treatment (within 30 days after the last dose of protocol 
treatment) 
 Clinic visit 
 Vital signs (heart rate, blood pressure, and respiratory rate) 
 Physical exam 
 Weight 
 ECOG performance status 
 Record AEs (using CTCAE v4.0 grading criteria) 
 Laboratory assessments 
o Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
platelet count 
o Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin 
o Serum calcium, magnesium, phosphorus 
 Research blood draw for CTCs, PBMCs, and Streck tube. See section 9.5. 
 Optional research biopsy. See section 9.5. 

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5.1.15 
PFS Follow-up Procedures 
Because the primary endpoint of the study is PFS, patients who are taken off treatment 
for any reason other than disease progression will REMAIN ON PROTOCOL and 
continue with the protocol mandated schedule of events (i.e. staging studies) until 
progressive disease, start of new anti-cancer therapy, or death, whichever comes first.  
For example, patients who are randomized to Arm B (fulvestrant + ganetespib) and who 
discontinue ganetespib without evidence of progression should continue on fulvestrant 
alone and continued to be followed for progression with staging studies/evaluations per 
protocol.   
5.1.16 
Survival Follow-up Procedures 
Subject survival information will be collected every 3 months (+/- 2 weeks) from date of 
last dose of study drug (first treatment they we assigned to) until the subject’s death, or 
until the subject is lost to follow-up, or up to 2 years from last dose of study drug, 
whichever comes first.   
For patients who receive post-protocol care at a participating institution, survival 
information will be collected from medical records, supplemented by direct contact with 
a patient’s treating physician.  Patients who receive post-protocol care outside of a 
participating institution will be directly contacted by telephone.  If a patient or patient 
representative is not able to be successfully contacted, then the patient’s local physician 
will be contacted as an alternative.  Prior to deeming a patient lost to follow-up, a search 
will also be made of the Social Security Death Index and/or the National Death Index.  At 
the time of final survival reporting, any patients with missing survival data will also be 
searched through the Social Security Death Index and/or the National Death Index.  The 
consent form will include information detailing the follow up procedures in this trial. 
The following information will be collected: 
 
 The subject’s survival status, and if deceased, the date of death. 
 The method by which the survival status was assessed and the date it was assessed. 
 The cause of death, if known  
 Categorization of cause of death, if known (e.g. disease progression, protocol-related 
toxicity, other treatment-related toxicity, other, or unknown). 
 
5.2 
Agent Administration  
5.2.1 
Ganetespib 
 Administration -- 200 mg/m2 IV D1, 8, 15 of a 28-day cycle (i.e. 3 weeks on, 1 week 
off) 
 Ganetespib should be infused over 1 hour using non-PVC, non-DEHP IV bags and 
tubing with a 0.2μm in-line filter.  
 Based on preclinical data, use of vascular access devices (VADs) (such as ports and 
peripherally-inserted central catheters [PICCS]) containing silicone catheters or 
peripheral IV is permitted.  Use of VADs with catheters made of any other material 

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is not permitted.  Following ganetespib administration through a VAD, care should 
be taken to flush the line after each dose of study drug.   
o For patients with a pre-existing port: Prior to the first ganetespib 
administration, the treating investigator must send the name of the port device 
to the overall study PI and Coordinating Center contact and the overall study 
PI and/or her designate must approve the device prior to use for ganetespib 
administration. 
o For patients who will have a port placed during the study: prior to port 
placement, the treating investigator must send the name of the intended port 
device to the overall study PI and Coordinating Center contact and the overall 
study PI and/or her designate must approve the device prior to the insertion 
procedure. 
 Premedications: 
o Dexamethasone 10 mg IV, or therapeutic equivalents (Required) 
o Diphenhydramine HCL 25-50 mg, or therapeutic equivalents (Required) 
 Dose of diphenhydramine may be reduced per investigator discretion 
if patient experienced previous problems with 25mg or higher 
o Loperamide (Imodium®): Start dosing (2mg) 1-2 hours before ganetespib 
infusion (Suggested) 
o For patients who have successfully tolerated at least 2 cycles of ganetespib 
without a hypersensitivity reaction, routine premedication with 
dexamethasone and diphenhydramine prior to subsequent ganetespib 
infusions is not required and is left to the discretion of the treating provider.   
 No pre- or post-hydration is required 
 Dose modifications are outlined in Section 6 
5.2.2 
 Fulvestrant 
 Administration – 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection 
on Cycle 1 Day 1, Cycle 1 Day 15, and then on Day 1 of each subsequent cycle.   
 No dose modifications. 
 Commercial supply of fulvestrant will be used. 
 
5.3 
Definition of Dose-Limiting Toxicity 
 
There are no phase I data with the combination of fulvestrant + ganetespib.  Based upon the 
observed toxicities to date, mechanism of action, and metabolisms, no additive toxicities are 
anticipated.  However, for the first 10 patients assigned to Arm B, we will include an early 
stopping rule for Cycle 1 dose-limiting toxicity (DLT).  The DLT assessment period will be from 
Cycle 1 Day 1 until Cycle 2 Day 1. 
 
Dose-limiting toxicity (DLT) is based on the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE v4.0). DLT refers to toxicities experienced 
during the first cycle of treatment. A DLT will be defined as follows: 

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 Grade 3 or 4 hematologic or non-hematologic toxicity thought likely or definitely 
related to protocol therapy will be counted as a DLT, with the exception of: 
o Grade 3 diarrhea that responds to maximal supportive measures.  If grade 3 
diarrhea is persistent > 7 days despite maximal supportive measures, it will 
be counted as a DLT 
o Grade 3 fatigue 
o Grade 3 hot flashes 
o Grade 3 electrolyte disturbance, unless persistent for > 7 days despite 
maximal supportive measures.  
 
Management and dose modifications associated with the above adverse events are outlined in 
Sections 5.4 (General Concomitant Medication and Supportive Care Guidelines) and Section 6 
(Expected Toxicities and Dosing Delays/Dose Modifications). 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Medications taken prior to Cycle 1, Day 1 and during the study will be collected and noted in the 
medical record.  The following are the supportive care guidelines for the study.  The guidelines 
apply to all Arms of the study, except as otherwise noted: 
 
 For patients receiving ganetespib, it is preferred not to use concomitant use of 
medications that are associated with a high incidence of QT prolongation (e.g., 
quinolones and ondansetron).  See Appendix I for a list of medications that are known to 
predispose to Torsades de Pointes.   
 No other antineoplastic agents will be permitted during this study, with the exception of 
bisphosphonates and GnRH agonists under the guidelines as specified in Section 3.1.8 
and 3.1.10. 
 No concurrent radiation treatment will be permitted during this study 
 No treatment with chronic immunosuppressants (e.g., cyclosporine following 
transplantation or systemic steroids for treatment of autoimmune disease) will be 
permitted during this study; however, use of inhalant steroids and steroids given for 
antiemetic purposes  are permitted 
 For patients receiving ganetespib, caution should be exercised when concomitant 
medications that are cleared predominantly by the CYP3A4 or CYP2C19 pathways are 
administered.  Examples of compound classes metabolized predominantly by CYP3A4 or 
CYP2C19 are provided below: 
o CYP3A4 substrates:  benzodiazepines (e.g. midazolam), anticonvulsants (e.g. 
carbamazepine), calcium channel blockers (e.g. felodipine, nifedipine), 
antineoplastics (e.g. vincristine), macrolide antibiotics (e.g. erythromycin) and 
HIV antiviral agents. 
o CYP2C19 substrates:  proton pump inhibitors (e.g. omeprazole) and 
antidepressants (e.g. sertraline). 
The above information is precautionary only.  Investigators are encouraged to discuss the use of 
individual medications with the Principal Investigator on a case-by-case basis. 
 

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5.5 
Supportive Care Guidelines 
 
Patients should receive full supportive care, including antiemetics, blood transfusions, 
intravenous fluid, etc., as clinically appropriate.  The reason(s) for treatment, dosage, and dates 
of treatment should be recorded in the medical record.   
 
Antiemetics 
 
Patients may be given antiemetics at the discretion of the treating physician. 
 
Anti-infectives 
 
Antibiotics may be used at the discretion of the treating physician.  If there is a reasonable 
alternative, it is preferred that quinolones and other agents that may prolong QTc are avoided. 
 
Bisphosphonates 
 
Oral or intravenous bisphosphonate treatment is allowed if the first dose was given prior to 
initiation of protocol therapy.  Patients already receiving bisphosphonate therapy at the time of 
study entry may continue the treatment.  Patients with new bone metastases documented as part 
of study screening procedures may begin a bisphosphonate, provided the first dose is given prior 
to initiation of protocol-based therapy.  Bisphosphonates may not be started after the initiation of 
protocol-based therapy. 
 
Growth factors 
 
Patients may receive erythropoietin or other specific red blood cell growth factors and red blood 
cell transfusions will be permitted as clinically indicated during the study. 
Patients may receive bone marrow colony stimulating factors (such as granulocyte colony-
stimulating factor or granulocyte-macrophage colony-stimulating factor) as clinically indicated 
during the study. 
If an Investigator determines a patient is at risk for severe neutropenia or febrile neutropenia, 
granulocyte-colony stimulating factor (G-CSF) may be used prophylactically beginning with the 
first cycle.  G-CSF prophylactic use is recommended during subsequent treatment cycles in case 
of neutropenia lasting more than 7 days, febrile neutropenia, or documented infection with 
neutropenia.  
 
Diarrhea management guidelines 
 
Many patients will experience diarrhea, and some patients may experience Grade 3 or 4 diarrhea. 
The following proactive and ongoing management principles are necessary to avoid more serious 
complications of diarrhea. However, guidelines such as these should never replace sound clinical 
judgment.   
 
Experience suggests that diarrhea is an expected drug class effect for Hsp90 inhibitors and it 
typically starts 2-3 hours following administration of ganetespib in most patients.  However, 

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when appropriately managed with anti-diarrhea treatment, it is generally mild to moderate and its 
duration limited to 24 hours. 
 
Due to the risk of diarrhea while receiving ganetespib, all patients will be educated to use 
prophylactic medication (Lomotil® or Imodium®) before ganetespib administration and before 
the onset of gastrointestinal symptoms to mitigate the severity and duration.   
 
Suggested prophylaxis regimens are as follows: 
 
 Loperamide (Imodium®): Start dosing (2mg) 1-2 hours before ganetespib infusion and 
continue with 2 mg every four hours for 12 hours. This treatment may be continued for 
up to 24 hours in the absence of symptoms of diarrhea.  Due to inter-patient variability, 
adjustment to this regimen should be made on a case-by-case basis.  The maximum 
dosage of loperamide is 16 mg/24 hrs. 
 Dietary counseling: foods/liquids and quantities to intake or avoid 
 
Guidelines for Treatment of Diarrhea (Active Management): 
 In the event of diarrhea, patients will take loperamide at an initial 4 mg dose followed by 
2 mg doses every 4 hours. In the presence of uncomplicated grade 1 or 2 diarrhea, 
loperamide will be continued until the patient is free from diarrhea for 12 hours.  Total 
daily dose may not exceed 16 mg (8 capsules) 
 If mild to moderate diarrhea persists after 24 hours despite treatment with loperamide, a 
cocktail of atropine-diphenoxylate (lomotil) or equivalent and loperamide may be 
considered.  Loperamide 2 mg may be alternated with one tablet of Lomotil every 3 
hours. 
 For grade 3 or 4 diarrhea or complicated grade 1 or 2 (severe cramping, severe 
nausea/vomiting, decreased PS, fever, sepsis, grade 3 or 4 neutropenia, frank bleeding, 
dehydration), IV fluids will be used as appropriate, as well as prophylactic antibiotics.  
Hospitalization is recommended. 
 Grade 1-2 :  Loperamide 4mg first dose, then 2 mg every 4 hours until free from diarrhea 
for 12 hours 
 If Grade 1 or 2 diarrhea persists for more than 24 hours: Loperamide 2mg q 2 hrs 
 If Grade 1 or 2 diarrhea persists after 48 hours: Start 2L agents: a cocktail of 
Dyphenoxylate and atropine sulfate (Lomotil®). Alternate 2 mg loperamide with one 
tablet of Lomotil every 3 hours. 
 Grade 3 or 4 or Complicated Grade 1 or 2: IV fluids as appropriate. 
 
Management of hypersensitivity reactions 
 
Ganetespib contains a surfactant (polysorbate 80) that has been associated with hypersensitivity 
reactions in other medications administered by infusion.  Infusion type reactions associated with 
ganetespib (approximately 7% of patients) have been reported at doses of 10 to 200 mg/m2.  
Symptoms included pruritus, flushing, shortness of breath, chest tightness, dizziness, headache, 
increased systolic blood pressure and heart rate. These events were mostly grade 1 and grade 2 
and usually responsive to treatment with i.v. diphenhydramine HCl (Benadryl®) and steroids 

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(sometimes with H2 blockers).  In addition, subjects with infusion-type reactions usually could 
continue receiving ganetespib after pre-mediation with diphenhydramine HCl and steroids.   
 
Based on IB Edition 9, premedication is required prior to ganetespib infusion for at least 2 
cycles.  Premedications include: 
 
 Dexamethasone 10 mg IV, or therapeutic equivalents 
 Diphenhydramine HCL 25-50 mg, or therapeutic equivalents 
o Dose of diphenhydramine may be reduced per investigator discretion if patient 
experienced previous problems with 25mg or higher 
 
For patients who have successfully tolerated at least 2 cycles of ganetespib without a 
hypersensitivity reaction, routine premedication with dexamethasone and diphenhydramine 
prior to subsequent ganetespib infusions is not required and is left to the discretion of the 
treating provider.   
 
If, despite premedication, an infusion hypersensitivity reaction to ganetespib is suspected, the 
following management is provided as guidance only; treatment will be based on clinical 
presentation. Institution specific premedication and/or treatment procedures and regimens may 
also be appropriate in lieu of these guidelines. 
 
 Mild and moderate symptoms:   
 
1. 
Stop ganetespib administration 
2. 
Give i.v. diphenhydramine HCl (Benadryl®) 25-50 mg and dexamethasone 10 mg 
i.v. 
3. 
After recovery from symptoms, resume ganetespib infusion or re-schedule patient 
for re-treatment; a reduced flow rate may be considered 
 
In subsequent cycles, consider optimizing premedication regimen. 
 
 Severe symptoms (i.e., hypotension requiring pressor therapy, IV fluids, angioedema, 
respiratory distress requiring bronchodilator therapy, generalized urticaria): 
 
1. Stop ganetespib administration 
2.   Give intravenous dexamethasone and diphenhydramine HCl (Benadryl®) as above 
3.   Add intravenous H2 blocker 
4.   Add adrenaline (1:1000) or bronchodilators as indicated 
5.   Reschedule dose administration for the following day 
6.   In subsequent cycles, consider optimizing premedication regimen. 
 
If severe symptoms reoccur with optimal premedication, treatment with ganetespib should be 
discontinued permanently. 
 
The following is an example of an optimized premedication regimen: 
 

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 Dexamethasone 12 mg PO and diphenhydramine HCL 25-50 mg PO approximately 12-24 
hours prior to the next dose of ganetespib 
 Repeat dexamethasone 12 mg PO and diphenhydramine HCL 25-50 mg PO approximately 
4-6 hours prior to the re-challenge 
 
5.6 
Cardiovascular Guidelines 
 
In response to findings of a modest increase in QT interval 24 hours post-dose, additional ECG 
monitoring is being incorporated into the protocol pending data from an ECG evaluation that is 
being performed within the context of Study 9090-14. 
5.6.1 
Patients at High to Moderate risk for torsades de pointes 
For patients deemed at baseline by the treating investigator to be at moderate to high risk 
for torsades de pointes, the overall study PI should be consulted prior to registration to 
confirm the patient’s eligibility for the study, given that patients with significant 
cardiovascular co-morbidities are excluded from the trial. It is not anticipated that 
patients with moderate or high risk of torsades will generally be enrolled onto the study.  
In the rare instance that such a patient meets all eligibility requirements, including 
cardiovascular eligibility requirements, ECGs are required at the following timepoints for 
patients receiving ganetespib: 
 
 Baseline 
 Cycle 1 Day 2 (approximately 24 hours post Cycle 1 Day 1 ganetespib dose) 
 Pre-dose on Cycle 2 Day 1 
 Approximately 24 hours post Cycle 2 Day 1 dose 
 Pre-dose for each subsequent cycle 
 Approximately 24 hours post Day 1 of each subsequent cycle 
5.6.2 
Patients at Low risk for torsades de pointes 
For patients deemed at baseline by the treating investigator at low risk for torsades de 
pointes, ECG monitoring in triplicate is required at the following time points for patients 
receiving ganetespib: 
 
 Baseline 
 Cycle 1 Day 2 (approximately 24 hours post Cycle 1 Day 1 ganetespib dose) 
 Pre-dose on Cycle 2 Day 1 
 
If there is no evidence of QTc prolongation (QTc > 470 msec), subsequent EKGs are 
required: 
 
 Pre-dose, day 1 of each cycle 
 

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If there is evidence of QTc prolongation (QTc > 470 msec) on the pre-dose EKG, the 
patient is required to return for a repeat EKG ~24 hours post-ganetespib dose (applies to 
all cycles of treatment). 
 
If a patient has a reported QTc > 501 ms (QTc prolongation Grade 3 severity), at any 
ECG (an average of triplicate recordings), the patient may continue ganetespib treatment 
at a reduced dose of 120 mg/m2 after the QTc has decreased to at least < 470 ms.  
 
If a patient has a reported QTc > 501 ms or > 60 ms change from baseline and torsades de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia 
(QTc prolongation Grade 3 severity) or repeated Grade 3 or higher QTc prolongation, the 
patient must discontinue treatment with ganetespib.   
 
If a patient has a dose reduction or discontinues treatment due to QTc prolongation, the 
patient should have additional ECG monitoring in triplicate until the QTc interval returns 
to baseline. 
 
Patients with QTc prolongation of grade 3 severity or higher should be closely monitored 
during the first 72 hours post ganetespib infusion (i.e. electrolytes, concomitant 
medications) and at subsequent cycles of ganetespib treatment. 
 
Because of the QT study findings of a modest increase in QT interval prolongation at 24 
hours post dose, certain drugs should not be used by patients being treated with 
ganetespib. The use of any medication that has the potential for QTc prolongation and 
has been linked to the occurrence of torsades de pointes is strictly prohibited. See 
Appendix I for a list of drugs with a risk of torsades de pointes.  Investigators should note 
that Zofran (ondansetron) has been linked to QTc prolongation and the occurrence of 
torsades de pointes. Therefore it should not be used in patients being treated with 
ganetespib. The use of all other serotonin 5 HT3 antagonists is acceptable (e.g., 
palonsetron, granisetron, tropisetron). 
 
Medications that have the potential of prolonging the QT interval but are not linked to the 
occurrence of torsades de pointes should be avoided or used with caution. The decision to 
use such a medication should be made by the Investigator, taking into consideration the 
patient’s medical history and current QTc value.  In addition, Investigators should 
optimize patients’ electrolyte status and correct serum magnesium, potassium, and 
calcium as clinically indicated. 
 
5.7 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), 

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 Participant decides to withdraw from the study, or 
 General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 At the discretion of the MD, investigator, or Sponsor 
 
Patients who are randomized to Arm A may cross over to Arm C and receive combination 
therapy with fulvestrant + ganetespib at the time of centrally confirmed progression.  Treatment 
may then continue on the combination until one of the above criteria applies. 
 
It is anticipated that some patients in Arm B or Arm C may either choose or be taken off of 
ganetespib for reasons other than disease progression (i.e. for toxicity or patient preference).  
The following guidelines apply: 
 
 Patients who are taken off of ganetespib for toxicity at any time should remain on study 
and continue fulvestrant.  Restaging evaluations and clinic visits should continue on the 
protocol mandated schedule until either disease progression, intercurrent illness that 
prevents further administration of treatment, unacceptable adverse event(s), the 
participant decides to withdraw from the study, or general or specific changes in the 
participant's condition render the participant unacceptable for further treatment in the 
opinion of the treating investigator. 
 
 Patients being treated with fulvestrant + ganetespib whose disease remains stable or in 
response for at least 6 cycles may elect to discontinue ganetespib.  Once ganetespib is 
discontinued, it will not be restarted.  Patients who discontinue ganetespib should remain 
on study and continue fulvestrant.  Restaging evaluations and clinic visits should 
continue on the protocol mandated schedule until either disease progression, intercurrent 
illness that prevents further administration of treatment, unacceptable adverse 
event(s), the participant decides to withdraw from the study, or general or specific 
changes in the participant's condition render the participant unacceptable for further 
treatment in the opinion of the treating investigator. 
 
 Patients who are taken off fulvestrant and/or ganetespib for any reason other than 
centrally-confirmed progression or death should be followed according to study calendar 
D until evidence of disease progression, start of new anti-cancer therapy, withdrawal of 
consent for follow-up, or death, whichever comes first. 
 
5.8 
Duration of Survival and Adverse Event Follow Up  
 
Participants will be followed for survival for up to 4 years after the last dose of protocol 
therapy or until death, whichever occurs first. Participants removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
  
5.9 
Criteria for Removal from Study  
 
Participants will be removed from study treatment when any of the following occur: 

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 
Disease progression,  
 
Start of new anti-cancer therapy, or 
 
Participant decides to withdraw from the study treatment 
 
Subject death 
 
Note: Patients in Arm A who progress on fulvestrant alone may first cross over to Arm C 
(fulvestrant + ganetespib).   
Participants will be considered ‘Off Study’ when one of the following events occurs: 
 Death 
 Participant  decides to withdraw from the study follow-up procedures 
 4 years after the date of the last study treatment dose 
 
Note: Patients on either arm who discontinue assigned protocol treatment 
(fulvestrant and/or ganetespib) for any reason other than progression or death should 
not be removed from study but instead should continue to be followed per protocol 
(See Study Calendar D) until evidence of disease progression, start of new anti-cancer 
therapy, withdrawal of consent for follow-up, or death, whichever occurs first. 
 
The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator (or Protocol Chair), Dr. Nancy Lin at 617-632-
3352, page # 42012. 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v 4.0 which is identified and located on the CTEP website 
at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose 
of study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 

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6.1 
Anticipated Toxicities 
  
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine reporting. 
6.1.1 
Adverse Event Lists(s) for ganetespib 
Aggregate clinical data across all dose levels from the ongoing clinical studies show the 
following adverse events (AEs) of all grades as most common (>10%) by the Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term: 
 Diarrhea (72%) 
 Abdominal pain (22%) 
 Fatigue (51%) 
 Insomnia (16%) 
 Dyspnoea (17%) 
 Anorexia (22%) 
 Increase in aspartate aminotransferase (AST) (14%)  
 Increase in alkaline phosphatase (AP) (13%) 
 Nausea (37%) 
 Vomiting (20%) 
 Peripheral edema (15%) 
 Anemia (24%) 
 Constipation (15%) 
 Increase in alanine aminotransferase (ALT) (11%) 
 Headache (18%) 
 Back pain (15%) 
 Dizziness (13%) 
 Hypokalemia (11%) 
 Pyrexia (11%) 
 Dehydration (10%) 
 Skin rash (10%) 
Diarrhea is experienced by virtually all subjects treated at therapeutic doses.  Based on 
clinical experience to date, over-the-counter medications such as dyphenoxylate and 
atropine sulfate (Lomotil®) and loperamide (Imodium®) mitigate the severity and duration 
of the diarrhea.  It is recommended that medications, such as those listed above, should be 
utilized before ganetespib administration and before the onset of GI symptoms.  (See 
Protocol section 5.5 for recommended dosing instructions) 
Fatigue is observed in up to 50% of patients, mostly NCI CTCAE grade 1.  Some subjects 
have experienced grade 2 or 3 fatigue, which was managed by study drug dose reduction 

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per protocol.  In some subjects, medications (e.g. Ritalin) were used successfully to manage 
fatigue. 
To date, severe liver toxicity has not been observed.  In some subjects, transient elevations 
of transaminases or bilirubin have been observed, typically CTCAE grade 1 or 2; however 
a few grade 3 elevations were observed. 
6.1.2 
Adverse Event List(s) for fulvestrant 
The side effect profile includes injection site pain (9-12% of patients), nausea (10-13%), 
and bone pain (~10%).  In the CONFIRM trial, the most commonly reported toxicities (any 
grade) on the 500 mg arm were GI disturbances (20%), joint disorders (19%), injection site 
reactions (14%), and hot flashes (8%).6 The most common grade 3 or higher toxicities were 
GI disturbances (2%) and joint disorders (2%). Other grade 3 or higher toxicities were 
uncommon and did not exceed 1% frequency in this study.  Please refer to the package 
insert for a comprehensive list of adverse events. 
6.2 
Dose Modifications/Delays 
  
Dose delays and modifications will be made using the following rules.  Toxicity assessments will 
be done using the CTEP Active Version of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) v 4.0 which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
6.2.1 
Ganetespib 
 
Dose Level 
Dose 
Route 
Schedule 
Cycle Length 
Starting dose 
200 mg/m2 
IV 
D1, 8, 15 
28 days 
First dose 
reduction 
175 mg/m2 
IV 
D1, 8, 15 
28 days 
Second dose 
reduction 
150 mg/m2 
IV 
D1, 8, 15 
28 days 
 
As detailed in Sections 5.1 and 14.2, at the time of initial study design, it was decided 
that in the case of more than 2 DLTs within the first 10 patients on Dose Level 1 (starting 
dose 200 mg/m2), the study would close temporarily to accrual while the events were 
adjudicated.  Based upon results of this adjudication, the study would re-open at Dose 
Level -1 (starting dose 175 mg/m2).  In this event, there would be only 1 allowed dose 
reduction (i.e. to 150 mg/m2) for patients entered at this starting dose level.  Once 
decreased, doses would NOT be re-escalated.  This DLT rule was not triggered for the 
first 10 patients randomized to Arm B; therefore enrollment to Arm B has continued at 
Arm B Dose Level 1 and treatment on Arm C has continued at Arm B Dose Level 1.   
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, 
etc.). 

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All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
 
The following guidelines are provided for the modification of dose of ganetespib in the 
event of toxicities attributed by the investigator to this drug.  Toxicities unrelated to 
ganetespib will not ordinarily result in modification of ganetespib dose.   
 
Once a dose has been reduced, it should not be re-escalated. 
 
Missed doses should be skipped, rather than held.  Therefore, one cycle will nearly 
always be 4 weeks, allowing time for vacation, holidays, etc. 
 

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Dose Modification Guidelines for Ganetespib 
Toxicity 
Grade 
Guideline for 
management 
Ganetespib dose modification* 
Diarrhea  
1 
See Section 5.5 
None 
2 
See Section 5.5 
None;  
If unacceptable to patient or medically concerning despite
maximal supportive measures, then skip until recovery to
< grade 1 (or baseline), up to 21 days*.  Restart at same 
dose**. 
> 3 
 
If grade 3 or greater despite maximal supportive 
measures, skip until recovery to < grade 1 (or baseline), 
up to 21 days*.  
And then 
Reduce 1 dose level. 
Nausea/vomiting 
1 or 2 
Treatment as 
appropriate. 
None 
3  (First or 2nd 
occurrence) 
Treatment as 
appropriate. 
Skip until recovery to < grade 1 (or baseline), up to 21 
days*.  
And then 
Restart at same dose. 
3  (3rd or more 
occurrence) 
 
If grade 3 or higher despite optimal prophylactic 
measures, then skip until recovery to < grade 1 (or 
baseline), up to 
 21 days*.  
And then 
Reduce 1 dose level. 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
1 
No intervention 
None 
2 
Treatment as 
appropriate. 
None; If unacceptable to patient or medically concerning
then hold until recovery to < grade 1 (or baseline), up to 
21 days*.  Restart at same dose**. 
3 
Treatment as 
appropriate.  
Skip until recovery to < grade 1 (or baseline), up to 21 
days*. 
And then 
Reduce 1 dose level. 
Other non- 
Hematologic 
toxicity 
 
1 
No Intervention 
None 
2 
Treatment as 
appropriate 
None; If unacceptable to patient or medically concerning
then skip until recovery to < grade 1 (or baseline), up to 
21 days*.  Restart at same dose **. 
2 prolonged or 
clinically significant 
and  grade > 3 
Treatment as 
appropriate 
Skip until recovery to < grade 1 (or baseline), up to 21 
days 
And then 
Reduce 1 dose level* 

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Toxicity 
Grade 
Guideline for 
management 
Ganetespib dose modification* 
Infusion reactions 
 
 
3 
Treatment per 
institutional 
guidelines for 
infusion reactions
Contact Principal Investigator to determine whether 
patient may be retreated 
4 
Stop infusion  
Permanently discontinue 
Thrombocytopenia 1 or 2 
No intervention 
None 
3 
No intervention 
Skip until recovery to < grade 1 (or baseline), up to 21 
days 
And then 
Reduce 1 dose level* 
Hemoglobin 
1 or 2 
Treatment as 
appropriate 
None 
3 
Treatment as 
appropriate 
Skip until recovery to < grade 1 (or baseline), up to 21 
days 
And then 
Reduce 1 dose level* 
Neutropenia 
1 or 2 
No intervention 
None 
3 (ANC < 1,000/L) 
lasting > 7 days 
 
Skip until recovery to < grade 1 (or baseline), up to 21 
days 
And then 
Reduce 1 dose level* 
 Cardiac toxicity 
3  (first occurrence 
 of QTc > 501 ms on 
average of triplicate 
recordings) 
 
Reduce dose level to 120 mg/m2 after the QTc has 
decreased to at least < 470 ms.  
3  (repeat 
occurrence of QTc > 
501 ms on average 
of triplicate 
recordings) 
 
Permanently discontinue  
4  (QTc > 501 ms or  
> 60 ms change from 
baseline  
and torsades de pointes 
or polymorphic 
ventricular tachycardia 
or signs/symptoms  
of serious arrhythmia 
 
Permanently discontinue 
 
* if no recovery after 21 days, patients should go off study  
** if dose has been previously held for grade 2 toxicity and grade 2 symptoms recur, OR if the patient finds the 
symptoms unacceptable, hold dose until recovery to < grade 1 and then reduce dose one level 
 
In the case of grade 4 hematologic or non-hematologic toxicity, ganetespib should be 
skipped until recovery to grade 1 or less (or baseline), up to 21 days, and then the dose 
reduced to 150 mg/m2.  Subjects unable to tolerate ganetespib at a dose level of 150 
mg/m2 or whose ganetespib related toxicity has not returned to baseline or Grade < 1 
within 21 days should stop ganetespib.  Patients may continue on fulvestrant alone at this 
time.  Once permanently discontinued, ganetespib should not be restarted.   
 
In the case of a recurrent grade 3 event after prior dose reduction, ganetespib should be 
held until the related toxicity has returned to baseline or Grade < 1.  Subjects should be 

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reduced by 1 additional dose level (i.e. 2 dose levels from baseline) upon restarting study 
drug.  Only 2 dose reductions are allowed per protocol. 
6.2.2 
Fulvestrant 
Fulvestrant will be administered at a dose of 500 mg via intramuscular injection on Days 1 
and 15 of Cycle 1, and then on Day 1 of each subsequent 28-day cycle. 
There are no dose modifications of fulvestrant.  Commercial supply fulvestrant will be 
administered in this study.  The cost of fulvestrant will be billed to the patient and/or her 
insurance company. 
If fulvestrant-related adverse events occur, they should be managed using standard clinical 
practice.   
If grade 3 or 4 toxicity occurs that the treating investigator feels is related to fulvestrant, the 
study Principal Investigator should be contacted to discuss the case and determine whether 
continuation of protocol therapy is appropriate. 
7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
Ganetespib (STA-9090) 
 
Refer to the Investigator’s Brochure. 
7.1.1 
Description 
Classification: HSP-90 inhibitor 
 
Molecular formula: C20H20N4O3         M.W.: 364.40 g/mol 
 
Physical description: white to off white powder 
 
Ganetespib (STA-9090), chemical name 5-[2,4-dihydroxy-5-(1-methylethyl) phenyl]- 2,4-
dihydro-4-(1-methyl-1H-indol-5-yl)-3H-1,2,4-triazole-3-one, is a novel triazolone 
heterocyclic compound. Its molecular formula is C20H20N4O3.  STA-9090 is a white to 
off white powder with a molecular weight of 364.40 g/mol. 
 
7.1.2 
Form 
Ganetespib 300mg/vial (25mg/mL) 
Each vial contains 12mL of deliverable ganetespib (12.84mL total including an overage 
per USP requirements) at a concentration of 25 mg/mL in a PEG 300, polysorbate 80 and 
dehydrated alcohol cosolvent-surfactant system.  The drug product is a colorless to 
slightly yellow, clear solution, essentially free of visible particles.  The drug product vial 
can be identified with a dark blue cap and applicable label. 

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Caution: Ensure that the ganetespib 300mg/vial (25mg/mL), is used with the 
instructions provided below. (Another drug product ganetespib 8 mg/mL is 
available that uses different instructions for preparation)  
7.1.3 
Storage and Stability 
The Ganetespib 300mg/vial drug product should be stored at 20°C - 25°C (68°F – 77°F) 
with excursions allowed between 15°C and 30°C (59°F and 86°F) (USP Controlled 
Room Temperature). Alternatively, ganetespib may be store in a cool place between 8°C 
(46°F) and 20°C (68°F). DO NOT FREEZE.  
7.1.4 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
7.1.5 
Availability 
Ganetespib is an investigational agent and will be supplied free-of-charge by Synta 
Pharmaceuticals. 
7.1.6 
Preparation 
The dilution of ganetespib (STA-9090) (25 mg/mL) will be with D5W (5% Dextrose for 
Injection) to a concentration range of 0.1 mg/mL-1.1 mg/mL.  Deviation from the 
proposed concentrations must be approved by the sponsor prior to administration.  
Infusion of the study drug must be completed within 4 hours once diluted with D5W. 
Eligible subjects will receive ganetespib under the direction of a physician identified on 
the form FDA 1572.  STA-9090 administration will be given over 60 minutes.  The 
amount of ganetespib administered will be determined by the dose level to which the 
subject is assigned at study entry and by calculating the subject’s body surface area 
(BSA).  
 
Preparation Instructions for ganetespib 300mg/vial (25mg/mL) Infusion Solution 
Study drug preparation should be performed under standard aseptic conditions following 
chemotherapeutic precautions. 
In general, the following concentration range guidelines should be used when preparing 
ganetespib for infusion.  Sponsor approved deviations from these recommendations may 
be necessary based on an individual subject’s BSA and dose level.  However, at no time 
should a concentration be outside the range of 0.1 - 1.1mg/mL. The target infusion 
volume should always be 500mL. 
1. Calculate the total dose of ganetespib the subject is to receive based on their BSA:   
Total ganetespib dose (mg) = ganetespib dose (mg/m2) X BSA (m2) 

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2. Calculate the total volume of ganetespib drug product Solution (25mg/mL) needed: 
Total ganetespib Solution (mL) = Total ganetespib dose (mg) from Step 1 / 25mg/mL 
 
3. Calculate the total volume of 5% Dextrose for Injection (D5W) needed for 
preparation of the 500mL infusion solution: 
Total D5W Volume (mL) = 500mL – Total ganetespib Solution (mL) from Step 2 
 
4. Note: This step is required only for the Ganetespib 300/ml vial (25mg/ml) drug 
product if stored at 2C-8C. 
 
Remove the appropriate number of ganetespib vials from the refrigerator and let them 
sit at ambient room temperature for approximately 20 minutes.  
 
5. Into an empty 500mL, non-PVC, non-DEHP containing infusion bag or a 500mL 
glass bottle, transfer the calculated amount of D5W in Step 3 using a syringe and a 
needle. The D5W volume can also be adjusted to the calculated D5W volume in Step 
3 if pre-filled bags/bottles are used.   
Caution:  Non-PVC, non-DEHP bags must be used. 
 
6. Using a syringe and a 16G or 18G needle carefully withdraw the calculated amount of 
the ganetespib drug product solution from Step 2 and inject into the infusion bag 
containing D5W.  
Note: Because of the viscosity of the drug product the 16G needle is 
recommended for ease of withdrawal. 
 
7. Carefully squeeze the transfer ports, 4 corners of the bag, and the middle of the bag to 
ensure complete mixing of the drug product and D5W. Continue mixing by gently 
inverting the bag end-over-end 10 times. Visually inspect the final infusion solution. 
The final infusion solution should be clear and essentially free of any visible particles.   
Caution:  Do not use if a clear solution is not obtained.  Contact the study 
Sponsor. 
 
8. Attach the non-PVC, non-DEHP containing infusions set with a 0.22m end-filter to 
the infusion bag. 
Caution: Non-PVC, non-DEHP tubing with a 0.22µm filter must be used. 
 
9. Store the infusion solution at room temperature until use avoiding direct exposure to 
light.  Upon completing the infusion solution preparation, the one hour administration 
of the infusion solution must be completed within 4 hours. The time needed to 
prepare the dosing solution does not count against the 4 hour limit. There is no need 
to protect the IV bag from ambient light during the infusion. 
Caution: Do not refrigerate the infusion solution. 
Caution: The 1-hour infusion must be complete within 4 hours of completing the 
infusion solution preparation. 

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7.1.7 
Administration 
1. Set up the infusion pump to deliver the 500mL ganetespib infusion solution over 60 
minutes  
 
Note - Use of Vascular Access Devices: 
 
Based on preclinical data, use of vascular access devices (VADs) (such as ports 
and peripherally-inserted central catheters [PICCS]) containing silicone 
catheters are permitted.   
 
Use of VADs with catheters made of any other material is not allowed.   
 
Following ganetespib administration through a VAD, care should be taken to 
flush the line after each dose of study drug.  Please follow routine clinical 
practice for care of patients utilizing VADs.   
 
2. At the end of the infusion the IV tubing must be flushed with D5W to ensure 
complete delivery of the required dose of ganetespib. The infusion rate of the D5W 
flush should be at the same rate as the drug infusion. 
3. Dispose of used IV bags, tubing and used drug vials per institutional guidelines. 
7.1.8 
Ordering 
Ganetespib will be ordered and supplied by Synta Pharmaceuticals once the protocol is 
approved.  Please refer to Appendix G: Section 4.0 for additional information. 
7.1.9 
Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.) 
7.1.10 
Destruction and Return 
At the end of the study, unused supplies of ganetespib should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. 
7.1.11 
Pharmacokinetics 
The pharmacokinetics of STA-9090 administered at various doses to subjects with solid 
tumors on a weekly or twice-weekly schedule is under investigation in 2 Phase I trials. 

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Preliminary data and calculated parameters are available in subjects with solid tumors for 
doses up to 259 mg/m2. Cmax and AUC increase in approximate proportion to dose 
irrespective of dosing day with virtually identical dose-exposure ratios for Day 1 and Day 
15, indicating linear pharmacokinetics and a lack of drug accumulation.  Distribution and 
elimination phases of STA-9090 show maximum concentration at the end of the infusion 
declining by approximately 10-fold within the first hour and nearly 100-fold within 10 
hours following infusion termination.  Mean terminal half-lives have ranged from 
approximately 5.2 to 14 hours.  STA-9090 plasma concentrations on Day 1 and 15 are 
comparable following either once or twice weekly dosing, indicating the lack of drug 
accumulation.   
7.1.12 
Toxicity 
Given that current clinical data are limited, continued careful monitoring for the 
following adverse events based upon STA-9090 nonclinical toxicology assessments: 
cytopenias including lymphopenia and neutropenia; infection; loose stools, diarrhea, or 
bloody diarrhea; nausea/vomiting; dehydration; electrolyte disturbances; abnormal serum 
chemistries (i.e. liver function tests, creatinine, CPK); injection site reactions; pulmonary 
symptoms; bone infarction/bone pain; and skin rash. Pronounced local reactions may 
occur if STA-9090 is extravasated or improperly administered. Animal toxicology studies 
may not predict adverse events in humans. Therefore other unanticipated adverse events 
may occur and careful general clinical monitoring is warranted.  
 
Reported adverse events for other HSP90 inhibitors include, but are not limited to, 
nausea, vomiting, diarrhea, dehydration, stomatitis, anemia, neutropenia, 
thrombocytopenia, hepatotoxicity, bilirubinemia, anorexia, fatigue, myalgia, hypoxia, 
dyspnea, pulmonary infiltrates, cardiac toxicity, pancreatitis, fever, and hypersensitivity 
reactions. Given that some of these adverse events may be mechanism-based, careful 
monitoring for the adverse events listed above is recommended. 
 
Gastrointestinal symptoms have been the most frequently observed AEs and include 
diarrhea, nausea, vomiting, abdominal pain and bloating.  Due to the potential for 
dehydration, subjects should be advised to maintain appropriate hydration.  Blood 
chemistries, including electrolytes, should be regularly monitored, and corrected as 
appropriate. 
 
Fatigue is observed frequently, in up to 50% of subjects; mostly NCI CTC Grade 1.  
Anemia, typically NCI CTC Grade 1 was reported in approximately 30% of subjects, 
although the relationship to study drug was unclear.  No other bone marrow suppressive 
effects were reported.  To date, severe liver toxicity has not been observed and liver 
toxicity was not the dose-limiting toxicity in the Phase I trials.  In some subjects, 
transient elevations of transaminases or bilirubin were observed, typically NCI CTC 
Grade 1 or 2, however a few Grade 3 elevations were observed. 
 
Interim analysis of ECG intervals suggests that administration of ganetespib is associated 
with an acute, modest, transient decrease in heart rate (5-10 bpm) and accompanying 

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62 
increase in P-R interval (NCI CTC Grade 1).  These changes were not symptomatic and 
did not lead to brady-arrhythmias.  Mean QRS did not appear to change in any consistent 
way.  Similar observations have been described for other HSP90 inhibitors and seem to 
represent a drug class effect. 
 
7.2 
Fulvestrant 
 
Fulvestrant is commercially available and considered standard-of-care for patients with 
hormone receptor positive, metastatic breast cancer.  The dose, schedule, and mode of 
administration used in this trial are identical to the dose, schedule, and mode of administration 
approved for use for this indication by the U.S. FDA. 
 
Fulvestrant will be charged to the patient and/or insurance company as it is considered 
standard-of-care. 
7.2.1 
Description 
Fulvestrant injection is commercially available as a sterile, single patient, prefilled 
syringe containing 250 mg at a concentration of 50 mg/mL.  The solution is a clear, 
colorless to yellow, viscous liquid.  In addition to the fulvestrant, each injection contains 
as inactive ingredients alcohol, USP, benzyl alcohol, NF, and benzyl benzoate, USP, as 
co-solvents and castor oil, USP, as a co-solvent and release rate modifier.   
7.2.2 
Storage and Stability 
Syringes of fulvestrant should be stored in the original container and refrigerated at 2-
8°C. 
7.2.3 
Preparation 
Remove syringe from tray and check that it is not damaged. Peel open the safety needle 
outer packaging. Break the seal of the white plastic cover on the syringe luer connector to 
remove the cover with the attached rubber tip cap. Twist to lock the needle to the luer 
lock connector. 
Remove needle sheath. Remove excess air from the syringe (a small bubble may remain). 
7.2.4 
Administration 
Fulvestrant will be administered at a dose of 500 mg (2 x 250 mg injections) IM on Cycle 
1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, and on Day 1 of each subsequent cycle.  Cycle 
length = 28 days.   
 
Fulvestrant will be administered slowly into each buttock. 
 
Immediately upon withdrawal of syringe from patient activate needle protection device 
by pushing lever arm forward until needle tip is fully covered. 
 

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Visually confirm that the needle arm has advanced and that the needle tip is fully 
covered.  If unable to activate, discard immediately into an approved sharps container. 
 
7.2.5 
Toxicity 
The side effect profile includes injection site pain (9-12% of patients), nausea (10-13%) 
and bone pain (~10%).  In the CONFIRM trial, the most commonly reported toxicities 
(any grade) on the 500 mg arm were GI disturbances (20%), joint disorders (19%), 
injection site reactions (14%), and hot flashes (8%).6 The most common grade 3 or higher 
toxicities were GI disturbances (2%) and joint disorders (2%). Other grade 3 or higher 
toxicities were uncommon and did not exceed 1% frequency in this study. 
 
Please refer to the package insert for a comprehensive list of adverse events. 
7.2.6 
Drug Interactions 
In in vitro studies of human hepatocytes, fulvestrant is metabolized predominantly by 
glucuronidation.  The metabolites are thought to have no estrogenic activity and minimal 
anti-estrogenic activity. 
 
In studies using human liver microsomes, fulvestrant inhibited the activity of CYP1A2, 
2C9, and 3A4 minimally and in healthy volunteer studies fulvestrant did not affect 
metabolism of CYP3A4 substrates. CYP3A4 did metabolize fulvestrant in these studies; 
however the human hepatocyte studies noted above indicate conjugation is a more 
important metabolic pathway.  In addition, studies in healthy volunteers indicate that 
fulvestrant metabolism is not significantly affected by inducers or inhibitors of CYP3A4, 
nor does fulvestrant affect metabolism of CYP3A4 substrates.  Thus, fulvestrant is not 
expected to be involved in significant drug interactions mediated by CYP3A4. 
 
As per Chouinard, et al., fulvestrant is glucuronidated by UGT1A1, 1A3, 1A4 and 1A8 
and ganetespib has been shown to inhibit UGT-mediated metabolism of furosemide 
(UGT1As); however, laboratory work completed at Synta specifically addressing 
possible UGT-mediated interactions with ganetespib indicates that an alteration of 
fulvestrant metabolism by ganetespib is unlikely.  Fulvestrant metabolism is unaffected 
by the presence of ganetespib at ganetespib concentrations of 1, 10, and 20 M in human 
hepatocytes in vitro.  For reference, at 216 mg/m2 ganetespib, Cmax is approximately 16 
M. At 150 mg/m2 it is approximately 11 M (9090-02). 
 
Synta also addressed DDI potential from the perspective of a possible effect of 
fulvestrant on ganetespib in vitro.  There was no alteration of ganetespib metabolism by 
fulvestrant.  Concentrations of 0.3 and 3 M fulvestrant and 1, 10, and 20 M of 
ganetespib were used.  
  

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8. CORRELATIVE/SPECIAL STUDIES  
 
See section 9.5 for details on specimen collection, processing, and shipping instructions.  
 
The biomarker studies are designed to be hypothesis generating.  It is anticipated that promising 
findings will be validated in the context of future studies. 
 
The key determinants of whether a tumor will or will not respond to Hsp90 inhibition remain 
poorly defined. The basal level of HSP90 per se has not proven to be predictive. Although 
activation of the heat shock response in surrogate normal tissue or even tumor tissue can serve as 
a sensitive pharmacodynamic endpoint for Hsp90 inhibition, it also fails to predict anticancer 
response. The frustrating lack of predictive markers arises, to a great extent because HSP90 does 
not act alone, but rather as part of a complex network of additional heat shock proteins, co-
chaperones and accessory molecules. This network’s architecture makes the potential for cross-
talk and compensation enormous. It also explains the disappointing lack of power seen for 
elevation of any single heat shock protein as an independent predictor of outcome in cancers 
including breast.  We hypothesize that activation of Heat Shock Factor 1 (HSF1), the major 
transcriptional regulator of inducible expression for the entire heat shock network, can serve as 
an indicator of the relative level of proteotoxic stress within a particular tumor and consequently 
the “load” on the Hsp90-based chaperone machinery. This load could in turn determine which 
patients are more or less likely to derive clinical benefit from endocrine therapy alone or the 
combination of endocrine therapy + HSP90 inhibitor. In pilot work using commercial tissue 
microarrays, we have found clear immunohistochemical evidence for HSF1 activation in ~40-
50% of the ER+ breast cancer cases.  We have also found a correlation between HSF1 activation 
and patient outcomes among patients with ER+ breast cancer within the Nurses’ Health Study 
(Santagata et al, unpublished data, manuscript in preparation). 
 
As detailed in Section 1.4, we will collect archival tumor specimens, on-study biopsy specimens, 
and blood specimens at a variety of timepoints in order to explore a series of correlative aims. 
 
As the primary correlative endpoint, HSF1 will be measured semi-quantitatively in archived 
breast tumor specimens (primary and/or metastatic; whatever is available for a particular patient) 
by immuno-histochemistry (IHC) according to methods we have developed within the Nurses’ 
Health Study (Santagata et al, unpublished data, manuscript in preparation). The level of HSF1 
mRNA and that of a panel of genes known to be regulated at the transcriptional level by HSF1 
will be measured using a custom Gene Expression CodeSet and the nCounter Analysis System 
developed by Nanostring Technologies.  The custom CodeSet designed for this study will 
include an activation signature consisting of sequences regulated by HSF1. Genes reported to be 
estrogen-regulated which could be impacted by fulvestrant and/or ganetespib therapy will be 
included as well as other breast cancer progression-related genes such as hormone receptors and 
kinases.  Cytokeratins will be included in an effort to normalize for tumor/epithelial cell content 
of specimens being analyzed. With multiplexed target profiling of up to 800 transcripts in a 
single reaction, nCounter Gene Expression CodeSets deliver gold-standard levels of sensitivity, 
precision and linearity across a wide range of basic research and translational medicine 
applications. No amplification is required and protocols have been developed that permit 

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quantitative analysis starting with 100ng or less of total RNA from formalin-fixed tissue as well 
as raw cell or blood lysates. These features make possible the analysis of very small amounts of 
tissue available from archived materials and core biopsies.  
 
As a control for tumor tissue, NanoString CodeSets will be used to analyze normal peripheral 
blood lymphocytes (PBL) obtained from the same patient before and after drug exposure. Levels 
of the highly inducible HSP70 family member HSP72 have been used as a pharmacodynamic 
endpoint in many previous HSP90 inhibitor trials, but measurements were made at the protein 
level by more cumbersome, less sensitive and less quantitative immunoassays. Although HSP72 
has clearly not been predictive of anticancer response in patients, no patient data are available on 
the drug-induced modulation of other heat shock protein classes or the wide range other genes 
included in our custom CodeSet. Likewise, no data are available on whether fulvestrant and its 
modulation of ER signaling will alter regulation of the heat shock response in either normal or 
tumor tissue. 
 
As a complement to monitoring RNA expression signatures in biopsy specimens by NanoString 
CodeSet, ER, PR, AR, and HSF1 will be assessed at the protein level in circulating tumor cells 
(CTCs) before and after drug treatment. CTCs offer a non-invasive approach to obtain and 
characterize metastatic breast cancer cells, but their usefulness has been limited by the very low 
yields available from conventional isolation methods. Krop et al have recently reported an 
improved technique that provides a much higher yield of relatively pure CTCs, facilitating their 
molecular characterization.  Typically starting from 7.5 ml of whole blood, a median tumor cell 
number of 117 can be obtained. The purity of samples ranges from 60-70 % as estimated by 
immunostaining. 
 
During isolation of CTCs, integrity of tumor cell membrane can be compromised. This technical 
limitation should be less problematic in evaluating the nuclear localized/DNA bound ER, PR, 
AR, and HSF1 proteins.  We propose to evaluate these proteins in CTCs at baseline, Cycle 2 Day 
8, Cycle 2 Day 9, and at time of progression.  Exploratory comparisons of Arm A and Arm B 
will allow for assessment of the effect of fulvestrant plus Hsp90 inhibition versus fulvestrant 
alone. Amplification of EGFR and HER2 has been postulated as potential resistance mechanisms 
to endocrine therapy.  EGFR and HER2 will also be assessed at the timepoints listed above to 
explore potential correlates to upfront and acquired resistance. 
 
9.  STUDY CALENDAR 
 
All subjects must sign an informed consent document prior to initiation of any study related 
procedures.  The informed consent document must be signed within 30 days before 
randomization.  Baseline laboratory evaluations must be completed within 14 days before 
randomization.  Baseline measurements including scans must be completed within 28 days 
before randomization.  QTc must be documented by 12-lead ECG within 28 days before 
randomization.  In the event that the participant's condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 

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All assessments must be performed prior to administration of any study medication.  
Ganetespib should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted.  All study assessments should be performed within +/- 3 days of the protocol-
specified date; however, for study assessments minor deviations in scheduling are allowed to 
account for holidays, vacations, etc. and will not be considered protocol violations.  For 
patients initially assigned to Arm A, after cross-over to Arm C (fulvestrant + ganetespib), 
fulvestrant dosing may occur up to +/-7 days in order to allow “synchronization” of the 
fulvestrant and ganetespib “Day 1”. 
Each study cycle should last ~28 days.  Doses of ganetespib that are missed for any reason 
should not be considered “held,” but should be considered “skipped”.  For example, if a patient 
is unable to receive Cycle 3 Day 8 (+/- 3 days) of treatment for any reason, the dose should be 
skipped and the patient should proceed on the appropriate calendar date to Cycle 3 Day 15 
treatment.  The purpose of this rule is to hold the cycle length reasonably constant in order to 
allow “synchronization” of the fulvestrant and ganetespib cycles (since it is unlikely that 
fulvestrant will be held for any reason).  For the purpose of case report forms (CRF) and 
protocol charts, for patients receiving both fulvestrant and ganetespib, the cycle number should 
be assigned according to the ganetespib dosing (i.e., day 1 of the ganetespib cycle is 
considered day 1 of the cycle to be reported in the CRF).  For patients receiving fulvestrant 
only, day 1 of fulvestrant dosing should be considered day 1 of the cycle. 
 
 
Four study calendars are provided below: 
 
A) Arm A—fulvestrant alone 
 
B) Arm B—fulvestrant + ganetespib 
 
C) Arm C— Patients initially assigned to Arm A, after crossover to fulvestrant +  
Ganetespib 
 
D) Calendar of Events for Patients who are Taken Off Assigned Protocol Therapy for 
Reason Other than Progression or Death. 

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9.1 
STUDY CALENDAR A 
ARM A: Fulvestrant Alone—Initial Therapy 
Note: The study calendar below describes initial study procedures for Arm A.   
 
Patients who progress on fulvestrant alone may cross over to Arm C, fulvestrant + ganetespib and 
should be followed at that time according to Study Calendar C, or they may elect to discontinue 
study treatment altogether.   
 
 
Patients who discontinue fulvestrant for a reason other than progression should be followed at that 
time according to Study Calendar D. 
 
 
*Patients who are taken off Arm A for reason other than progression and who are not followed on 
study calendar D for any reason, should have “off-treatment” evaluation and tests as described in 
the “At time of progression or off-treatment” column below. Patients are then followed for survival 
status as described in the “follow-up” column below.  
 
 
 
Pre-
Study 
C1 
D1 
C1 
D15 
C2 
D1 
C2 
D8 
C2 
D9 
C3 
D1 
Day 1 
of each 
cycle 
Every 
2 
cycles 
At time of 
progression 
or off-
treatment* 
Follow-
Up 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Confirm 
eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent 
medications 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
Physical 
examination 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
Vital signsa 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
X 
 
ECOG 
performance 
status 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
CBC w/diff, plts 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
Serum chemistryb 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
PT,PTTc 
 
 
 
 
 
 
 
 
 
 
 
B-HCGd 
X 
 
 
 
 
 
 
 
 
 
 
CEA, CA27-29e 
 
X 
 
 
 
 
Xe
 
Xe
X 
 
12-lead EKG 
X 
 
 
 
 
 
 
 
 
Xf 
 
Adverse event 
evaluationg 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
Tumor 
measurementsh 
X 
 
 
 
 
 
 
 
Xh 
X 
 
Bone scani 
X 
 
 
 
 
 
 
 
Xi
X 
 
Fulvestrant 
 
X 
X 
X 
 
 
X 
X 
 
 
 
Research 
specimen 
collection  
(see section 9.5) 
X 
X 
 
 
X 
X 
 
 
 
X 
 
Survival Status 
(see Section 5.1.16) 
 
 
 
 
 
 
 
 
 
 
X 
q3months 
 

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a. Vital signs: heart rate, blood pressure, respiratory rate 
b. Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose (random), 
total bilirubin, alkaline phosphatase, ALT, AST, albumin, calcium, magnesium, phosphorus 
c. PT, PTT if clinically indicated prior to biopsy (-ies) per standard institutional guidelines.   
d. In women of childbearing potential only (including premenopausal women with intact uterus and ovaries on 
GnRH agonist). 
e. All patients should have baseline tumor marker measurement and tumor marker measurement at time of cross-
over.  Tumor markers are required at other timepoints only when elevated at baseline. 
f. EKG required at time of progression only for patients intending to cross over to Arm C. 
g. Baseline symptoms should be documented using the CTCAE v 4.0 grading scale.  Adverse events should be 
documented on day 1 of each cycle, at each clinic visit, and at time of progression, using the CTCAE v 4.0 grading 
scale. 
h. Radiologic imaging studies to evaluate tumor status should be done every 2 cycles +/- 7 days. However, patients 
who have been on-study for >1 year are permitted to have tumor imaging performed every 2-4 cycles. Contrast 
computed tomography (CT) (or without contrast if contraindicated) of chest and abdomen is preferred.  Magnetic 
resonance imaging (MRI) of chest and abdomen is an acceptable alternative.  Note: PET-CT scans are not allowed 
per protocol for primary assessment of response.  PET-CT scans may be done according to clinical judgment to 
supplement CT or MRI scans in cases where results of the PET-CT may clarify or resolve a clinical question.  If 
palpable/visible lesions (e.g. chest wall nodule, etc) are being used as target lesions, measurements and photographs 
should be taken as well.   
i. A bone scan should be done at baseline and at time of cross-over in all patients.  Patients with evaluable but non-
measurable disease and with bone metastases should also undergo bone scan once every 2 cycles, unless all of the 
bony disease is encompassed within the area visualized by the restaging CT and/or MRI.  Patients with bone only 
disease will be evaluated for progression but not for objective response. Patients with measurable disease by 
RECIST 1.1 need not undergo routine bone scans(with the exception of the baseline and time of cross-over scan) 
unless there is a clinical indication (example: new bone pain).  Bone progression is defined as a bone event requiring 
intervention (e.g. surgery/radiation), the occurrence of a pathologic fracture or the appearance of new lytic lesions or 
other new bone destruction thought to be related to cancer by X-ray, MRI, or CT scan.  Changes in bone scan should 
not be used to define progression.  Disease “hot spots” detected on bone scan should be evaluated radiographically 
by X-ray, MRI, or CT scan to ascertain the presence of bone destruction versus a healing reaction.  The appearance 
of new lesions on bone scan may constitute progressive disease if associated with clinical symptoms suggestive of 
disease progression.  Patients with bone metastases will also be considered as having progressive disease if there are 
new and/or progressive lesions in non-bone sites. 
 
 
 
 
 
 
 

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9.2 
STUDY CALENDAR B 
 
Arm B: Fulvestrant + Ganetespib 
 
Note: The study calendar below describes study procedures for Arm B.   
 
Patients who discontinue ganetespib and/or fulvestrant for a reason other than progression should be 
followed at that time according to Study Calendar D. 
 
*Patients who are taken off Arm B for reason other than progression and who are not followed on 
study calendar D for any reason, should have “off-treatment” evaluation and tests as described in 
the “At time of progression or off-treatment” column below. Patients are then followed for survival 
status as described in the “follow-up” column below. 
 
 
 
Pre-
Study 
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
C2 
D8 
C2 
D9 
C2 
D15 
C3 
D1 
Day 
1 of 
each 
cycle 
D8 and 
D15 of 
each cycle 
(cycle 3  
forward) 
Every 
2 cycles 
At time of 
progressio
n or off-
treatment* 
Follow- 
Up 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm 
eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent 
medications 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
X 
 
Physical exam 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
X 
 
Vital signsa 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
ECOG perf. 
status 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
X 
 
CBC w/diff, 
plts 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Serum 
chemistryb 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
PT, PTTc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B-HCGd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CEA, CA27-29e 
 
X 
 
 
 
 
 
 
Xe
 
 
Xe 
X
12-lead ECG 
X 
Xf 
 
 
Xf 
 
 
 
 
Xf 
 
 
 
 
Adverse event 
evaluationg 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
X 
 
Tumor 
measurementsh 
X 
 
 
 
 
 
 
 
 
 
 
Xh 
X 
 
Bone scani 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Fulvestrant 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
Ganetespib 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Research 
Specimen 
Collection  
(see section 9.5) 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
X 
 
Survival Status 
(see Section 5.1.16) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
q3 months 
 

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a. Vital signs: heart rate, blood pressure, respiratory rate 
b. Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose (random), 
total bilirubin, alkaline phosphatase, ALT, AST, albumin, calcium, magnesium, phosphorus 
c. PT, PTT if clinically indicated prior to biopsy (-ies) per standard institutional guidelines 
d. In women of childbearing potential only (including premenopausal women with intact uterus and ovaries on 
GnRH agonist). 
e. All patients should have baseline tumor marker measurement.  Tumor markers are required at other time points 
only when elevated at baseline. 
f. For Arms B and C only: For patients at low risk for torsades de pointes an EKG must be performed Cycle 1 Day 2 
(approximately 24 hours post Cycle 1 Day 1 ganetespib dose) and pre-dose (ganetespib) Day 1 of all subsequent 
cycles. If a Day 1 pre-dose QTc > 470ms then a repeat EKG is required approximately 24 hours post-ganetespib 
dose. Additional EKGs are required for patients at moderate to high risk for torsades de pointes. See section 5.6 for 
details.  
g. Baseline symptoms should be documented using the CTCAE v 4.0 grading scale.  Adverse events should be 
documented on day 1 of each cycle, at each clinic visit, and at time of progression. 
h. Radiologic imaging studies to evaluate tumor status should be done every 2 cycles +/- 7 days. However, patients 
who have been on-study for >1 year are permitted to have tumor imaging performed every 2-4 cycles. Contrast 
computed tomography (CT) (or without contrast if contraindicated) of chest and abdomen is preferred.  Magnetic 
resonance imaging (MRI) of chest and abdomen is an acceptable alternative.  Note: PET-CT scans are not allowed 
per protocol for primary assessment of response.  PET-CT scans may be done according to clinical judgment to 
supplement CT or MRI scans in cases where results of the PET-CT may clarify or resolve a clinical question.  If 
palpable/visible lesions (e.g. chest wall nodule, etc) are being used as target lesions, measurements and photographs 
should be taken as well.   
i. A bone scan should be done at baseline and at time of cross-over in all patients.  Patients with evaluable but non-
measurable disease and with bone metastases should also undergo bone scan once every 2 cycles, unless all of the 
bony disease is encompassed within the area visualized by the restaging CT and/or MRI.  Patients with bone only 
disease will be evaluated for progression but not for objective response. Patients with measurable disease by 
RECIST 1.1 need not undergo routine bone scans(with the exception of the baseline and time of cross-over scan) 
unless there is a clinical indication (example: new bone pain).  Bone progression is defined as a bone event requiring 
intervention (e.g. surgery/radiation), the occurrence of a pathologic fracture or the appearance of new lytic lesions or 
other new bone destruction thought to be related to cancer by X-ray, MRI, or CT scan.  Changes in bone scan should 
not be used to define progression.  Disease “hot spots” detected on bone scan should be evaluated radiographically 
by X-ray, MRI, or CT scan to ascertain the presence of bone destruction versus a healing reaction.  The appearance 
of new lesions on bone scan may constitute progressive disease if associated with clinical symptoms suggestive of 
disease progression.  Patients with bone metastases will also be considered as having progressive disease if there are 
new and/or progressive lesions in non-bone sites. 
 
 
 
 

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9.3 
STUDY CALENDAR C 
 
ARM C: Patients Assigned Arm A, After Cross-Over to Fulvestrant + Ganetespib 
Note: Patients who progress on fulvestrant alone may cross over to fulvestrant + ganetespib.  The first dose 
of ganetespib should be given only AFTER central confirmation of progression but within 2 weeks of 
documented progression on fulvestrant alone.  Cycle number will re-set to Cycle 1 and be captured in case 
report forms as post-crossover treatment.   Fulvestrant may be given +/- 7 days of schedule in order to allow 
“synchronization” of fulvestrant and ganetespib cycles. 
 
*Patients who are taken off Arm C for reason other than progression and who are not followed on 
study calendar D for any reason, should have “off-treatment” evaluation and tests as described in 
the “At time of progression or off-treatment” column below. Patients are then followed for survival 
status as described in the “follow-up” column below. 
 
 
 
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
C2 D8 
and 
C2D15 
C2 
D8 
and 
C2 
D9 
C3D1 
Day 
1 of 
each 
cycle 
D8 
and 
D15 
of 
each 
cycle 
Every 
2 
cycles 
At time of 
progression 
or off-
treatment* 
Follow- 
Up 
Concurrent 
medications 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
Physical 
examination 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
Vital signsa 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Weight 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
ECOG 
performance 
status 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Serum 
chemistryb 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
PT, PTTc 
 
 
 
 
 
 
 
 
 
 
 
 
CEA, CA27-29 
 
 
 
 
 
 
Xd
 
 
Xd
X 
 
12-lead EKG 
Xh 
 
 
Xh 
 
 
 
Xh 
 
 
 
 
Adverse event 
evaluatione 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
Tumor 
measurementsf 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
Bone scang 
 
 
 
 
 
 
 
 
 
Xg
Xg 
 
Fulvestrant 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Ganetespib 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Research 
Specimen 
Collection  
(see section 9.5) 
 
 
 
 
 
 
 
 
 
 
X 
 
Survival Status  
(see Section 5.1.16) 
 
 
 
 
 
 
 
 
 
 
 
X 
q3 months 
 
a. Vital signs: heart rate, blood pressure, respiratory rate 
b. Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose (random), 
total bilirubin, alkaline phosphatase, ALT, AST, albumin, calcium, magnesium, phosphorus 

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c. Patients receiving ganetespib and who are on warfarin should have PT-INR checked at baseline, 1 week, 2 weeks, 
and 4 weeks after start of ganetespib and as clinically indicated thereafter.  Patients not on warfarin are not required 
to have PT, PTT checked at any time, except if clinically indicated prior to a biopsy. 
d. Tumor markers should be drawn at off-study.  Other timepoints are required only when elevated at time of cross-
over. 
e. Adverse events should be documented on day 1 of each cycle, at each clinic visit, and at time of cross-over, using 
the CTCAE v 4.0 grading  
f. Radiologic imaging studies to evaluate tumor status should be done every 2 cycles +/- 7 days. However, patients 
who have been on-study for >1 year are permitted to have tumor imaging performed every 2-4 cycles. Contrast 
computed tomography (CT) (or without contrast if contraindicated) of chest and abdomen is preferred.  Magnetic 
resonance imaging (MRI) of chest and abdomen is an acceptable alternative.  Note: PET-CT scans are not allowed 
per protocol for primary assessment of response.  PET-CT scans may be done according to clinical judgment to 
supplement CT or MRI scans in cases where results of the PET-CT may clarify or resolve a clinical question.  If 
palpable/visible lesions (e.g. chest wall nodule, etc) are being used as target lesions, measurements and photographs 
should be taken as well.   
g. A bone scan should be done at baseline and at time of cross-over in all patients.  Patients with evaluable but non-
measurable disease and with bone metastases should also undergo bone scan once every 2 cycles, unless all of the 
bony disease is encompassed within the area visualized by the restaging CT and/or MRI.  Patients with bone only 
disease will be evaluated for progression but not for objective response. Patients with measurable disease by 
RECIST 1.1 need not undergo routine bone scans(with the exception of the baseline and time of cross-over scan) 
unless there is a clinical indication (example: new bone pain).  Bone progression is defined as a bone event requiring 
intervention (e.g. surgery/radiation), the occurrence of a pathologic fracture or the appearance of new lytic lesions or 
other new bone destruction thought to be related to cancer by X-ray, MRI, or CT scan.  Changes in bone scan should 
not be used to define progression.  Disease “hot spots” detected on bone scan should be evaluated radiographically 
by X-ray, MRI, or CT scan to ascertain the presence of bone destruction versus a healing reaction.  The appearance 
of new lesions on bone scan may constitute progressive disease if associated with clinical symptoms suggestive of 
disease progression.  Patients with bone metastases will also be considered as having progressive disease if there are 
new and/or progressive lesions in non-bone sites. 
h. For Arms B and C only: For patients at low risk for torsades de pointes an EKG must be performed Cycle 1 Day 2 
(approximately 24 hours post Cycle 1 Day 1 ganetespib dose) and pre-dose (ganetespib) Day 1 of all subsequent 
cycles. If a Day 1 pre-dose QTc > 470ms then a repeat EKG is required approximately 24 hours post-ganetespib 
dose. Additional EKGs are required for patients at moderate to high risk for torsades de pointes. See section 5.6 for 
details. 
 
 
 
 
 
 
 
 
 
 

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9.4 
STUDY CALENDAR D 
Calendar of Events for Patients who Discontinue Study Treatment for Reasons 
Other than Progression or Death. 
 
As detailed in Section 5.6 and Section 5.8, participants will be removed from study when any of 
the following occur 
 
 Disease progression,  
 Start of new anti-cancer therapy, or 
 Participant decides to withdraw from the study follow up procedures 
 Subject death 
 
Prior to removal from study, patients in Arm A who progress on fulvestrant alone may first 
cross over to the combination arm.  Patients in Arm A who discontinue fulvestrant for any 
reason other than centrally confirmed progression or death, and who do not cross over 
should continue to be followed according to the study calendar below, until evidence of 
disease progression, start of new anti-cancer therapy, withdrawal of consent to 
follow-up, or death, whichever occurs first. 
 
 For patients in Arm B or Arm C, once ganetespib is discontinued for any reason, patients 
should not be removed from study but instead should remain on fulvestrant and 
continue to be followed per protocol according the study calendar below, until 
evidence of disease progression, start of new anti-cancer therapy, withdrawal of 
consent to follow-up, or death, whichever occurs first .  Patients who choose to 
discontinue fulvestrant without evidence of disease progression should also be 
followed per protocol, as specified below, until evidence of disease progression, start 
of new anti-cancer therapy, withdrawal of consent to follow-up, or death, whichever 
occurs first.   
 
 
 
Every 4 weeks 
Every 8 weeks 
Off-Study 
Follow-Up 
Concurrent medications 
X 
 
X 
 
Physical examination 
X 
 
X 
 
Vital signsa 
X 
 
X 
 
ECOG performance 
status 
X 
 
X 
 
CBC w/diff, plts 
 
X 
X 
 
Serum chemistryb 
 
X 
X 
 
CEA, CA27-29 
 
 
Xe
 
Adverse event 
evaluationg 
X 
 
X 
 
Tumor measurementsi 
 
Xi 
X 
 
Bone scanj 
 
X 
X 
 
Fulvestrant, if 
applicable (see above) 
X 
 
 
 
Research Specimen 
Collection  
(see section 9.5) 
 
 
X 
 

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Survival Status  
(see section 5.1.16) 
 
 
 
X 
q3 months  
 
a. Vital signs: heart rate, blood pressure, respiratory rate 
b. Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose (random), 
total bilirubin, alkaline phosphatase, ALT, AST, albumin, calcium, magnesium, phosphorus 
c. Patients receiving ganetespib and who are on warfarin should have PT-INR checked at baseline, 1 week, 2 weeks, 
and 4 weeks after start of ganetespib and as clinically indicated thereafter.  Patients not on warfarin are not required 
to have PT, PTT checked at any time, except if clinically indicated prior to a biopsy. 
d. In women of childbearing potential only. 
e. All patients should have baseline tumor marker measurement.  Tumor markers are required at other timepoints 
only when elevated at baseline. 
g. Baseline symptoms should be documented using the CTCAE v 4.0 grading scale.  Adverse events should be 
documented on day 1 of each cycle, at each clinic visit, and at time of cross-over, using the CTCAE v 4.0 grading 
scale. 
i. Radiologic imaging studies to evaluate tumor status should be done every 2 cycles +/- 7 days.  However, patients 
who have been on-study for >1 year are permitted to have tumor imaging performed every 2-4 cycles. Contrast 
computed tomography (CT) (or without contrast if contraindicated) of chest and abdomen is preferred.  Magnetic 
resonance imaging (MRI) of chest and abdomen is an acceptable alternative.  Note: PET-CT scans are not allowed 
per protocol for primary assessment of response.  PET-CT scans may be done according to clinical judgment to 
supplement CT or MRI scans in cases where results of the PET-CT may clarify or resolve a clinical question.  If 
palpable/visible lesions (e.g. chest wall nodule, etc) are being used as target lesions, measurements and photographs 
should be taken as well.   
j. A bone scan should be done at baseline in all patients.  Patients without bone metastases at baseline do not require 
additional bone scans as part of this study, unless clinically indicated on the basis of symptoms, laboratory 
evaluation, etc. Patients with evaluable but non-measurable disease and with bone metastases should also undergo 
bone scan once every 2 cycles, unless all of the bony disease is encompassed within the area visualized by the 
restaging CT and/or MRI.  Patients with bone only disease will be evaluated for progression but not for objective 
response. Patients with measurable disease by RECIST 1.1 need not undergo routine bone scans(with the exception 
of the baseline and time of cross-over scan) unless there is a clinical indication (example: new bone pain).  Bone 
progression is defined as a bone event requiring intervention (e.g. surgery/radiation), the occurrence of a pathologic 
fracture or the appearance of new lytic lesions or other new bone destruction thought to be related to cancer by X-
ray, MRI, or CT scan.  Changes in bone scan should not be used to define progression.  Disease “hot spots” detected 
on bone scan should be evaluated radiographically by X-ray, MRI, or CT scan to ascertain the presence of bone 
destruction versus a healing reaction.  The appearance of new lesions on bone scan may constitute progressive 
disease if associated with clinical symptoms suggestive of disease progression.  Patients with bone metastases will 
also be considered as having progressive disease if there are new and/or progressive lesions in non-bone sites. 
 
   

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9.5 
SPECIMEN SUBMISSION REQUIREMENTS 
 
The following specimens are to be submitted to the indicated lab or location.  Refer to the information in sections 9.5.1-9.5.3 for 
specimen collection scheduling, billing, processing, and shipping instructions. 
 
Specimen Type 
Time Point 
Shipping Condition 
Ship tog 
Pre-
Study 
C1  
D1a 
C2 
D8 
C2 
D9 
At time of 
progressionc 
Off-
treatment 
without 
progressionc 
Off 
Studyc 
Archival blocks 
(Section 9.5.1) 
X 
 
 
 
 
 
 
Ambient temperature 
Danielle Gore 
Optional biopsy 
(Section 9.5.2) 
X 
 
 
 
X 
(Arms A & B 
only) 
 
X 
OCT: Frozen (dry ice) 
Trizol (FNA): Ambient 
RPMI (FNA): ice/ice 
pack 
Danielle Gore 
Required biopsy 
(Section 9.5.2) 
 
 
 
X (Arms 
A&B only) 
 
 
 
10 mL Streck tube 
(Section 9.5.3) 
 
Xb 
(Arms A 
& B only) 
 
 
Xf 
X 
X 
Ambient temperature 
Danielle Gore 
10 mL Lavender 
top tube 
(Section 9.5.3) 
 
Xb 
(Arms A 
& B only) 
 
 
 
 
 
Ambient temperature 
Danielle Gore 
PBMC collection 
(2 PAXgene tubes) 
(Section 9.5.3)  
 
X 
(Arms A 
& B only) 
X 
(Arms A & 
B only) 
X 
(Arms A & 
B only) 
X 
X 
X 
Frozen (dry ice) 
Luke Whitesell/ 
Whitehead 
Institute 
Circulating tumor 
cells (2- 7.5 mL 
CellSave tubes) 
(Section 9.5.3) 
 
X 
(Arms A 
& B only) 
X (Arms A 
& B only) 
X (Arms 
A&B only) 
X 
X 
X 
Ambient temperature 
Danielle Gore 
a. Samples may be collected at any time after documentation of written consent and confirmation of protocol eligibility, but BEFORE the first dose of 
protocol treatment.  The best time to obtain this is on Cycle 1 Day 1.  
b. If baseline sample collection is missed for any reason, the sample should be drawn at a future appointment. 
c. Off-study blood samples should be drawn within 30 days of off-study.  Time of progression blood samples may be counted as the “off study” blood 
sample if the patient is coming permanently off-study.  Time of progression blood samples are drawn if patient progresses on Arms A or B (1st Regimen) 
or Arm C (2nd Regimen). 

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77 
Coded laboratory specimens will be stored in the Tumor Bank of the DFCI.  These specimens 
will become the property of DFCI.  Patients will be informed that their specimens may be used 
for research by investigators at DF/HCC and Whitehead Institute.  Specimens will be identified 
with a sample ID number; all patient identifying material will be removed. 
9.5.1 
Archival tissue 
Confirmation of availability of archival blocks (or unstained slides) of primary and/or 
metastatic tissue is required prior to eligibility.  Tissue blocks should be sent to Dana-
Farber Cancer Institute within in 2 weeks of the start of protocol therapy.  If blocks 
cannot be submitted, 10-20 unstained slides are acceptable.  If unstained slides will be 
sent as an alternative, those slides should not be sent until specifically requested by the 
DFCI study coordinator.  
    
Complete a DFCI 11-477 Specimen Requisition (Archival Tissue Blocks/Slides and CTC 
Samples) form (Appendix J) and ship archival tissue blocks/slides at ambient temperature 
to: 
 
Danielle Gore 
Dana-Farber Cancer Institute 
450 Brookline Avenue, DA157 
Boston, MA 02215 
 
Email Danielle Gore with the sample information and tracking information the day before 
shipping specimens dgore@partners.org 
 
If requested, blocks will be returned to sites after the completion of the specimen 
analysis.   
9.5.2 
Tissue Biopsies 
Tissue specimens will be collected from tumor lesions using standard institutional 
procedures.  See Appendix B for standard operating procedures of biopsies through the 
Brigham & Women’s Hospital interventional radiology service.  Treating investigators 
should use their best judgment in approaching appropriate patients for optional biopsies 
at the indicated time points.   
 
Tumor tissue may be collected at the following time points on this study: 
 
 Baseline (OPTIONAL) 
 Cycle 2 Day 9 (REQUIRED for patients with biopsy-accessible disease) 
 Time of cross-over (Arm A only)—(OPTIONAL) 
 Off-study/time of progression (OPTIONAL) 
 

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Tissue Biopsy Guidelines 
 
 The cost of the on-treatment (Cycle 2) research biopsy will be covered by the 
study.  For the baseline, time of cross-over, and off-study biopsies, the research 
biopsy will be covered by the study if it is being done for research only.  However, at 
these time points, it is recognized that biopsies might be considered to aid in clinical 
management (for example, to re-assess ER, PR, and HER2 status).  In the case of a 
clinically indicated biopsy (with an additional “research pass”), the cost of the biopsy 
will be charged to the patient and/or her insurance company. 
 For Arm A patients: The Cycle 2 Day 9 biopsy may occur +/- 3 days, and on the same 
day as the Cycle 2 Day 9 research blood draw.   If the Cycle 2 Day 9 biopsy is missed 
(i.e. due to scheduling problems, procedure cancellation, etc), then it should be 
performed instead on Cycle 2 Day 16 +/- 3 days, and the Cycle 2 research blood tests 
should be rescheduled to occur around the delayed biopsy (i.e. Cycle 2 Day 15 and 
Cycle 2 Day 16).   
 For Arm B patients: Obtain the Cycle 2 Day 9 biopsy 18-48 hours after the Cycle 2 
Day 8 dose of ganetespib.  If the Cycle 2 Day 8 dose is held for any reason (e.g. for 
toxicity), the Cycle 2 biopsy should be performed between 18-48 hours after the 
Cycle 2 Day 15 dose of ganetespib. 
 Patients who undergo an attempted Cycle 2 research biopsy procedure for the purpose 
of this protocol, and in whom inadequate tissue is obtained, are not required to 
undergo a repeat biopsy in order to continue on protocol.   
 
The amount of tissue collected will follow the guidelines listed below.  If a patient has 
more than one site of disease, only one site needs to be biopsied, and the site is left to the 
discretion of the patient and her treating physician.  Core biopsies are preferred over fine 
needle aspirates when both are technically feasible.  However, fine needle aspirates are 
acceptable and may be used.   
 
Breast: 
 A goal of 3-6 core biopsy (or FNA specimens) will be obtained using standard 
institutional guidelines for a diagnostic core biopsy of a breast mass  
 
Skin/Chest wall:  
 A goal of two 5-mm punch biopsies  
 
Lymph node/Soft tissue:  
 A goal of 3-6 core biopsy (or FNA) specimens will be obtained using an 18-gauge 
needle (or fine needle). 
 
Liver: 
 A goal of 3-6 core biopsy (or FNA) specimens will be obtained using an 18-gauge 
needle (or fine needle) 
 

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Lung: 
 Because of the risk of pneumothorax associated with lung biopsies, additional care 
should be taken in discussing the case with radiology and/or thoracic surgery prior to 
proceeding with a biopsy and the number of research samples attempted adjusted per 
clinical judgement. If other more easily accessible sites are available, they should be 
prioritized 
for 
biopsy. 
Either 
core 
biopsy 
or 
fine 
needle 
aspirations 
acceptable/allowable 
 A goal of 3 core biopsy specimens will be obtained using an 18-gauge needle (or fine 
needle) 
 A goal of 3-6 FNA passes will be obtained using standard institutional guidelines for 
needle gauge.  As with all other biopsy sites, less than the goal amount is allowed and 
subject to the clinical judgment of the physician performing the procedure. 
 
Bone: 
 Because the yield of malignant tissue from bone biopsies tends to be relatively low, if 
a patient has another accessible site of disease (e.g., skin, lymph node, liver), that site 
should be biopsied preferentially. If bone is the only biopsy-accessible site, then a 
goal of 1-3 core biopsy specimens will be obtained using an 11 to 13-gauge needle. 
 
Pleural Fluid: 
 A goal of 500 cc of pleural fluid will be obtained with a standard thoracentesis 
procedure, with or without image guidance, according to the clinical judgment of the 
treating physician and clinician performing the procedure.  Less than the goal amount 
is acceptable, and should be based upon the clinical judgment of the Investigator and 
the clinician performing the procedure.  If more than the goal amount of fluid is 
obtained, then the entire specimen (with the exception of what is needed for clinical 
purposes, if applicable) will be stored in the tissue bank.   
 
Ascites fluid: 
 A goal of 500 cc of ascites fluid will be obtained with a standard paracentesis 
procedure, with or without image guidance, according to the clinical judgment of the 
treating physician and clinician performing the procedure.  Less than the goal amount 
is acceptable, and should be based upon the clinical judgment of the Investigator and 
the clinician performing the procedure.  If more than the goal amount of fluid is 
obtained, then the entire specimen (with the exception of what is needed for clinical 
purposes, if applicable) will be stored in the tissue bank.   
 
Please note that the above are guidelines for the amount of tissue to be obtained at 
the baseline biopsy, and are not meant to replace clinical judgment at the time the 
procedure is performed.  Less than the goal quantity of tissue is accepted for each type 
of biopsy, and will be left to the clinical judgment of the physician performing the 
procedure. If ascites or pleural fluid is to be used as the investigational biopsy specimen, 
consideration should be given to confirming the malignant nature of the ascites or pleural 
fluid prior to study entry. 
 

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Risks of Research Biopsies and Procedures for Minimizing Risk 
 
Potential risks according to site are: 
 
Breast (core biopsy/FNA): 
 Likely: local discomfort and minor bleeding.  
 Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, pneumothorax, damage to adjacent 
organs. 
 
Skin/chest wall (punch biopsy):  
 Likely: local discomfort and minor bleeding.  
 Less likely: moderate or major bleeding, or infection 
 
Lymph node or soft tissue (core needle biopsy/FNA): 
 Likely: local discomfort and minor bleeding.  
 Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, pneumothorax, damage to adjacent 
organs. 
 Additional risks may be present if i.v. conscious sedation is required. 
 
Liver (core needle biopsy/FNA): 
 Likely: local discomfort and minor bleeding 
 Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, bowel perforation or damage to 
adjacent organs 
 Additional risks may be present if i.v. conscious sedation is required. 
 
Lung (FNA):   
 Likely: local discomfort and minor bleeding 
 Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, bowel perforation or damage to 
adjacent organs, lung collapse 
 Additional risks may be present if i.v. conscious sedation is required. 
 
Bone (core needle biopsy/FNA): 
 Likely: local discomfort and minor bleeding 
 Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, bowel perforation or damage to 
adjacent organs 
 Additional risks may be present if i.v. conscious sedation is required. 
 
Pleural fluid (thoracentesis): 
 Likely: local discomfort and minor bleeding 

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 Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, pneumothorax, damage to adjacent 
organs 
 
Ascites fluid (paracentesis): 
 Likely: local discomfort and minor bleeding 
 Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, bowel perforation or damage to 
adjacent organs 
 
In order to minimize the risk of a biopsy, only qualified personnel will perform these 
procedures.  Prior to the procedure, the physician performing the procedure will discuss 
the risks with each study participant, answer any questions, and obtain a separate 
procedure consent.  Patients will be evaluated for co-morbidities or concomitant 
medications that may increase the risk of potential complications.  For biopsies of lesions 
that are not superficial and clearly palpable, imaging studies such as CT or ultrasound 
will be used to guide the biopsy in order to minimize the risk of damage to adjacent 
structures.  After lymph node biopsies, patients will be observed a minimum of 2 hours 
(range 2-4 hours) after the procedure, or according to standard institutional guidelines.  
After liver biopsies, patients will be observed a minimum of 4 hours (range 4-6 hours) 
after the procedure, or according to standard institutional guidelines.  Less than the goal 
quantity of tissue is accepted for each type of biopsy, and will be left to the clinical 
judgment of the physician performing the procedure.   
 
 
 
Risks of Anesthesia 
 
Local Anesthesia 
All biopsy procedures require local anesthesia using xylocaine (Lidocaine®) or related 
compounds.  There is a small risk of an allergic reaction associated with these drugs. 
 
In order to minimize the risk of local anesthesia, only qualified personnel will perform 
the biopsy procedure.  Patients will be queried if they have had previous allergic 
reactions to local anesthetics.   
 
Intravenous Conscious Sedation 
Certain biopsy procedures, such as lymph node, liver, or bone biopsies, may require 
intravenous conscious sedation (IVCS).  IVCS is a minimally depressed level of 
consciousness that retains the patient’s ability to maintain a patent airway independently 
and continuously and to respond appropriately to physical stimulation and verbal 
commands. 
 
The risks of intravenous conscious sedation include: inhibition of the gag reflex and 
concomitant risk of aspiration, cardiopulmonary complications (myocardial infarction, 
cardiac arrhythmias, hypoxemia), and allergic reactions to the sedative or analgesic 
medications.  These risks are small but real; for example, in a prospective study of 14,149 
patients undergoing IVCS during upper gastrointestinal endoscopies, the rate of 

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immediate cardiopulmonary events was 2 in 1000.  The 30-day mortality was 1 per 2,000 
cases.  In this study, there was a strong association between lack of monitoring and use of 
high-dose benzodiazepines with adverse outcomes.  There was also an association 
between the use of local anesthetic sprays to the oropharynx and the development of 
pneumonia. 
 
In order to minimize the risk of intravenous conscious sedation, only qualified personnel 
will be responsible for conscious sedation.  A minimum of two individuals will be 
involved in the care of patients undergoing conscious sedation—the physician performing 
the biopsy procedure, and the individual (M.D. or R.N.) who monitors the patients and 
his/her response to both the sedation and the procedure, and who is capable of assisting 
with any supportive or resuscitative measures.  The room where the procedure utilizing 
IVCS takes place will have adequate equipment to provide supplemental oxygen, monitor 
vital signs, and maintain an airway should this be necessary.  An emergency cart will also 
be immediately accessible to the room where the procedure is to take place, and 
emergency support services will be available on page.  Patients will be screened and 
evaluated for their fitness to undergo conscious sedation by a trained physician.  Patients 
with active cardiac disease are excluded from this study.  No local anesthetic spray to the 
oropharynx will be necessary, given that endoscopy is not a planned procedure.  
Following the procedure, patients will be observed closely in the recovery room for a 
minimum of 2 hours. 
 
General Anesthesia 
 
Because of the higher risk of general anesthesia compared with local anesthesia or 
intravenous conscious sedation, biopsies that would require general anesthesia in order to 
be performed are not permitted on this protocol, unless they are being done for clinical 
reasons, and excess tissue that otherwise would have been discarded is then banked for 
the purpose of this protocol.  
 
Tissue Biopsy Processing 
 
Following the biopsy of a specimen, all tissue cores will be snap-frozen in OCT 
compound intra-operatively.  This sample handling is optimal for obtaining high quality 
total RNA from human tumor tissue for microarray studies.  After the biopsy is 
performed, the tissue mass is placed on a dry sterile gauze and the tumor tissue is 
separated using forceps.  Two pieces (cores) of tumor tissue are placed on a pre-frozen 
bed of OCT in each cassette, typically ending up with 3 cassettes per biopsy (the last 
cassette will contain many small pieces of tumor tissue).  Cassettes are then filled with 
OCT, completely covering the tissue and limiting the amount of bubbles (forceps can be 
used to pop any bubbles). Tissue must be frozen immediately by placing cassettes on dry 
ice in a biohazard cooler; freezing of samples in OCT with dry ice takes about 10 minutes 
freezing time. Once samples are frozen, place in plastic bag; label bag with date, protocol 
number, patient number, patient initials, and number of biopsy samples included.  Store 
in -80oC freezer until the time of shipment.  
 

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For patients who undergo fine needle aspiration (FNA) rather than core biopsy or punch 
biopsy 3 passes should be collected.  The first pass should be evacuated and rinsed 
directly into 2mL of room temperature Trizol to collect the RNA; a second pass should 
be evacuated and rinsed directly into another 2mL of room temperature Trizol to collect 
the DNA; the last pass should be evacuated and rinsed directly into 10-20mL of RPMI 
and prepared as a cell block. 
 
For patients who have pleural fluid or ascites collected, samples should be collected in a 
sterile vacutainer.  The fluid sample should be split into three equal aliquots.  One aliquot 
should be spun down into a pellet and snap frozen in an ETOH/dry ice bath or in liquid 
N2.  One aliquot should be fixed and processed as a standard cell block.  One aliquot 
should be spun down and transferred into Cell Save preservative tubes (7.5 mL) in the 
research lab.  Fluid samples can be transported and stored at room temperature up to 72 
hours before processing. Do not refrigerate or freeze the sample.  Samples must be 
processed within 72 hours of collection, but best results are obtained if the sample is 
processed as soon as possible. 
 
All samples will be anonymized by assigning a unique sample ID number prior to use.  
Histopathologic review will be performed at DFCI/BWH on hematoxylin and eosin-
stained sections taken from two tissue planes and study samples will be obtained from the 
tissue sandwiched in between these two sections.  This will assure that the 
histopathologic review is representative of the specimens that we actually process.  If a 
sample is sufficiently large, multiple aliquots of at least 250 mg/piece will be frozen in 
separate tubes.  These will be labeled to identify that the aliquots came from the same 
original specimen. 
 
Tissue biopsy collection and processing materials are not provided by the study. Coded 
laboratory specimens will be stored in the Tumor Bank of the DF/HCC.  These 
specimens will become the property of DF/HCC.  In cases where the research sample is 
forfeited for clinical purposes, this sample will be flagged in spreadsheet to indicate it can 
be used for research purposes if there is any left over after clinical use. 
 
Please see Appendix C for additional processing details specific to the laboratories at 
Dana Farber Cancer Institute and Brigham and Women’s Hospital. 
 
Tissue Biopsy Shipping 
 
Complete a DFCI 11-477 Specimen Requisition (Biopsy/Research Blood) form 
(Appendix K) and ship all biopsies samples to: 
Danielle Gore 
Dana-Farber Cancer Institute 
450 Brookline Avenue, DA157 
Boston, MA 02215 
 
 
Email Danielle Gore with the sample information and tracking information the day before 
shipping specimens: dgore@partners.org 

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Shipping note: Frozen and ambient specimens obtained and shipped on the same day to 
Danielle Gore (e.g., Progression or Off Study Biopsy Specimens, Streck Tubes, and 
Circulating Tumor Cells) may be placed in a combination shipping box which contains 
separate compartments for frozen and ambient samples.  If a combination shipping box is 
not available, two shipping boxes should be used.  Frozen samples shipped to Luke 
Whitesell/Whitehead Institute obtained on the same day as these specimens must always 
be placed in a separate shipping box.    
9.5.3 
Blood Sample Collection 
Blood will be collected at the indicated time points to be processed and banked in the 
DF/HCC Clinical Trials Core laboratory for future research purposes.  Blood samples are 
collected four ways: 
 
 Streck Tubes 
 Lavender Top Tubes 
 PBMC/PAXgene Tubes 
 Circulating Tumor Cells/CellSave tubes 
 
These samples will be used to look at DNA, RNA and protein in future studies. Refer to 
the details below for scheduling, collection, processing, and shipping details. 
 
 
Streck Tubes 
 
One 10 mL Streck tube will be collected and processed at baseline and time of 
progression (all study Arms) for evaluation of cell free circulating DNA (cfDNA).  Tubes 
are provided by the Sponsor as needed.  
 
 If the baseline sample is missed for any reason, it should be drawn at a future 
appointment.   
 For Arm A patients: The Cycle 2 Day 8 sample may be drawn +/- 3 days.  Draw the 
Cycle 2 Day 9 research blood 18-48 hours after the Cycle 2 Day 8 research blood draw 
and on the same day as the cycle 2 research biopsy. If the Cycle 2 Day 9 biopsy is 
missed (i.e. due to scheduling problems, procedure cancellation, etc), then it should be 
performed instead on Cycle 2 Day 16 +/- 3 days, and the Cycle 2 research blood tests 
should be rescheduled to occur around the delayed biopsy (i.e. Cycle 2 Day 15 and 
Cycle 2 Day 16).  If a patient on Arm A does not undergo the Cycle 2 biopsy, then the 
Cycle 2 Day 9 blood draw is not required. However, the patient is still required to 
undergo the Cycle 2 Day 8 research blood draw.   
 For Arm B patients: Draw Cycle 2 Day 8 research blood 2-4 hours after ganetespib 
administration.  Draw Cycle 2 Day 9 research blood 18-48 hours after ganetespib 
administration and on the same day as the cycle 2 research biopsy. The cycle 2 Day 9 
research blood draw is required for all Arm B patients, including patients who do not 
undergo the cycle 2 research biopsy.  If the Cycle 2 Day 8 dose is held for any reason 

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(e.g. for toxicity), or if the Cycle 2 Day 8 biopsy is instead rescheduled to Cycle 2 Cay 
16, then draw the Cycle 2 research blood 2-4 hours after the Cycle 2 Day 15 dose of 
ganetespib and again 18-48 hours after the Cycle 2 Day 15 dose of ganetespib (i.e. on 
the same day as the cycle 2 research biopsy). 
 
Complete a DFCI 11-477 Specimen Requisition (Biopsy/Research Blood) form 
(Appendix K).  Fill the Streck tube completely and immediately mix by gentle inversion 
8 to 10 times.  Inadequate or delayed mixing may result in inaccurate results.  Ship within 
24 hours of collection at ambient temperature overnight to: 
 
Danielle Gore 
Dana-Farber Cancer Institute 
450 Brookline Avenue, DA157 
Boston, MA 02215 
 
Email Danielle Gore with the sample information and tracking information the day before 
shipping specimens: dgore@partners.org 
 
Tube precautions:  
 If samples cannot be shipped within 24 hours of collection, contact DFCI.  DO NOT 
FREEZE OR REFIDGERATE TUBES as this could result in cfDNA breakage.   
 Do not use tubes after expiration date.   
 Fill the tube completely; overfilling or underfilling of tubes will result in an incorrect 
blood-to-additive ratio and may lead to incorrect analytic results.  
 
See Appendix F for additional processing details specific to the laboratories at Dana 
Farber Cancer Institute.  
 
Shipping note: Streck tubes samples are sent Ambient.  Frozen and ambient specimens 
obtained and shipped on the same day to Danielle Gore (e.g., Progression or Off Study 
Biopsy Specimens, Streck Tubes, and Circulating Tumor Cells) may be placed in a 
combination shipping box which contains separate compartments for frozen and ambient 
samples.  If a combination shipping box is not available, two shipping boxes should be 
used.  Frozen samples shipped to Luke Whitesell/Whitehead Institute obtained on the 
same day as these specimens must always be placed in a separate shipping box.    
 
Lavender top tube 
 
One 10 mL lavender top tube will be collected at baseline in order to extract germline 
DNA to be used as normal DNA reference for tumor tissue-based studies. If the sample is 
missed for any reason, it should be drawn at a future appointment. These collection tubes 
are provided by the Sponsor as needed.  
 
Complete a DFCI 11-477 Specimen Requisition (Biopsy/Research Blood) form 
(Appendix K) and ship lavender top tubes at ambient temperature to: 

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Danielle Gore 
Dana-Farber Cancer Institute 
450 Brookline Avenue, DA157 
Boston, MA 02215 
 
Email Danielle Gore with the sample information and tracking information the day before 
shipping specimens: dgore@partners.org 
 
PBMC analyses 
 
For PBMC analyses, blood will be drawn directly into two PAXgene blood RNA tubes 
(ref #762165) from Qiagen/BD.   PAXgene tubes will be collected at baseline (C1D1), 
C2 D8 andC2D9 (Arms A & B only), at progression/end of treatment and end of study. 
The Cycle 2 Day 9 sample should be collected as close as possible to 24 hours after the 
Cycle 2 Day 8 dose and not more than 48 hours after the C2D8 dose.  
  
 For Arm A patients: The Cycle 2 Day 8 sample may be drawn +/- 3 days.  Draw the 
Cycle 2 Day 9 research blood 18-48 hours after the Cycle 2 Day 8 research blood draw 
and on the same day as the cycle 2 research biopsy. If the Cycle 2 Day 9 biopsy is 
missed (i.e. due to scheduling problems, procedure cancellation, etc), then it should be 
performed instead on Cycle 2 Day 16 +/- 3 days, and the Cycle 2 research blood tests 
should be rescheduled to occur around the delayed biopsy (i.e. Cycle 2 Day 15 and 
Cycle 2 Day 16).  If a patient on Arm A does not undergo the Cycle 2 biopsy, then the 
Cycle 2 Day 9 blood draw is not required. However, the patient is still required to 
undergo the Cycle 2 Day 8 research blood draw.   
 For Arm B patients: Draw Cycle 2 Day 8 research blood 2-4 hours after ganetespib 
administration.  Draw Cycle 2 Day 9 research blood 18-48 hours after ganetespib 
administration and on the same day as the cycle 2 research biopsy. The cycle 2 Day 9 
research blood draw is required for all Arm B patients, including patients who do not 
undergo the cycle 2 research biopsy.  If the Cycle 2 Day 8 dose is held for any reason 
(e.g. for toxicity), or if the Cycle 2 Day 8 biopsy is instead rescheduled to Cycle 2 Cay 
16, then draw the Cycle 2 research blood 2-4 hours after the Cycle 2 Day 15 dose of 
ganetespib and again 18-48 hours after the Cycle 2 Day 15 dose of ganetespib (i.e. on 
the same day as the cycle 2 research biopsy). 
 
After the blood draw samples will sit at room temperature for two hours and then sit for 
24 hours in a -20º C freezer.  Following this, samples will be stored at  -80º C until 
several samples have accumulated at which point samples will be shipped to Dr. Luke 
Whitesell’s laboratory at the Whitehead Institute for Biomedical Research (Address 
below).  A supply of PAXgene tubes will be shipped to participating sites as necessary. 
After the PBMC research blood draw, samples will sit at room temperature for two hours 
and then sit for 24 hours in a -20º C freezer.  Following this, samples will be stored at -
80º C until several samples have accumulated as tubes may be batched for shipping.  
 
Complete a DFCI 11-477 Specimen Requisition (PBMC Tubes) form (Appendix K) and 

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ship PBMC tubes on dry ice to: 
 
Luke Whitesell 
Whitehead Institute 
9 Cambridge Center 
Cambridge, MA 02142 
 
Circulating Tumor Cells 
 
Blood samples for CTC analysis will be collected in two 7.5 mL (15mL total) CellSave 
tubes at baseline (C1D1), C2 D8 andC2D9 (Arms A & B only), at progression/end of 
treatment and end of study.  The Cycle 2 Day 9 sample should be collected as close as 
possible to 24 hours after the Cycle 2 Day 8 dose and not more than 48 hours after the 
C2D8 dose.  
 
 For Arm A patients: The Cycle 2 Day 8 sample may be drawn +/- 3 days.  Draw the 
Cycle 2 Day 9 research blood 18-48 hours after the Cycle 2 Day 8 research blood draw 
and on the same day as the cycle 2 research biopsy. If the Cycle 2 Day 9 biopsy is 
missed (i.e. due to scheduling problems, procedure cancellation, etc), then it should be 
performed instead on Cycle 2 Day 16 +/- 3 days, and the Cycle 2 research blood tests 
should be rescheduled to occur around the delayed biopsy (i.e. Cycle 2 Day 15 and 
Cycle 2 Day 16).  If a patient on Arm A does not undergo the Cycle 2 biopsy, then the 
Cycle 2 Day 9 blood draw is not required. However, the patient is still required to 
undergo the Cycle 2 Day 8 research blood draw.   
 For Arm B patients: Draw Cycle 2 Day 8 research blood 2-4 hours after ganetespib 
administration.  Draw Cycle 2 Day 9 research blood 18-48 hours after ganetespib 
administration and on the same day as the cycle 2 research biopsy. The cycle 2 Day 9 
research blood draw is required for all Arm B patients, including patients who do not 
undergo the cycle 2 research biopsy.  If the Cycle 2 Day 8 dose is held for any reason 
(e.g. for toxicity), or if the Cycle 2 Day 8 biopsy is instead rescheduled to Cycle 2 Cay 
16, then draw the Cycle 2 research blood 2-4 hours after the Cycle 2 Day 15 dose of 
ganetespib and again 18-48 hours after the Cycle 2 Day 15 dose of ganetespib (i.e. on 
the same day as the cycle 2 research biopsy). 
 
Samples should be shipped overnight to the can sit at room temperature for up to 72 
hours but must be mixed immediately with fixative to help prevent clotting and 
transferred to SuperFrost Plus slide as cytospin preparation. Leftover slides will be 
banked at -20 degrees C for future processing. A supply of CellSave tubes will be 
shipped to participating sites as necessary. 
 
See Appendix C for additional processing details specific to the laboratories at Dana 
Farber Cancer Institute and Brigham & Women’s Hospital.  
 
Complete a DFCI 11-477 Specimen Requisition (Archival Tissue Blocks/Slides and CTC 
Samples) form (Appendix J) and ship CTC tubes at ambient temperature to: 

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Danielle Gore 
Dana-Farber Cancer Institute 
450 Brookline Avenue, DA157 
Boston, MA 02215 
 
Email Danielle Gore with the sample information and tracking information the day before 
shipping specimens: dgore@partners.org 
 
Shipping note: Frozen and ambient specimens obtained and shipped on the same day to 
Danielle Gore may be placed in a vertical combination shipping box (containing separate 
compartments for frozen and ambient samples).  If a vertical combination shipping box is 
not available, two shipping boxes should be used.  Frozen samples shipped to Luke 
Whitesell/Whitehead Institute obtained on the same day as these specimens must always 
be placed in a separate shipping box.    
 
10. MEASUREMENT OF EFFECT  
 
Although response is not the primary endpoint of this trial, participants with measurable 
and/or non-measurable disease will be assessed by RECIST 1.1 criteria. For the purposes of 
this study, participants should be reevaluated every 8 weeks. In addition to a baseline scan, 
confirmatory scans and clinical measurements with calipers (if applicable) should also be 
obtained > 4 weeks following initial documentation of an objective response. 
 
10.1 
Antitumor Effect– Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks. 
Confirmatory scans should be obtained not less than 4 weeks following initial documentation 
of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) (Eisenhauer et 
al., 2009) guidelines.  Changes in the diameter (unidimensional measurement) of the 
tumor lesions are used in the RECIST criteria. 
10.1.1 
Definitions 
Evaluable for PFS.  All participants randomized on this study are considered to be 
evaluable for PFS (whether or not they are eligible, have measurable disease, or 
receive protocol therapy). 
Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 

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Evaluable for objective response. Only those participants who have measurable 
disease present at baseline and have had their disease re-evaluated will be considered 
evaluable for response. These participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective 
disease progression or die prior to the end of cycle 1 will also be considered 
evaluable.) 
10.1.2 
Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) 
lesion that can be accurately measured in at least one dimension with longest 
diameter  >20 millimeters (mm) using conventional techniques (CT, MRI, x-ray) or  
>10 mm with spiral CT scan. Measurable lesions must be at least 2 times the slice 
thickness in mm. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
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 (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
A lesion in a previously irradiated area is not eligible for measurable disease 
unless there is objective evidence of progression of the lesion prior to study 
enrollment. Lesions in previously irradiated areas must be clearly identified as 
such. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with > 10 to < 15mm short axis, 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses identified by physical exam that are not measurable by reproducible 
imaging techniques, and cystic lesions are all considered non-measurable. 
Target lesions. All 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. Lesions must be accurately measured 
in 1 dimension with a minimum size of 10 mm by CT or MRI (slice thickness no 
greater than 5 mm), 20 mm by chest x-ray. Nodes must have a short axis > 15 mm. 
The short axis of target nodes should be included in the sum of the longest dimension 
of target lesions in the calculation of response. Nodes that shrink to < 10 mm are 
considered normal. (If the patient has a sum of largest diameters of target lesions 
other than nodes that is zero, then the patient can be classified as having a CR if each 
target node has a short axis < 10 mm).  Target lesions should be selected on the basis 
of their size, be representative of all the involved organs, and should be lesions that 
can be followed with reproducible repeated measurements.  

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Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered target lesions if the soft tissue component meets the definition of 
measurability as defined above. Cystic lesions thought to represent cystic metastases can 
be considered as target lesions. However, if non-cystic lesions are present, these are 
preferred for selection as target lesions. Lesions in previously irradiated areas or areas 
subject to other loco-regional therapy are usually not considered measurable unless there 
has been demonstrated progression of that lesion.  
Non-target lesions. All other lesions, including small lesions < 10 mm or pathological 
lymph nodes measuring > 10 mm to < 15 mm in short axis, as well as truly non-
measurable lesions, which include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.  
10.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, 
or digital measurement tool. 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. 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). For 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; however, CT is preferable. 
Conventional CT and MRI. These techniques 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. 
Ultrasound (US). When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 

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lesions, and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should 
follow the NCI Guidelines for using FDG PET as an indicator of therapeutic response 
(L.K. Shankar, J.M. Hoffman, S. Bacharach, M.M. Graham, J. Karp, A.A. Lammertsma, 
S. Larson, D.A. Mankoff, B.A. Siegel, A. Van den Abbeele, J. Yap, D. Sullivan. 
Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic 
response in patients in National Cancer Institute Trials. J Nucl Med, 47(6):901-903, 
2006). Patients should avoid strenuous exercise and be on a low carbohydrate diet for 24 
hours prior to the scan. Patients should fast for 4 hours or longer prior to the FDG 
injection and should have a serum glucose of less than 200 mg/dL at the time of FDG 
injection. A 10-20 mCi dose of FDG should be injected for typical adult patients. For 
longitudinal studies with multiple scans, particular attention should be paid to ensure 
consistent patient preparation and acquisition parameters between the follow-up scan and 
the baseline scan. When designing a study where PET scans are going to be utilized as 
one of the modalities to evaluate efficacy, it is important to consult with physicians in 
nuclear medicine in designing the appropriate criteria to be utilized. 
Note: In this protocol, PET scans are not to be used for primary assessment of 
response.  PET scans and/or PET-CT scans may be used to supplement CT or 
MRI scans when a clinical question as to response status still exists. 
Endoscopy, Laparoscopy. The utilization of these techniques 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 reference centers. 
However, such techniques may be useful to confirm 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 normal limit, they must normalize for a 
subject to be considered in complete clinical response. Specific additional criteria 
for standardized usage of prostate-specific antigen (PSA) and CA-125 response in 
support of clinical trials are being developed. 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 

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stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
10.1.4 
 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
node must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study with at least a 5 mm absolute 
increase in the sum of all lesions. The appearance of one or more new lesions* denotes 
disease progression.  
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
Note: If tumor response data is missing for target lesions, the overall assessment must be 
UN unless there is new disease that would result in an overall assessment of PD. 
However, if there is missing or unevaluable data for non-target lesions, but data is 
available for all target lesions, the overall response for that time point will be assigned 
based on the sum LD of all target lesions. Additionally, the assessment of CR cannot be 
made if there is missing or unevaluable data for non-target lesions. In this case, the 
overall assessment would be PR. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality, or findings thought to 
represent something other than tumor (ex: new bone lesions may be healing or flare of 
pre-existing lesions). However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a 
new lesion is equivocal (because of small size, etc.), follow-up evaluation will clarify if 
it truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered.  
10.1.5 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis).  

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Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a subject to be considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target 
lesions and/or maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions* (new lesions must 
be > slice thickness) and/or unequivocal progression of existing non-target lesions.  
Overall level of substantial worsening that merits discontinuation of therapy. A useful 
test that can be applied when assessing non-targets 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. 
 
Unknown (UN): Assessment of non-target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality, or findings thought to 
represent something other than tumor (ex: new bone lesions may be healing or flare of 
pre-existing lesions). However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a 
new lesion is equivocal (because of small size, etc.), follow-up evaluation will clarify if 
it truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered.  
10.1.6 
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). The participant's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for when 
Confirmation is Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not evaluated 
No 
PR 

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SD 
Non-CR/Non-
PD/Not evaluated 
No 
SD 
Documented at least once >4 
wks from baseline 
PD 
Any 
Yes or No
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note:   Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration". Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
NonCR/non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Non-CR/non-PD is preferred over stable disease for non-target disease since SD is increasingly used 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised.  
 
10.1.7 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) 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 overall complete response: The duration of overall CR is measured from 
the time measurement criteria are first met for CR until the first date that recurrent 
disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 

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10.1.8 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
until time of progression or death, whichever comes first.  Patients who stop protocol-
therapy (either ganetespib or fulvestrant or both) for a reason other than progression or 
death should be followed for progression, as detailed in Study Calendar D until the 
patient progresses, initiates alternative anti-cancer treatment, dies, or withdraws consent, 
whichever comes first.  If the initiation of non-protocol anti-cancer treatment occurs 
first, then the patient’s PFS will be censored at the time of last disease evaluation before 
start of the non-protocol anti-cancer treatment. 
10.1.9 
Overall Survival 
Overall survival is defined as duration of time from start of treatment to death due to any 
cause, or censored on the date last known alive. 
10.1.10 
 Response Review 
The study will use the DF/HCC Tumor Imaging Metrics Core (TIMC) for central 
protocol measurements.  For patients in Arm A, central confirmation of progression 
including DF/HCC TIMC review and confirmation by the overall study PI is required 
prior to crossover to Arm C and receipt of ganetespib. 
10.2 
Guidelines for Following Patients with Non-Measurable but Evaluable Disease 
 
Patients with non-measurable but evaluable disease will be evaluated for progression but not for 
objective response.  Bone progression is defined as a bone event requiring intervention (e.g., 
surgery/radiation), the occurrence of a pathologic fracture or the appearance of new lytic lesions 
or other new bone destruction thought to be related to cancer by X-ray, MRI, or CT scan.  
Changes in bone scan alone should not be used to define progression.  Disease “hot spots” 
detected on bone scan should be evaluated radiographically by X-ray, MRI, or CT scan to 
ascertain the presence of bone destruction versus a healing reaction.  The appearance of new 
lesions on bone scan may constitute progressive disease if associated with clinical symptoms 
suggestive of disease progression.  In cases of uncertainty, FDG-PET may also be used to 
provide additional data; however, it should be noted that early “flare” responses may suggest 
response to therapy rather than progression (Ellis et al, J Am Med Assoc 2009).  If a patient with 
bone-only disease progresses in another organ site per RECIST, that patient will also be counted 
as progressing. 
11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 
Definitions 
11.1.1 
Adverse Event (AE) 

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An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not considered to 
be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
11.1.2 
Serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that: 
  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
 Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of 
stay). Hospitalization admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not considered SAEs if the 
illness or disease existed before the person was enrolled in the trial, provided that it 
did not deteriorate in an unexpected manner during the trial (e.g., surgery performed 
earlier than planned). 
 Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not worsen 
 emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
 respite care 
11.1.3 
Expectedness 
Adverse events can be 'Expected' or 'Unexpected.'  
 

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Expected adverse event 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk.   
 
Refer to Section 6 for a listing of expected adverse events associated with the study 
agent(s). 
 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies 
in nature, intensity or frequency from information provided in the current adverse event 
list, the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk.   
11.1.4 
Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment.  
 Unlikely - The AE is doubtfully related to the study treatment. 
 Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 
Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded 
in the participant’s medical record and on the appropriate study-specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  

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11.3 
Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, each 
participating investigator is required to abide by the reporting requirements set by the DF/HCC. 
The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious adverse 
events to the study sponsor and/or others as described below.  
11.4 
Reporting to the Study Sponsor 
 
Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the DF/HCC Overall Principal 
Investigator on the local institutional SAE form. This includes events meeting the criteria 
outlined in Section 11.1.2, as well as the following: 
 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are unexpected and 
possibly, probably or definitely related/associated with the intervention. 
 
 All Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically 
listed in the protocol as not requiring reporting. 
 
 All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of continuing 
review.  
 
Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within 24 hours of learning of the occurrence. In the event that the 
participating investigator does not become aware of the serious adverse event immediately (e.g., 
participant sought treatment elsewhere), the participating investigator is to report the event 
within 24 hours after learning of it and document the time of his or her first awareness of the 
adverse event. Report serious adverse events by telephone, email or facsimile to: 
 
Nancy Lin, MD 
Tel: 617-632-2335 
Fax: 617-632-1930 
Pager: 617-632-3352, #42012 
Email: nlin@partners.org 

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Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. 
 
Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator on the 
toxicity Case Report Forms.   
11.5 
Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI 
Office for Human Research Studies (OHRS). 
 
Other investigative sites should report serious adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to: 
 
Nancy Lin, MD 
Tel: 617-632-2335 
Fax: 617-632-1930 
Pager: #42012 
Email: nlin@partners.org 
 
The DF/HCC Principal Investigator will submit SAE reports from outside institutions to the 
DFCI Office for Human Research Studies (OHRS) according to DFCI IRB policies and 
procedures in reporting adverse events.  
11.6 
Reporting to the Food and Drug Administration (FDA) 
 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA. The DF/HCC Overall Principal Investigator will report to the 
FDA, regardless of the site of occurrence, any adverse event that is serious, unexpected and 
reasonably related (i.e., possible, probable, definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 7 calendar days after initial 
receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
 
  

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Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-FDA-
0178) using Form FDA 3500A (Mandatory Reporting Form for investigational agents). Forms 
are available at http://www.fda.gov/medwatch/getforms.htm.  
11.7 
Reporting to Synta Pharmaceuticals, the Manufacturer 
 
All adverse events meeting the regulatory (21CFR Subpart B §312.32 and Section 11.1.2 of this 
protocol) definition of serious must be reported to Synta Drug Safety. 
 
Synta Drug Safety will provide SAE Report Forms and an SAE Completion Guideline for 
distribution by the Sponsor to each study site. 
 
Serious adverse events should be reported to Synta within 24 hours of learning of the occurrence.  
Notification of SAEs may be made initially by telephone at 1-866-255-0025.  All written reports 
and copies of source documents should be faxed to Synta Global Safety Surveillance at 1-888-
975-2207. 
 
In addition copies of all FDA 3500A MedWatch forms submitted to FDA will be sent to Synta 
Global Safety Surveillance by the DF/HCC Overall Principal Investigator.  
11.8 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
11.9 
Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention, throughout the study, and within 30 days of the last study intervention 
should be followed to their resolution, or until the participating investigator assesses them as 
stable, or the participating investigator determines the event to be irreversible, or the participant 
is lost to follow-up. The presence and resolution of AEs and SAEs (with dates) should be 
documented on the appropriate case report form and recorded in the participant’s medical record 
to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the 
SAE report (e.g., hospital discharge summary, consultant report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. Participating investigators should notify the DF/HCC 
Overall Principal Investigator and their respective IRB of any unanticipated death or adverse 
event occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study.   
 
 

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12. DATA AND SAFETY MONITORING 
12.1 
Data Reporting 
12.1.1 
Method  
The QACT will collect, manage, and monitor data for this study.  
12.1.2 
Data Submission  
The schedule for completion and submission of case report forms (paper or electronic) to 
the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of scheduled response 
evaluation 
Off Study Form 
Within 14 days of being taken off study for 
any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
12.2 
Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 

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days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
.  
12.3 
Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the DF/HCC 
Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or 
inspections is to examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately reported in 
accordance with the protocol, institutional policy, and any applicable regulatory requirements 
 
All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and will 
continue during protocol performance and completion.  Please refer to Appendix G: Data 
Safety Monitoring Plan for additional details. 
 
12.3.1 
Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center 
Data and Safety Monitoring Plan.  The specific responsibilities of the Overall PI, 
Coordinating Center, and Participating Institutions and the procedures for auditing are 
presented in Appendix G. 
 
The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 

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13. REGULATORY CONSIDERATIONS 
13.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
13.2 
Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. The 
participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file.  
13.3 
Ethics 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
 US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  

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 State laws 
 DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. In such case, the deviation must 
be reported to the IRB according to the local reporting policy.  
13.4 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays.  
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies.  
 
14. STATISTICAL CONSIDERATIONS  
14.1 
Background Data for Sample Size Justification 
 
This study will enter patients who have either relapsed within 1 year of completing adjuvant 
endocrine therapy and/or who have progressed through at least one line of metastatic endocrine 
therapy.  Patients who have previously received either fulvestrant or an HSP90 inhibitor are 
excluded.  There is no limit on the number of prior lines of metastatic endocrine therapy.  Up to 
one line of chemotherapy for metastatic disease is allowed. 
 
The EFECT trial entered patients with ER-positive metastatic breast cancer who have progressed 
on a non-steroidal aromatase inhibitor.4 Patients were randomized to receive fulvestrant versus 
exemestane.  Approximately 60% of patients had received 2 or more prior lines of hormonal 
therapy (adjuvant + metastatic).  Median time to progression was 3.7 months in both groups.  
Overall response rate was similar (7.4% v 6.7%; p=0.74).  Clinical benefit rate (CR + PR + SD > 
6 months) was also similar (32.2% v 31.5%; p=0.85).  The proportion of patients who came off 
study for a reason other than progression was not specifically reported in this study.  However, at 

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the time of study reporting, 82% of the fulvestrant group and 87% of the exemestane group had 
experienced a defined progression event.   
 
CALGB 40302 entered patients with ER-positive metastatic breast cancer who had previously 
been treated with an aromatase inhibitor, up to 2 lines of endocrine therapy for metastatic 
disease, and up to 1 prior line of metastatic chemotherapy.5  Patients were randomized to 
fulvestrant with or without lapatinib.  The study was terminated early for futility after the third 
planned interim analysis.  Approximately half of patients had received prior tamoxifen; 28% of 
patients had bone-only disease. Median progression-free survival in the fulvestrant alone arm 
was 4.0 months. 
14.2 
Primary Clinical Objective and Sample Size Justification 
 
Progression Free Survival (PFS): Progression-free survival is defined as time from 
randomization until time of progression or death, whichever comes first.  Patients who stop 
protocol therapy (either fulvestrant or ganetespib or both) for a reason other than progression or 
death should continue to be followed for progression per Study Calendar D.  For subjects who do 
not progress or die, PFS will be censored at the time of last tumor evaluation before initiation of 
alternative anti-cancer treatment.   
 
Analysis Population: All randomized patients will be included in the analysis of PFS.  The 
analysis will be conducted based on intention to treat (ITT).  However, data imputation will not 
be used for PFS.  So patients with no follow-up at all will be censored for PFS at the date of 
randomization.  
 
If the interim safety analysis indicates that the starting dose of ganetespib should be decreased to 
175 mg/m2, these patients will be combined with the patients who received a starting dose of 200 
mg/m2 in the ITT analysis.  That is, all randomized patients will be included in the ITT analysis, 
regardless of starting dose and regardless of whether or not treatment was stopped early for any 
reason. 
 
Power Calculation 
 
The primary objective of this randomized, phase II study is to investigate whether ganetespib, 
when given in combination with fulvestrant, improves progression-free survival (PFS) compared 
to fulvestrant alone, in patients with ER-positive, metastatic breast cancer. This study will have a 
1:2 randomization ratio: 24 patients will be randomized to Arm A (fulvestrant alone) and 47 
patients will be randomized to Arm B (fulvestrant + ganetespib), for a total of 71 randomized 
patients.  The expected accrual rate is ~3.5 to 4.5 patients per month over a period of ~20 
months. 
 
As this is an exploratory phase II study, no interim efficacy analyses are planned and there are no 
early stopping rules for efficacy (or lack of efficacy) in this study. 
 
The primary comparison will be a one-sided log rank test of whether PFS is longer in patients 
randomized to Arm B (fulvestrant + ganetespib) than those randomized to Arm A (fulvestrant).  

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A maximum of 20% of patients (n=14) on this trial may be entered on the strata for patients with 
non-measurable but evaluable disease (a category which includes but is not limited to patients 
with bone-only disease).  The primary comparison will not be stratified by type of disease 
(measurable or non-measurable) because the stratification is being used as a mechanism to limit 
the number of patients with only non-measurable disease.   
 
Based upon data from the EFECT trial, we further assume that up to 11 patients (15%) may be 
censored for PFS because of being lost to follow-up or receiving non-protocol anti-cancer 
therapy before they have progressed or died, and that this probability is not different in the two 
arms.4 To be conservative, we assume that this censoring occurs very close to the time that the 
patient enters the study, so the effective total sample size will be 60, with 20 patients randomized 
to fulvestrant alone and 40 patients randomized to fulvestrant + ganetespib. 
 
Assuming that PFS has an exponential distribution, and that the true median PFS on Arm A 
(fulvestrant alone) is 4.0 months, and that accrual takes 20 months (3.5 patients per month), there 
will be 80% power to detect a prolongation of true median PFS to 8.0 months in Arm B 
(fulvestrant + ganetespib), using a one-sided 0.05 log-rank test if the patients are followed for 20 
months after accrual ends (so, 40 months after accrual starts).  If accrual takes only 15 months 
(4.5 patients per month) and follow up extends to 22 months after accrual ends, there will also be 
80% power.  If the true median PFS on the single agent arm is longer than 4 months, the power 
calculations will still be correct as long as the ratio of medians remains the same (e.g. true 
medians of 5 and 10 months will have the same power as the true medians of 4 and 8 months, 
provided that the patients are followed long enough to have the same number of expected PFS 
events, which is 57). 
14.3 
Interim Safety Analysis 
 
There are no phase I data with the combination of fulvestrant and ganetespib.  Based upon the 
observed toxicities to date, mechanism of action, and drug metabolism, no additive or synergistic 
toxicities are anticipated.  However, an interim safety analysis will be conducted among the first 
10 patients randomized to Arm B (fulvestrant + ganetespib) and who receive at least one dose of 
ganetespib.  No interim safety analysis will be conducted in patients randomized to Arm A, as 
fulvestrant is an approved agent in this setting with a very well-described toxicity profile.  
Accrual to the study will be placed on hold while the interim safety analysis is being conducted 
and results of the interim safety analysis will be submitted for review and approval by the 
DF/HCC IRB prior to re-opening the study for continued accrual. 
 
DLT is based on the CTEP Active Version of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v4.0). DLT refers to toxicities experienced during the first cycle of 
treatment. A DLT will be defined as follows: 
 Grade 3 or higher hematologic or non-hematologic toxicity thought likely or 
definitely related to protocol therapy will be counted as a DLT, with the exception of: 

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o Grade 3 diarrhea that responds to maximal supportive measures.  If grade 3 
diarrhea is persistent > 7 days despite maximal supportive measures, it will 
be counted as a DLT 
o Grade 3 fatigue 
o Grade 3 hot flashes 
o Grade 3 electrolyte disturbance, unless persistent > 7 days despite maximal 
supportive measures.  
 
All DLTs will be adjudicated by the study Principal Investigator and shared with the Synta 
medical monitor. 
 
If more than 2 of the first 10 patients randomized to Arm B who receive some ganetespib have a 
DLT during the first cycle of therapy, study accrual will be temporarily suspended and the events 
will be adjudicated.  Results will be shared with patients already enrolled on study, but they will 
be allowed to continue on therapy.   
 
With this design, the probability of stopping accrual at or before 10 patients is 0.18 if the true 
DLT rate is 15%, 0.68 if the true DLT rate is 20%, and 0.90 if the true DLT rate is 45%. 
 
If more than 2 patients of the first 10 have confirmed DLTs, the study will then re-open at Dose 
Level -1.  If more than 2 of the first 10 patients randomized to arm B at Dose Level -1, study 
accrual will be temporarily suspended and the events will be adjudicated.  If the events are 
confirmed by the Principal Investigator to be true DLTs, the study will close permanently to new 
accrual.  Results will be shared with patients already enrolled on study, but they will be allowed 
to continue on therapy.   
 
With this design, the probability of stopping accrual at or before 10 patients at Dose Level -1 is 
0.18 if the true DLT rate is 15%, 0.68 if the true DLT rate is 20%, and 0.90 if the true DLT rate 
is 45%. 
14.4 
Analysis of Secondary Clinical Endpoints 
 
Safety and toxicity: All patients who received at least one dose of protocol therapy (fulvestrant, 
ganetespib, or both) will be included in the safety/toxicity analysis.  Toxicity will be graded 
according to NCI CTCAE, Version 4.0.  The proportion of patients who experience each type 
and grade of toxicity will be presented in tabular form.  Toxicity will be described separately in 
Arm A (pre-crossover), Arm C (post-crossover), and Arm B. 
 
Objective Response Rate: All patients with measurable disease at baseline will be included in the 
analysis of response rate.  Response will be assessed using RECIST 1.1, as described in Section 
10.  The response rate will be calculated separately in Arms A, B, and C.  Response rates in Arm 
A and Arm B will be compared using a one-sided Fisher exact test.  An intent to treat analysis 
will be used, so all patients randomized in the measurable disease stratum will be used in the 

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analysis; patients with no follow-up response evaluation will be assumed to be non-responders.  
Assuming that 57 patients are entered in the measurable disease stratum, there will be 81% 
power to decide that the ganetespib arm has a better response rate if the true response rates on the 
two arms are as different as 36% and 5%, or 44% and 10%. 
 
Clinical benefit rate: Clinical benefit will be defined as CR + PR + SD>/= 6 months.  All patients 
will be included in the analysis of clinical benefit.  CBR will be calculated separately in Arms A 
and B, and compared using a one-sided Fisher exact test.  All patients randomized on study will 
be used in this analysis, and patients with no follow-up response evaluation will be assumed not 
to have clinical benefit.  With 71 patients randomized, there will be 80% power to decide that the 
ganetespib arm has a better clinical benefit rate if the true benefit rates on the two arms are as 
different as 63% and 30%, or 73% and 40%. 
 
Overall survival: Overall survival is defined as duration of time from randomization to death due 
to any cause, or censored on the date last known alive. All randomized patients will be included 
in the analysis of OS.  OS will be estimated separately in Arm A and Arm B.  OS will be 
analyzed at the same time as the final analysis of PFS, although it is acknowledged that the 
percent of survival censoring at that time will be larger than the percent of PFS censoring, and 
this will limit the power to detect survival differences between the arms. 
14.5 
Analysis of Correlative Endpoints 
 
The proposed studies of whether any markers are predictive or prognostic are exploratory and 
primarily hypothesis-generating in nature.  For this reason, there will be no adjustment for 
multiple comparisons.   
14.5.1 
HSF1 and Outcome 
The primary correlative objective is to test whether high nuclear expression of HSF1 
nuclear localization (as assessed in archival breast tumor samples) is associated with PFS, 
separately in the fulvestrant only arm (i.e., the single agent arm) and the ganetespib plus 
fulvestrant arm (the combination arm). It is possible that the direction of the relationship 
between HSF1 and PFS is different in each arm, so we will test this hypothesis separately 
in the two arms.  We hypothesize that high nuclear expression of HSF1 could be 
predictive of poor outcome in the fulvestrant-treated patients but could be predictive of 
improved outcome in patients treated with the combination of fulvestrant and ganetespib.   
 
For the power calculations, we assume that the direction of effect could be in either 
direction for each of the treatment arms and we will use a two-sided test. We assume that 
all patients have tissue for analysis. Archival metastatic specimens will take priority over 
archival primary tumor, in situations when both are available.  We will analyze the 
relationship of HSF1 (dichotomized as high positive versus low positive/negative) with a 
dichotomized variable for PFS (above/below median PFS calculated in each group 
separately).  It is not known what the frequency of HSF1 high positivity is in patients 
with metastatic disease.  However data from primary tumor specimens in the Nurses’ 
Health Study indicate that 23% of ER+ tumors are HSF1 negative, 48% are HSF1 low, 
and 28% are HSF1 high.   It is expected that the percent of patients with high nuclear 

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expression of HSF1 in metastatic specimens will be larger than the percent of primary 
patients with high nuclear HSF1 expression.  It is also possible that patients who develop 
metastases are more likely to have high nuclear HSF1 expression in their archival 
primary tumor specimens than are patients who do not develop metastases.  So it seems 
justified to assume that more than 28% of the patients on this study will have high 
nuclear HSF1 expression in their archival specimens.  We assume that the percentage of 
patients entered on this study who have high nuclear HSF1 expression in archival 
specimens will be between 30% and 50%. 
 
In these calculations, a two-sided significance level of 0.05 is used.  The minimal 
acceptable power is assumed to be 80%.  Because of the small sample sizes, sometimes a 
power between 81% and 83% was the smallest attainable power that was 80% or greater. 
 
The primary analysis for the association of high nuclear expression of HSF1 and PFS will 
be based on a two-sided Fisher exact test of whether HSF1 high positivity is associated 
with a larger or smaller percent of patients with PFS greater than the median PFS on that 
arm.  So, if the two arms of the study have different medians, then this comparison will 
be based on different medians in each group.  This also means that in each arm (with the 
possible exception of the 11 out of the 71 total patients who may be lost to follow-up or 
begin non-protocol anti-cancer therapy before progression), at the time of analysis all 
patients will have had a PFS event before the group median or else be followed for PFS 
at least past the median PFS on that arm.  (As a further secondary analysis, we will 
examine the time to PFS event for HSF1 high positive and HSF1 low positive/negative 
patients, separately for the two arms.  However, we do not now have estimates of the 
distribution of time to PFS that are sufficiently robust for the two arms to allow us to do 
power calculations on this method of analysis.) 
 
The power tables below show the range of differences that could be detected given the 
assumptions above.   
 
For single-agent arm (fulvestrant alone): 
 
 
 
50% have high nuclear HSF1 
expression 
30% have high nuclear HSF1 expression 
Total 
N 
Rando 
Ratio 
This 
Arm 
N 
Number 
HSF1 high 
pos 
Detect. 
Diff. 
True %s 
PFS > Med
Number 
HSF1 high 
pos 
Detect. 
Diff. 
True %s  
PFS > Med 
True %s  
PFS > Med 
60 
1:2 
20 
10 
68% 
84%, 16% 
6 
67% 
97%, 30% 
70%, 3% 
 
For combination arm (fulvestrant plus ganetespib): 
 
 
 
50% have high nuclear HSF1 
expression 
30% have high nuclear HSF1 expression 
Total 
N 
Rando 
Ratio 
This 
Arm 
N 
Number 
HSF1 high 
pos 
Detect. 
Diff. 
True %s 
PFS > Med
Number 
HSF1 high 
pos 
Detect. 
Diff. 
True %s  
PFS > Med 
True %s  
PFS > Med 
60 
1:2 
40 
20 
50% 
75%, 25% 
12 
52% 
86%, 34% 
66%, 14% 

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14.5.2 
Comparisons of fulvestrant and ganetespib effects in cycle 2 day 9 biopsy tumor 
tissue 
We will collect cycle 2 day 9 biopsies (required in patients with biopsy-accessible 
disease, see Section 3.1.14 and Section 8.1) to assess the effect of fulvestrant alone versus 
fulvestrant plus ganetespib within tumor specimens.  This time point for the research 
biopsy was chosen to allow adequate time for fulvestrant to reach steady-state levels and 
to permit HSP90 client proteins modulating growth and survival to be destabilized by 
ganetespib, thereby inducing downstream transcriptional changes.   
 
We assume that 20% of patients entered on study will have biopsy-inaccessible disease 
and that biopsies will not be done on these patients.  We assume that 60% of patients who 
undergo biopsies will have informative tissue for analysis.  Therefore, we assume that 
48% (0.80 x 0.60) of patients accrued to the trial will have tissue available for this 
analysis.   
 
We will compare the expression of ER, PR, AR, EGFR, HSF1,  and HER2 by 
immunohistochemistry (IHC) and amplification of EGFR and HER2 using fluorescence 
in situ hybridization (FISH) to assess the effect of fulvestrant alone versus fulvestrant 
plus ganetespib within tumor specimens.   
 
For this analysis, each of the markers will be described as “positive” or “negative”.  For 
ER, PR, AR, and EGFR, “positive” will be defined as  ≥ 1% nuclear staining (which 
includes low positive and well as high positive) and “negative” will be defined as < 1% 
nuclear  staining.  For HSF1, “positive” will be defined as either 2+ staining or  1+ 
staining, and “negative” as no staining or rare cells positive (Santagata et al, manuscript 
in preparation).  For HER2, we will use the standard 0-3+ scale, where categories 0, 1+, 
or 2+ count as negative and category 3+ counts as positive.  For EGFR and HER2 
amplification, FISH ratio > 2.0 will be considered positive and FISH ratio < 2.0 will be 
considered negative.  For each of these eight biologic markers, among patients who have 
usable tissue from the cycle 2 biopsy, we will test whether the fulvestrant arm or the 
fulvestrant plus ganetespib arm has a larger percent of patients with the positive category 
of the marker.  This will be done with a two-sided Fisher exact test with significance 
level of 0.05.  The minimal acceptable power was assumed to be 80%.  Because of the 
small sample sizes, sometimes a power between 81% and 84% was the smallest 
attainable power that was 80% or greater. The power calculations assume that overall 
(both treatment arms combined), between 35% and 65% of patients would be in the 
positive category. 
 
The power table below shows the types of differences that could be detected between the 
arms, given the assumptions above.  While the tests are two-sided, because there are only 
half as many patients on the fulvestrant alone arm as are on the fulvestrant plus 
ganetespib arm, the differences that have power are slightly different depending on which 
arm is truly associated with a larger percent of patients with positive biomarker result. 
 

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48% of Patients with Usable Metastatic Tissue:  True Treatment Difference 
in Percent of Patients with Positive Marker Detectable with Two-Sided Fisher Exact Test 
 
50%  Specimens are Positive 
35% are Positive 
N 
N 
with 
Tissue 
Arm with 
More 
Patients 
with 
“Positive” 
Marker  
N with 
Positive 
Marker 
Detect. 
Diff. 
True % 
Positive 
Marker 
Combo, Single
N with 
Positive 
Marker 
Detect 
Diff. 
True % 
Positive 
Marker 
Combo, Single
60 
28 
Combo 
14 
58% 
71%, 13% 
10 
54% 
55%, 1% 
60 
28 
Single 
14 
59% 
29%, 88% 
10 
58% 
15%, 73% 
 
All of the other categorical correlative objectives based on the cycle 2 biopsy or (e.g., 
comparing the two arms by assessing a set of genes using a Nanostring custom code set 
each categorized as increased, decreased, or neutral) will also be compared using a two-
sided Fisher exact test, but it isn’t easy to describe the detectable difference for outcomes 
that have three categories rather than two categories of biomarker results.  Fisher exact 
tests and descriptive statistics will be used to explore the relationship of biomarker results 
obtained from different types of specimens (cycle 2 biopsy, archival tissue, CTCs, and 
optional biopsies at the time of progression), both overall and within treatment arm.  With 
only 28 patients treated on the two arms expected to have usable tissue from the cycle 2 
biopsy, and with some of these patients expected to not have usable tissue from the other 
specimens sources, most of these comparisons will have very little power.   
 
Exploring the relationship of PIK3CA mutations and other oncogenes and PFS in each 
arm separately may involve a few Kaplan-Meier curves and a few log rank tests, but with 
only 43 patients treated on both arms combined with a PFS event at the time of analysis, 
and with some of these patients not having usable biopsy tissue, this exploration may be 
based mostly on tables of estimated medians of time to PFS event.  
14.6 
Reporting and Exclusions 
14.6.1 
Evaluation of toxicity.  
All participants will be evaluable for toxicity if they received any protocol therapy. 
14.6.2 
Evaluation of response.   
All participants randomized on the study who have RECIST measurable disease must be 
assessed for response to treatment, even if there are major protocol treatment deviations, 
or they receive no treatment, or if they are ineligible.  Participants who have no follow-up 
tumor evaluations, who die or receive non-protocol anticancer therapy before a response 
is noted, or who have unknown or not-assessable response will count as non-responders. 

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14.6.3 
Evaluation of progression-free survival.   
All participants randomized on the study must be assessed for PFS, even if there are 
major protocol treatment deviations, or they receive no treatment, or if they are ineligible.  
However, there will be no imputation of any missing progression-free survival times.       
  
 
  
14.6.4 
Analyses of Subsets of Patients.  
For all endpoints except toxicity, the primary analysis will be based on all randomized 
patients (and the primary analysis of toxicity will be based on all patients who receive at 
least one dose of one of the study agents).  However, in addition to the primary analysis, 
analysis of subsets of patients may be done (e.g., analysis restricted to eligible patients or 
to patients who receive at least one cycle of therapy).  However, these analyses of subsets 
will be considered exploratory and will not serve as the basis for drawing conclusions 
about treatment efficacy. 
 
15. PUBLICATION PLAN 
The data will be collected and analyzed by Dr. Nancy Lin, in conjunction with a DFCI 
biostatistician, and key co-investigators.  The results with be shared with Synta Pharmaceuticals.  
It is anticipated that results will be made public within 12 months of the end of data collection.  
Initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors.  The primary endpoint of the study will not be reported until the study 
is closed to accrual and the protocol-specified follow up period has elapsed.  A report will also 
be published in a peer-reviewed journal.  A full report of the outcomes will be made public no 
later than three years after the end of data collection.

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21. 
Board RE, Wardley AM, Dixon JM, et al: Detection of PIK3CA mutations in 
circulating free DNA in patients with breast cancer. Breast Cancer Res Treat 120:461-7 
 
22. 
Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, 
and survival in metastatic breast cancer. N Engl J Med 351:781-91, 2004 
 
23. 
Flores LM, Kindelberger DW, Ligon AH, et al: Improving the yield of circulating 
tumour cells facilitates molecular characterisation and recognition of discordant HER2 
amplification in breast cancer. Br J Cancer 102:1495-502, 2010 
 
 
 
 

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116 
 
17. APPENDICES  
 
Appendix A: Performance Status Criteria 
Appendix B: Cross Sectional Interventional Radiology-for BWH Use Only 
Appendix C: Tissue and Blood Acquisition Guideline-for DFCI and BWH Lab Use Only 
Appendix D: Tissue Specimen Release Form 
Appendix E:  How to Collect Blood Using PAXgene RNA tube 
Appendix F: Streck Collection and Processing Instructions-for DFCI Lab Use Only 
Appendix G: Data Safety Monitoring Plan 
Appendix H: Histology Laboratory Project Request Form 
Appendix I: List of Drugs Known to Predispose to Torsades de Pointes 
Appendix J: 11-477 Specimen Requisition (Archival Tissue Blocks/Slides and CTC Samples) 
Appendix K: 11-477 Specimen Requisition (Biopsy/Research Blood) 
Appendix L: 11-477 Specimen Requisition (PBMC Tubes) 
 
 

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- 117 - 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
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. 
 

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119 
APPENDIX B 
Cross-sectional Interventional Radiology Service 
Division of Abdominal Imaging and Intervention 
Department of Radiology 
Brigham and Women’s Hospital 
 
Experimental Protocol:  DFCI 11-477: Fulvestrant +/- ganetespib for ER+ Breast Cancer 
 
PI: Nancy Lin, MD DFCI pager # 42012 
 
CIS MD Coordinator:  Stuart Silverman, MD 
 
Study Coordinators:  Danielle Gore, Tel: 617-632-4870, DFCI Pager # 40503 
 
Study Nurses: Kathleen Roche, Elizabeth Kasparian, Margaret Haldoupis, Mary O’Driscoll, 
Myra St. Amand, and Elizabeth Tiani.  Main office tel: 617-632-3478. 
 
Sites likely to be biopsied: abdomen, pelvis, lung, bone, lymph nodes, peritoneal fluid, pleural 
fluid 
 
Synopsis:  The goal of this clinical protocol is to collect tissue specimens from areas of loco-
regional and distant metastases in patients with metastatic breast cancer being treated on a 
clinical trial of fulvestrant alone versus fulvestrant plus ganetespib.  These specimens will 
ultimately be used to assess the effects of endocrine therapy alone versus endocrine therapy plus 
on Hsp90 inhibitor on a variety of DNA, RNA, and protein levels. 
 
Coordination/Preparation:   
Arranged through Percipio order entry system. The fact that it is a research biopsy must be 
indicated in Percipio along with the F number and the DFCI protocol number in Percipio. Study 
coordinator will specify in the Percipio order the biopsy time point. The order should specify the 
F number, and which organ is preferred, but should also state that the interventionalist has the 
discretion to choose a different site if thought to be safer or higher yield. If there is a question 
regarding the biopsy, the abdominal CSIR attending can be consulted before or after the order is 
placed.   
 
DFCI personnel will be responsible for making sure that that patient has obtained a blue card 
(obtained via telephone 1-866-189-4056, that images are available for the CSIR team to review 
in advance of the Percipio request, arranging for appropriate blood work to be drawn (PT/INR, 
PTT, CBC), and notifying patients that 1) they should be expected to arrive 1 hr in advance of 
the biopsy, 2) the procedure will take approximately one hour, and 3) the recovery may last 4-6 
hours or longer. Also they should be notified that someone will need to be available to drive 
them home. Additional instructions will be provided by the CSIR nursing staff.  For questions, 
call CSIR coordinators at 617-732-7785. DFCI team will be present for procedure and to 
transport tissue, provide materials, fixatives, and requisitions. The DFCI study coordinator will 
receive and transport research specimens to the appropriate labs. 
 

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Special Needs:  Off Coumadin x 5 days and then recheck labs.  Patients should be off ASA for 
at least 5 days, or heparin (e.g., fragmin, Arixtra (LMW Heparin compound)) or NSAIDs for 
more than 48 hours. If there are risks of stopping these medications, these should be discussed 
with other care providers by DFCI personnel before the referral to CSIR. 
 
Billing:  Funding is provided by a Komen grant.  F # 8151631.  Contact for billing:  Thomas 
Deveau or James Huse, Clinical Trials Business Office, Ph 617-582-8406 or 617-632-6144, 
DFCI BP332A. 
Note:  Less than the goal quantity of tissue is accepted for each type of biopsy, and will be left to 
the clinical judgment of the physician performing the procedure. Procedure (if not bone): 
 
Set 
Needle             # Sample Preparation     
Destination 
1         18-20G cores*     3-6                Dry/cup    DFCI SM932 
 
  
 
 
    
 
 
DFCI pager# 49233 for pick up/processing.                     
*use 18G if safe to do so. Can use 20G or obtain fewer specimens, at discretion of 
interventionalist for safety reasons   
*if for safety reason only 22G fine needle aspiration biopsies are thought possible (whether per 
treating physician or interventionalist), then use the following protocol: 
 
Set 
Needle      # Sample   Preparation    Destination 
  1       FNAB            3*  
            *           DFCI SM932  
 
 
  
 
               DFCI pager# 49233 for pick up/processing.                                      
     
*Special notes regarding sample collection/preparation:                                                                 
1. One pass should be evacuated and rinsed directly into 2mL of room temperature Trizol for 
RNA analysis. 
2.  One pass should be evacuated and rinsed directly into 2mL of room temperature Trizol for 
DNA or RNA analysis. 
3.  One pass should be evacuated and rinsed directly into 10-20mL of RMPI to prepare a cell 
block 
 
 Procedure (bone ONLY): 
 
Set 
    Needle    # Sample   Preparation   Destination 
  1           11-13G          1-3     Dry/cup   DFCI SM932  
 
 
  
 
                 DFCI pager# 49233 for pick up/processing.                                    
                                                                     
  

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Procedure (Paracentesis or Thoracentesis) 
 
Set 
 
Needle    # Sample      Preparation     
 
 
Destination 
  
     Standard collection       DFCI SM932  
  1               *            500cc          tube/bottle    
 
      DFCI pager# 49233 
  
  
 
 
 
 
 
 
 
 
for pick-up/processing 
  
 
 
 
 
 
 
 
 
               
 
 
          
                              
 
                                                   
*As clinically indicated. 
  
 
 
SGS rev 6-18-12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C:   
Tissue and Blood Acquisition Guidelines 
FOR DANA FARBER CANCER INSTITUE AND BRIGHAM& WOMEN’S HOSPITAL LAB USE ONLY 
 
For Biopsies of Soft Tissue, Liver, Bone, Breast, Etc. 
 
1. After biopsy is performed, the tissue mass is placed on a sterile gauze 
2. Using forceps, separate the tumor tissue 
3. Place 2 pieces (cores) of tumor tissue on a pre-frozen bed of OCT in each cassette (typically end up with 3 
cassettes per biopsy); the last cassette will contain many small pieces of tumor tissue 
4. Fill cassettes with OCT 
a. 
Completely cover tissue with additional OCT 
b. Limit the amount of bubbles 
5. Tissue must be frozen immediately by placing  cassettes on dry ice in a biohazard cooler  
6. Transport samples to the lab (Smith building, 9th floor, Room SM-948) and complete freezing of samples in 
OCT with dry ice (about 10 minutes freezing time) 
7. Once samples are frozen, place in plastic bag; label bag with date, protocol number, patient number, and 
number of initials included 
8. Store in –80C freezer 
 
 
For Effusions and Ascites 
 
Email notification should be sent to Danielle Gore at dgore@partners.org to arrange sample pick up.  
 
Samples are to be collected in a sterile vacutainer.   
 
The coordinator will pick up ascites/ pleural fluid from BWH Cytology for cell pellet processing in Dr. Richardson’s 
lab (Smith building, 9th floor, Room SM-948) 
Fluid sample should be split into three equal aliquots.   
 
One aliquot should be spun down into a pellet and snap frozen in an ETOH/dry ice bath or in liquid N2.  This 
sample is stored in Dr. Richardson’s lab and should be registered in caTissue Blood Tissue Bank. 
 
One aliquot should be spun down into a pellet and fixed by Dr. Richardson’s lab,, and processed as a standard cell 
block by the Specialized Histopathology Services at BWH (Thorn building, 6th floor, Rooms 604/603B) .  The 
request for a standard cell block is submitted online through the DF/HCC Research Pathology Cores website: 
http://genepath.med.harvard.edu:8080/pathcore/ and it should specify: Specialized Histopathology Services (SHL):  
Cell paraffin block preparation from ascites/pleural fluid. Then, the fixed sample is taken to the Specialized 
Histopathology Services at BWH for processing as a standard block along with a print out of request, (Note: if the 
sample preparation is done by a clinical cytopathology laboratory, it is important to explain that the sample is for 
research purposes only and that no thin prep should be performed as this uses up a significant portion of the sample.) 
 
One aliquot should be spun down into a pellet that should be washed and re-suspended in PBS, and then transferred 
into Cell Save preservative tubes (7.5 mL) in the research lab. Samples should be submitted together with a 
Circulating Tumor Cell Core Facility request form to BWH CTC Core Facility.  
 
 
Pleural fluid samples can be transported and stored at room temperature (15-30 oC) up to 72 hours 
before processing. Do not refrigerate or freeze the sample. Samples must be processed within 72 hours of collection, 
but best results are obtained if the sample is processed as soon as possible.  

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For Fine Needle Aspiration Samples 
 
For patients who undergo fine needle aspiration (FNA), 3 passes should be collected: 
 
The first pass should be evacuated and rinsed directly into 2mL of room temperature Trizol to collect the RNA; a 
second pass should be evacuated and rinsed directly into another 2mL of room temperature Trizol to collect the 
DNA; the last pass should be evacuated and rinsed directly into 10-20mL of RPMI and prepared as a cell block. 
 
The 2 samples suspended in trizol are to be brought to April Greene-Colozzi in Dr. Richardson’s lab (Smith 486) for 
RNA & DNA analysis. The 1 aliquot in RPMI should be spun down into a cell pellet, washed and resuspended in 
ethanol (by Richardson lab), and brought to Cytopathology: 
 
Brigham and Women’s Hospital 
Medical Research Building, Room 306 
c/o Joyce Bookbinder 
617-732-4715 
 
Appendix H should accompany the sample. Sample should be labeled with a BOT number (assigned by Richardson 
lab; must be requested from April).  
 
Joyce’s team will create the block and send it to Histology to embed in paraffin. When complete (appx 24 hours), 
the block is ready for pickup. 
 
Block is picked up Amory 3 Histology in BWH. 
 
For CTC Samples 
 
Blood samples are to be collected at at the timepoints specified in the Specimen Submission Calendar (Section 9.5). 
. Samples may be drawn Monday through Friday but not the day before a holiday (unless prior arrangements to 
receive the sample have been made).   
 
1.   Samples are to be collected in Cell Save preservative tubes (7.5 mL).  Label tube with sample identifier / study 
ID number, protocol number, time point, and date of collection.   
2.  Draw a minimum of 5 mL of blood/tube (required in order to process the sample). 
3.  Gently invert each tube 4 times to ensure proper mixing of the blood with the fixative. 
4.  Blood samples can be shipped/transported and stored at room temperature (15-30 oC) up to 72 hours 
before processing. Do not refrigerate or freeze the sample. Samples must be processed within 72 hours of collection, 
but best results are obtained if the sample is processed as soon as possible.  Samples should be submitted with a 
CTC request form. Do not submit clotted samples or samples containing less than 4ml of blood. Samples should be 
shipped by same day courier or overnight parcel directly to: 
  
 
Dana-Farber Cancer Institute 
Attn:  Danielle Gore 
450 Brookline Ave., DA157 
Boston, MA 02215 
  
Email notification should be sent to dgore@partners.org prior to shipment of sample.  Danielle will send a reply 
email to confirm receipt of the sample. 
 
 
Blood for Germline DNA 
 

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124 
One 10 mL lavender top tube will be collected at baseline and banked in order to extract germline DNA to be used 
as normal DNA reference for tumor tissue-based studies. 
 
 
Blood for cfDNA: 
 
One 10 mL Streck tube will be collected at the timepoints specified in Section 9.5, Specimen Submission Calendar.  
The tube must be filled completed and gently inverted 8-10 times immediately after collection.  Blood collected in 
the Streck tube can be stored for 14 days between 6-37 degrees C and can be mailed at room temperature.   
 
 
Blood for PBMC samples 
 
Blood will be drawn into two PAXgene blood RNA tubes (ref #762165) from Qiagen/BD.  After the blood draw, 
samples will sit at room temperature for two hours and then sit for 24 hours in a -20º C freezer.  Following this, 
samples will be stored at -80º C until several samples have accumulated. Blood samples are to be collected at the 
timepoints specified in Section 9.5, Specimen Submission Calendar. Samples will be stored at -80º C until pick-up is 
coordinated with a member of Dr. Whitesell’s laboratory at Whitehead Institute for Biomedical Research in 
Cambridge, MA.   
 
 
  

 
125 
 
 
 
CIRCULATING TUMOR CELL CORE LABORATORY - REQUISITION FORM 
Alarice Lowe, M.D., Director 
75 Francis St., MRB-315 
Boston, Massachusetts 02115 
                                                                  Tel: 617-525-8696   Fax: 617-739-6192   aclowe@partners.org 
 
REQUIRED CLIENT INFORMATION:  
 
Billing Information : 
Principal Investigator_________________ 
Additional Contact___________________  
 
Partners Institutions: 
Results via mail, fax, or both: __________  
 
PeopleSoft Business Unit:__________ 
Address____________________________  
 
Fund #_____________ 
             ____________________________             Partners Fund end Date:_________ 
Fax_______________________________ 
Email______________________________  
 
All Others (including DFCI):  
Telephone__________________________  
 
Email Invoice to:____________________ 
 
 
* Enumeration uses an Epithelial Cell Kit and provides a numerical result. 
 
* Profile Kit isolates cells for downstream analysis. 
 
For Lab Use Only: 
Tube 
Sample ID #  
Protocol # 
Draw 
Date 
Draw 
Time 
Service Requested (check one)* 
1 
 
11-477 
 
 
 Enumeration 
 Profile Kit (select one) 
       cytospin - methanol fixation 
       cytospin - 3:1 fixation 
       cytospin - air dried 
       tube 
2 
 
11-477 
 
 
 Enumeration 
 Profile Kit (select one) 
       cytospin - methanol fixation 
       cytospin - 3:1 fixation 
       cytospin - air dried 
       tube 
3 
 
11-477 
 
 
 Enumeration 
 Profile Kit (select one) 
       cytospin - methanol fixation 
       cytospin - 3:1 fixation 
       cytospin - air dried 
       tube 
Date and time processed 
Initials/Comments 

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126 
 
Appendix D 
Tissue Specimen Release Form 
[Date] 
Dear «FName» «MName» «LName»: 
Thank you very much for your participation in “DFCI 11-477: Randomized Phase II Trial of 
Fulvestrant versus Fulvestrant + Ganetespib for Hormone Receptor-Positive Breast Cancer.”  In 
order to study the biology of breast cancer, we need to examine actual tumor specimens 
potentially evaluating molecular and genetic markers that may help us further understand why 
some tumors respond to certain treatments but others do not.  The research sample we have 
collected from your biopsy, coupled with samples of existing stored tumor specimens from 
pathology departments will make potential biological studies uniquely valuable. 
 
We are therefore attempting to obtain existing tissue blocks and slides available from previous 
procedures (such as biopsies or surgeries).  We hope you will agree to help in this research effort 
by reading the attached HIPAA notice and signing the specimen release form below.  We will 
then contact the institution(s) where you had your surgery (-ies).   
 
Thank you very much for your cooperation.  If you should have any questions about this study, 
please do not hesitate to contact Clinical Research Coordinator, TBD at DFCI at <add phone, 
add email>. 
 
Sincerely, 
 
 
 
Nancy Lin, MD 
Principal Investigator 
------------------------------------------------------------------------------------------------------------ 
I have read the attached HIPAA information regarding my protected health information and hereby grant permission 
to the research team at the Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 to examine the 
pathology records and specimens pertaining to my diagnosis of breast cancer. 
 
Signed:_________________________________________ Date:___________________________ 
 
Name:_____________________________________Birthdate:____________________________ 
 
Where Initial Breast Surgery was done (If applicable)____________________________________ 
 
Address:________________________________________________________________________ 
 
City:________________________________State:______________Zip:_____________________ 
 
Where Biopsy (ies) of Recurrence was done (If applicable)_________________________________ 
_ 
Address:________________________________________________________________________ 
 
City:________________________________State:______________Zip:______________________ 

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Appendix D 
Tissue Specimen Release Form 
 
 
<Insert DF/HCC institution address here> 
 
 
 
 
Subject Name 
 
 
Date of Birth  
 
 
 
 
 
 
SSN 
 
 
 
 
 
I hereby grant the <insert DF/HCC institution here> permission to obtain my tissue specimens 
from outside institutions.   
 
 
 
 
 
 
Signature of Subject  
 
 
 
 
 
Date 
 
 
 
 
 
 
Please send tissue specimen(s) to: 
 
<insert contact information here> 
 
 
 
 

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How to Collect Blood Using the  
PAXgene
™ Blood RNA Tube 
For Molecular Diagnostic Testing 
 
Required Items: 
1a.  Ensure that the PAXgene 
Blood RNA Tube (B) is at room 
temperature (18°C-25°C) prior to 
use and properly labeled with 
patient identification. 
1b.  If the PAXgene Blood RNA Tube 
is the only tube to be drawn, a small 
amount of blood should be drawn 
into a “Discard Tube” (A) prior to 
drawing blood into the PAXgene 
Blood RNA Tube. Otherwise, the 
PAXgene Blood RNA Tube should 
be the last tube drawn in the 
phlebotomy procedure. 
Venipuncture:2.  Using a BD 
Vacutainer® Safety-Lok™ Blood 
Collection Set (C), collect blood into 
the PAXgene Blood RNA Tube using 
your institution’s recommended 
standard procedure for venipuncture.
Blood Collection: 
3a.  Hold the PAXgene Blood RNA 
Tube vertically, below the blood 
donor’s arm, during blood collection. 
3b.  Allow at least 10 seconds for 
a complete blood draw to take 
place. Ensure that the blood has 
stopped flowing into the tube 
before removing the tube from the 
holder. (See Figure 1) 
After Blood Collection: 
4a.  Gently invert the PAXgene 
Blood RNA Tube 8 to 10 times. 
4b.  Store the PAXgene Blood RNA 
Tube upright at room temperature 
(18°C-25ºC) or at 4ºC.*  
1 
RNA 
Stabilization 
Reagent 
RNA 
StabilizedWh
ole Blood 
2 
Ref# 
762165 
3 
BD Vacutainer® Safety-
Lok™ Blood Collection Set
Ref# 367281 North America 
Ref# 367286 Other Countries 
BD Customer Service/Orders:
888.237.2762 (North America)  
32.53.720.337 (Europe) 
4 
www.PreAnalytiX.com 
*Refer to PAXgene® Blood RNA Tube 
handbook. 
PAXgene and PreAnalytiX are registered trademarks of PreAnalytiX, Hombrechtikon, CH ©2005 PreAnalytiX 
GmbH 
BD and all other trademarks are the property of Becton, Dickinson and Company. ©2005 
BD 
Printed in USA    05/05    VS5933-
1

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DFCI IRB Protocol #: 11-477 
 
 
 
 
 
APPENDIX G 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
 
1.0 INTRODUCTION 
 
1.1 Purpose 
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 
 
2.1 DF/HCC Sponsor 
 
2.2 Coordinating Center  
 
2.3 DF/HCC Quality Assurance Office for Clinical Trials (QACT) 
 
2.4 Participating Institution 
 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
3.1 Protocol Distribution 
 
3.2 Protocol Revisions and Closures 
 
3.3 Informed Consent Requirements 
 
3.4 IRB Documentation 
 
3.5 IRB Re-Approval 
 
3.6 Participant Confidentiality and Authorization Statement 
 
3.7 DF/HCC Multi-Center Protocol Confidentiality 
 
3.8 DF/HCC Multi-Center Protocol Registration Randomization  
 
3.9 Initiation of Therapy 
 
3.10 Eligibility Exceptions 
 
3.11 Verification of Registration, Dose Levels, and Arm Designation 
 
3.12 DF/HCC Protocol Case Number 
 
3.13 Protocol Deviations, Exceptions and Violations 
 

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4.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
 
4.1 Guidelines for Reporting Serious Adverse Events  
 
4.2 Guidelines for Processing IND Safety Reports  
 
5.0 DATA MANAGEMENT 
   
5.1 Data Forms Review 
 
5.2 Incomplete or Questionable Data 
 
5.3 Missing Forms 
 
6.0 REQUISITIONING INVESTIGATIONAL DRUG 
 
7.0 MONITORING: QUALITY CONTROL 
 
7.1 Ongoing Monitoring of Protocol Compliance 
 
7.2 Evaluation of Participating Institution Performance 
 
8.0 AUDITING: QUALITY ASSURANCE 
 
8.1 DF/HCC Sponsored Trials 
 
8.2 Participating Institution 
 
8.3 DF/HCC Sponsor and Coordinating Center  
 
8.4 Sub-Standard Performance 
 
8.5 Corrective Actions 
 
 

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1.0 INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that 
will be participating in the research protocol. 
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-center Protocol:  A research protocol in which one  or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Children’s Hospital Boston (CHB), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol 
as well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines 
(CTEP, Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  
The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also 
typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, 
management and conduct of the protocol at all research locations. In applicable protocols, the 
DF/HCC Sponsor will serve as the single liaison with any regulatory agencies (i.e. CTEP 
Protocol and Information Office (PIO), FDA, OBA etc.). The DF/HCC Sponsor has ultimate 
authority over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC 
Principal Investigator; however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  
The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order 

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that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. Should the 
DF/HCC Sponsor decide to use a CRO, the CRO will be deemed the Coordinating Center.   
 
DF/HCC Quality Assurance Office for Clinical Trials: A unit within DF/HCC developed to 
computerize and manage data, and to provide a Quality Control and Quality Assurance function 
for DF/HCC trials.   
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities:  
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Dr. Nancy Lin, will accept responsibility for all aspects of conducting a 
DF/HCC Multi-Center protocol which includes but is not limited to:  
 
 Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments.  
 Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
 Submit the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol. 
 Assure all Participating Institutions are using the correct version of the protocol. 
 Ensure that each participating investigator and study team receives adequate protocol 
training and/or a Site Initiation Visit prior to enrolling participants and throughout trial’s 
conduct as needed. 
 Ensure the protocol will be provided to each participating site in a language 
understandable to all site personnel when English is not the primary language.  
 Monitor progress and overall conduct of the study at all Participating Institutions.  
 Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. 
FDA) reporting requirements are met.  
 Review data and maintain timely submission of data for study analysis.  
 Act as the single liaison with FDA (investigator-held IND trials) as applicable. 
 Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol. 
 Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the DF/HCC Sponsor. 
 Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site.  
 
 
2.2 Coordinating Center  
 
The Coordinating Center will assume the following general responsibilities: 

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 Assist in protocol development  
 Maintain copies of Federal Wide Assurance and Institutional Review Board (IRB) 
approvals from all Participating Institutions. 
 Maintain FDA correspondence, as applicable. 
 Maintain updated roster of participants.  
 Verify eligibility. 
 Verify response. 
 Oversee the data collection process from Participating Institutions. 
 Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to DF/HCC Sponsor for timely review.   
 Distribute adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB 
Adverse Event Reporting Policy to all participating investigators. 
 Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with. 
 
 
 Monitor Participating Institutions either by on-site or virtual monitoring.  
 Maintain Regulatory documents of all Participating Institutions.  
 Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc).  
 Maintain documentation of all communications. 
 Ensure that each Participating Institution has the appropriate assurance on file with the 
Office of Human Research Protection (OHRP).     
 
2.3 DF/HCC Quality Assurance Office for Clinical Trials (QACT) 
 
In addition to the Coordinating Center, the DF/HCC QACT provides the following support 
services to assist the DF/HCC Sponsor: 
 
 Develop protocol specific case report forms (eCRFS). 
 QA/QC data of protocol specific CRFs.  
 Provide a central participant registration, which includes review of consent and 
eligibility. 
 Provide auditing services (funding and QACT approval required). 
 
2.4 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable Federal Regulations and 
DF/HCC requirements, the protocol and HIPAA requirements. All Participating Institutions will 
provide a list of personnel assigned to the role for oversight of data management at their site to 
the Coordinating Center.  
 
The general responsibilities for each Participating Institution are as follows: 
 
 Commit to the accrual of participants to the protocol. 
 Submit protocol and/or amendments to their local IRB. 
 Maintain a regulatory binder in accordance with DF/HCC requirements. 

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 Provide the Coordinating Center with regulatory documents as requested. 
 Participate in protocol training prior to enrolling participants and throughout the trial as 
needed (i.e. teleconferences). 
 Update Coordinating Center with research staff changes on a timely basis. 
 Register participants through the Coordinating Center.  
 Submit source documents, research records, and CRFs per protocol specific submission 
guidelines to the Coordinating Center. 
 Submit Serious Adverse Event (SAE) reports to local IRB per local requirements and to 
the Coordinating Center, in accordance with DF/HCC requirements.  
 Submit protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
 Secure and store investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements. 
 Have office space, office equipment, and internet access that meet HIPAA standards. 
 For protocols using investigational agents, the Participating Institution will order their 
own investigational agents regardless of the supplier (i.e. pharmaceutical company).  
 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its 
IRB of these revisions. 
 
 Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 
90 days from receipt of the notification. 
 
 Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to 
protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions 
will be implemented immediately followed by IRB request for approval. 
 
 Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating Center, 

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will update the Participating Institutions on an ongoing basis about protocol accrual data 
so that they will be aware of imminent protocol closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the 
DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center 
Protocols.  This document will be provided separately to each Participating Institution. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior 
to submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that only 
attending physicians obtain informed consent and re-consent to interventional trials (i.e. drug 
and/or device trials).   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
 
 Approval letter of the Participating Institution's IRB  
 Copy of the Informed Consent Form approved by the Participating Institution’s IRB  
 Participating IRB’s approval for all amendments 
 
It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the Coordinating Center their 
IRB approval for amendments to a protocol.    
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.   
 
3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information known 
as the Health Insurance Portability and Accountability Act (HIPAA). Any information, related to 

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the physical or mental health of an individual is called Protected Health Information (PHI). 
HIPAA outlines how and under what circumstances PHI can be used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an Authorization.  This Authorization may or may not be 
separate from the informed consent document.  The Coordinating Center, with the approval from 
the DFCI IRB, will provide a consent template, which covered entities (Participating Institutions) 
must use.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its 
trials.  However, because of the nature of these trials, certain protected health information must 
be collected per NCI requirements. These are the primary reasons why DF/HCC has chosen to 
use Authorizations, signed by the participant in the trial, rather than limited data sets with data 
use agreements. 
 
3.7  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center must have 
the participant’s full name & social security number “blacked out” and the assigned DF/HCC 
QACT case number (as described below) and DF/HCC protocol number written in (with the 
exception of the signed informed consent document). Participant initials may only be included or 
retained for cross verification of identification. 
 
3.8 DF/HCC Multi-Center Protocol Registration Randomization  
Please refer to Protocol Section 4.3 for participant registration and randomization information.  
Treatment cannot begin until site has received confirmation that the participant has been 
registered with DFCI QACT.  
 
3.9 Initiation of Therapy 
 
Participants must be registered with the DF/HCC QACT before receiving treatment.  Treatment 
may not be initiated until the Participating Institution receives a faxed or e-mailed copy of the 
participant’s registration confirmation memo from the Coordinating Center. Therapy must be 
initiated per protocol guidelines.  The DF/HCC Sponsor and DFCI IRB must be notified of any 
exceptions to this policy. 
 
3.10 Eligibility Exceptions 
 
The DF/HCC QACT will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC QACT requires each institution to fully comply with 
this requirement. 
 
3.11 Verification of Registration, Dose Levels, and Arm Designation 
 

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A registration confirmation memo for participants registered to DF/HCC Multi-Center Protocol 
will be faxed or emailed to the registering institution within one business day of the registration. 
Treatment may not be initiated until the site receives a faxed or e-mailed copy of the registration 
confirmation memo. 
 
3.12 DF/HCC Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five digit protocol case number.  This number is unique to the participant on this trial 
and must be used for QACT CRF/eCRF completion and correspondence, and correspondence 
with the Coordinating Center.   
 
3.13 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe derivations from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB. 
 
3.13.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
  
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation.   
 
3.13.2 Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, 
deviations and violations. The DF/HCC Sponsor will also be responsible for ensuring that 
all protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the 
DFCI IRB. The Participating Institution must submit the deviation request to the 
Coordinating Center who will then submit the deviation request to the DFCI IRB. Upon 

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DFCI IRB approval the deviation is submitted to the Participating Institution IRB, per 
institutional policy. A copy of the Participating Institution’s IRB report and determination 
will be forwarded to the Coordinating Center within 10 business days after the original 
submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
Participating Institution, the Coordinating Center will submit the report to the DF/HCC 
Sponsor for review. Subsequently, the Participating Institution’s IRB violation/deviation 
report will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. 
DF/HCC will forward all violation reports to CTEP via an internal DF/HCC process, as 
applicable. 
 
4.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
 
The study teams at all participating institutions are responsible for protecting the safety, rights 
and well-being of study participants. Recording and reporting of adverse events that occur during 
the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety.   The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
4.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed 
in protocol section 11.  
 
 
 
 
 
Participating Institutions must report the AEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB SAE Reporting Requirements.  
 
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the DFCI IRB Reporting Requirements.  Participating 
Investigators will review any distributed AE reports, send a copy to their IRB according to their 
local IRB’s policies and procedures, and file a copy with their regulatory documents. 
 
 
 
4.2 Guidelines for Processing IND Safety Reports  

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FDA regulations require sponsors of clinical studies to notify the FDA and all participating 
investigators of any adverse experience associated with the use of the investigational agent that is 
both serious and unexpected. The DF/HCC Sponsor will review all IND Safety Reports and 
ensure that all IND Safety Reports are distributed to the Participating Institutions.  The 
Participating Institutions will review, and submit to their IRB according to their institutional 
policies and procedures.   
 
5.0 DATA MANAGEMENT 
 
The DF/HCC QACT develops a set of either paper or electronic case report forms (CRF/eCRFs), 
for use with the protocol.  These forms are designed to collect data for each study. The DF/HCC 
QACT provides a web based training for eCRF users. 
   
5.1 Data Forms Review 
 
When data forms arrive at the DF/HCC QACT, they are reviewed for completeness, protocol 
treatment compliance, adverse events (toxicities) and response. Data submissions are monitored 
for timeliness and completeness of submission. Participating Institutions are notified of their data 
submission delinquencies in accordance with the following: 
 
5.2 Incomplete or Questionable Data 
 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC QACT Data Analyst or study monitor.  
Responses to all queries should be completed and submitted within 14 calendar days.  Responses 
may be returned on the written query or on an amended paper case report form, or in the case of 
electronic queries, within the electronic data capture (eDC) system. In the case of a written query 
for data submitted on a paper case report form, the query must be attached to the specific data 
being re-submitted in response.   
 
5.3 Missing Forms 
 
If study forms are not submitted on schedule, the Participating Institution will receive a Missing 
Form Report from the Coordinating Center noting the missing forms.  These reports are 
compiled by the DF/HCC QACT and distributed a minimum of four times a year.  
 
6.0 REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of investigational agent is specified in the protocol.  
 
Participating Institutions should order their own agent regardless of the supplier (i.e., a 
pharmaceutical company.)   
 

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If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the 
agent can be ordered once the protocol is approved by the local IRB.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent 
according to state and federal requirements. The local IRB should be kept informed of who will 
supply the agent (i.e. a pharmaceutical company) so that any regulatory responsibilities can be 
met in a timely fashion.  
 
 
7.0 MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance and 
data accuracy. The Coordinating Center, with the aid of the QACT provides quality control 
oversight for the protocol. 
 
7.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions will be required to submit participant source documents to the 
Coordinating Center for monitoring. The Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and participant safety. Monitoring will occur before the clinical phase of the protocol begins, 
continue during protocol performance and through study completion. Additional monitoring 
practices may include but are not limited to; source verification, review and analysis of the 
following: eligibility requirements of all participants, informed consent procedures, adverse 
events and all associated documentation, study drug administration/treatment, regulatory files, 
protocol deviations, pharmacy records, response assessments, and data management.  
 
Participating institutions will be required to participate in monthly Coordinating Center initiated 
teleconferences.  “Newsletters” highlighting overall protocol progress and important 
announcements will be distributed as deemed appropriate by the protocol chair. 
 
Virtual monitoring visits will begin after at least 3 participants have been enrolled or after 1 
participant has been enrolled if no additional enrollment has occurred in a 6 month period.  
Virtual monitoring will continue approximately every 6 months and may occur more frequently 
if there are significant findings or discrepancies.  Virtual monitoring will be performed by the 
Coordinating Center’s Clinical Research Specialist (CRS). The data will be reviewed for 
completeness, quality, and adherence to the protocol requirements. Sites will be asked to provide 
de-identified source documentation via fax, email, or mail as specified by the Clinical Research 
Specialist for all virtual monitoring visits. A virtual site initiation visit (SIV) will be conducted 
with each participating site prior to study activation. Participating sites many not begin enrolling 
until the SIV has occurred. 
 

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All data submitted to the DF/HCC QACT will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. The Coordinating Center and if 
applicable, QACT Data Analysts assigned to the protocol, will perform the ongoing protocol 
data compliance monitoring. 
 
7.2 Evaluation of Participating Institution Performance 
 
7.2.1 Monitoring Reports 
 
The DF/HCC Sponsor will review all Participating site monitoring reports to ensure 
protocol compliance and to fulfill sponsor responsibilities. The DF/HCC Sponsor may 
increase the monitoring activities at Participating Institutions that are unable to comply 
with the protocol, DF/HCC Sponsor requirements or federal and local regulations. 
Participating Institutions may also be subject to an audit as determined by the DF/HCC 
Sponsor. 
 
8.0 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and 
procedures were followed. Auditing is the systematic and independent examination of all trial 
related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per 
the protocol, Standard Operating Procedures (SOPs), and the Code of Federal Regulations 
(CFR). 
 
8.1 DF/HCC Sponsored Trials 
 
One on-site audit will be conducted by QACT assuming at least 3 participants are treated at a 
participating site.  An audit may be triggered if deficiencies are noted related to consent 
practices, eligibility, missing, incomplete, or questionable data submission, or any other issue the 
protocol chair deems appropriate for audit. If a participating site is selected for audit, 
approximately 3-4 participants would be audited at the site over a 2 day period.  If violations 
which impact participant safety or the integrity of the study are found, more participant records 
may be audited.  
 
8.2 Participating Institution 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal) and re-audit dates (if applicable), which involve this protocol. 
All institutions will forward a copy of final audit and/or re-audit reports and corrective action 
plans (if applicable) to the Coordinating Center, within 12 weeks after the audit date.  
 

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8.3 DF/HCC Sponsor and Coordinating Center  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if applicable. 
The Coordinating Center, must forward these reports to the DF/HCC QACT per DF/HCC policy 
for review by the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC 
Audit Committee could accept or conditionally accept the audit rating and final report. 
Conditional approval could require the DF/HCC Sponsor to implement recommendations or 
require further follow-up.  For unacceptable audits, the DF/HCC Audit Committee would 
forward the final audit report and corrective action plan to the DFCI IRB as applicable. 
 
8.4 Sub-Standard Performance 
 
The DF/HCC Sponsor and DFCI IRB are charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol. 
 
8.5 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, will be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. 
 

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APPENDIX H: HISTOLOGY LABORATORY PROJECT REQUEST FORM 

 
 
 
          HISTOLOGY LABORATORY  
                 PROJECT REQUEST FORM  
 
Researcher Name: _PI: Nancy Lin, MD (CRC: Danielle Gore)  
Date Submitted:  MM/DD/YY 
Researcher Contact Information: nlin@partners.org (617 632 6973;  
dgore@partners.org (617-632-4174) 
DFCI Protocol #: 11-477 
 
Grant#/Cost Center #/Purchase Order#: F8151631________________________________ 
IMPORANT NOTE:  This must be a current PeopleSoft Number for you to charge to the grant directly to Kronos.  If you are not sure, 
you must check with your requestor. 
 
BILLING INFORMATION 
  
Contact Name & INSTITUTION: Jennifer Savoie____________________________________________________ 
 
 
Contact Address:  Dana-Farber Cancer Institute 450 Brookline Avenue, Yawkey 1250, Boston MA 02215  
 
 
Contact Phone Number/Email Address:  dgore@partners.org 617 632 4870_______________________________ 
 
Estimated Cost of Supplies: ______________________________________________________________________________ 
(Prior authorization required by manager for cost estimate)                                                                                                    
 
Researcher: Please fill out the detailed description of type of work performed  
(Include number and type of slides and stains, etc.) 
 
 
 
 
 
 
 
   
   
 
 
 
 
Sunday 
Date:   /     / 
Monday 
Date:   /     / 
Tuesday 
Date:    /     / 
Wednesday 
Date:    /     / 
Thursday 
Date:    /    / 
Friday 
Date:    /     / 
Saturday 
Date:    /     / 
 
  
Time In 
************ 
Time Out 
************ 
Total Hours 
Worked 
 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
__________ 
 
TECHNICAL 
DIRECTOR  
TIME 
ESTIMATE 
 
 
TECHNICIAN   
ASSIGNED  
TO PROJECT:   
 
PROJECT APPROVED BY (Jim Pepoon or Jack McCabe): 
___________________________________________________ 
PLEASENOTE:  ALL OVERTIME REQUESTS MUST BE DISCUSSED WITH THE LAB MANAGER BEFORE PROJECTS CAN BEGIN.  
TECHNICIANS WILL BE ASSIGNED/APPROVED BASED ON LABORATORY WORKLOAD.  TIME REPORT MUST BE COMPLETED EACH 
WEEK AND SUBMITTED WITH TECHNICIAN’S WEEKLY TIMESHEET.
 
DEPARTMENT OF 
PATHOLOGY 
ACCESSION NUMBER: 
 
BR _____- __________ 
 
Teaching: 
Project: 
GENERAL/SPECIAL INSTRUCTION: 
 
Need a cell block pellet to be processed and embedded and 1 H&E section cut from block. Label as BOT XXXX and place in 
Dr. Andrea Richardson’s mailbox in pathology. 
 
 
Number of Blocks to be processed/embedded: 1  
Number of special stains: 
 
Number of H&E slides:     1                                                                      Number of IHC/ISH: 
 
Number of unstained/no bake slides:                                                     Other:  

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APPENDIX I: List of Drugs Known to Predispose to Torsades de Pointes 
 
Substantial evidence supports the conclusion that these drugs, when used as directed in labeling, can prolong the QT interval and can have 
a risk of Torsades de pointes (TdP) in some patients. Generic 
Generic Name 
Brand Name  
Class/Clinical Use  
Comments  
Amiodarone  
Cordarone®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females>Males,TdP risk 
regarded as low  
Amiodarone  
Pacerone®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females>Males,TdP risk 
regarded as low  
Arsenic trioxide  
Trisenox®  
Anti-cancer / Leukemia  
Astemizole  
Hismanal®  
Antihistamine / Allergic 
rhinitis  
No Longer available in U.S.  
Azithromycin  
Zithromax®  
Antibiotic / bacterial infection  
Bepridil  
Vascor®  
Anti-anginal / heart pain  
Females>Males  
Chloroquine  
Aralen®  
Anti-malarial / malaria infection  
Chlorpromazine  
Thorazine®  
Anti-psychotic/ Anti-emetic / schizophrenia/ nausea  
Cisapride  
Propulsid®  
GI stimulant / heartburn  
No longer available in U.S.  
Citalopram  
Celexa®  
Anti-depressant / depression  
Clarithromycin  
Biaxin®  
Antibiotic / bacterial infection  
Disopyramide  
Norpace®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females>Males  
Dofetilide  
Tikosyn®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females > Males  
Domperidone  
Motilium®  
Anti-nausea / nausea  
Not available in U.S.  
Dronedarone  
Multaq®  
Anti-arrhythmic / Atrial Fibrillation  
Droperidol  
Inapsine®  
Sedative;Anti-nausea / anesthesia adjunct, nausea  
Erythromycin  
E.E.S.®  
Antibiotic;GI stimulant / 
bacterial infection; increase GI 
motility  
Females>Males  
Erythromycin  
Erythrocin®  
Antibiotic;GI stimulant / 
bacterial infection; increase GI 
motility  
Females>Males  
Escitalopram  
Cipralex®  
Anti-depressant / Major 
depression/ Anxiety disorders  
Changed from Possible Risk to 
Risk- 12/2/12  
Escitalopram  
Lexapro®  
Anti-depressant / Major 
depression/ Anxiety disorders  
Changed from Possible Risk to 
Risk- 12/2/12  
Flecainide  
Tambocor®  
Anti-arrhythmic / abnormal heart rhythm  
Halofantrine  
Halfan®  
Anti-malarial / malaria 
infection  
Females>Males  
Haloperidol  
Haldol®  
Anti-psychotic / schizophrenia, 
agitation  
TdP risk with I.V. or excess 
dosage 
Ibutilide  
Corvert®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females>Males  
Levomethadyl  
Orlaam®  
Opiate agonist / pain control, 
narcotic dependence  
Not available in U.S.  
Mesoridazine  
Serentil®  
Anti-psychotic / schizophrenia  
Removed from US market in 
2004  
Methadone  
Dolophine®  
Opiate agonist / pain control, 
narcotic dependence  
Females>Males  
Methadone  
Methadose®  
Opiate agonist / pain control, 
narcotic dependence  
Females>Males  
Moxifloxacin  
Avelox®  
Antibiotic / bacterial infection  
Ondansetron  
Zofran®  
Somatostatin analog / nausea and vomiting  
Ondansetron  
Anset®  
Somatostatin analog / nausea and vomiting  
Ondansetron  
Zuplenz®  
Somatostatin analog / nausea and vomiting  
Ondansetron  
Emetron®  
Somatostatin analog / nausea and vomiting  
Ondansetron  
Ondavall®  
Somatostatin analog / nausea and vomiting  

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer                             Protocol version date: 4/29/2015  
148 
 
Generic Name 
Brand Name  
Class/Clinical Use  
Comments  
Pentamidine  
NebuPent®  
Anti-infective / pneumocystis 
pneumonia  
Females>Males  
Pentamidine  
Pentam®  
Anti-infective / pneumocystis 
pneumonia  
Females>Males  
Pimozide  
Orap®  
Anti-psychotic / Tourette's tics  
Females>Males  
Probucol  
Lorelco®  
Antilipemic / 
Hypercholesterolemia  
No longer available in U.S.  
Procainamide  
Pronestyl®  
Anti-arrhythmic / abnormal heart rhythm  
Procainamide  
Procan®  
Anti-arrhythmic / abnormal heart rhythm  
Quinidine  
Quinaglute®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females>Males  
Quinidine  
Cardioquin®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females>Males  
Sevoflurane  
Ulane®  
Anesthetic, general / anesthesia  Label warning for patients with 
congenital long QT or patients 
taking QT prolonging drugs  
Sevoflurane  
Sojourn®  
Anesthetic, general / anesthesia  Label warning for patients with 
congenital long QT or patients 
taking QT prolonging drugs  
Sotalol  
Betapace®  
Anti-arrhythmic / abnormal 
heart rhythm  
Females>Males  
Sparfloxacin  
Zagam®  
Antibiotic / bacterial infection  
No longer available in U.S.  
Terfenadine  
Seldane®  
Antihistamine / Allergic 
rhinitis  
No longer available in U.S.  
Thioridazine  
Mellaril®  
Anti-psychotic / schizophrenia  
Vandetanib  
Caprelsa®  
Anti-cancer / Thyroid cancer  
  

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer                             Protocol version date: 4/29/2015  
149 
 
 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer                             Protocol version date: 9/23/2014 
 
 
APPENDIX J: 11-477 SPECIMEN REQUISITION (Archival Tissue Blocks/Slides and CTC Samples) 
 
Complete this form and include with the specimen shipment.  Label ALL materials with participant initials, DFCI participant study ID, and the date and 
time the specimen was obtained. Include a pathology report with any archival tissue specimens being submitted.  
 
Ship specimen(s) to:  
Danielle Gore 
 
 
Dana-Farber Cancer Institute 
 
 
450 Brookline Avenue, DA157 
 
Boston, MA 02215 
_______________________________________________________________________________________________________________________ 
Specimen Information 
Participant Initials (FML): __________  DFCI Participant Study ID Number: _____________    Date specimen(s) shipped:_______________________  
Time Point   
 Pre-study/Baseline   
 Cycle 1 Day 1    
 Cycle 2 Day 8/Day 9    
 Off Treatment (without progression)  
 Progression on 1st Regimen (Arm A or B)  
 Progression on 2nd Regimen (Arm C)  
 Off Study 
                                
Specimen Type  
(indicate inclusion in shipment by checking box) 
Pathology Number(s) or  
Serial Coding 
Quantity 
submitted 
Date specimen 
obtained 
Time specimen 
obtained 
(24 Hour Clock) 
 Archival tissue block 
 
 
 
 
 10-20 unstained slides  
 
 
 
 
 CTC (CellSave) tubes 
 
 
 
 
 Other, specify: 
 
 
 
 
 Other, specify: 
 
 
 
 
 
 
Responsible contact: _______________________________          Mailing address 
(if blocks need 
to be returned): 
__________________________________________  
__________________________________________ 
__________________________________________ 
__________________________________________ 
Email: ___________________________________________ 
Phone number: ____________________________________ 
Site: _____________________________________________ 
 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer                             Protocol version date: 4/29/2015  
151 
 
 
APPENDIX K: 11-477 SPECIMEN REQUISITION (Biopsy/Research Blood) 
 
Complete this form and include with the specimen shipment.  Label ALL materials with participant initials, DFCI participant study ID, collection time 
point and collection date.  
 
Ship specimen(s) to:   Danielle Gore 
 
 
Dana-Farber Cancer Institute 
 
 
450 Brookline Avenue, DA157 
 
Boston, MA 02215 
 
_______________________________________________________________________________________________________________________ 
 
Specimen Information 
Participant Initials (FML): ___________     DFCI Participant Study ID Number: _____________    Date specimen(s) shipped: ____________________ 
Time Point   
 Pre-study/Baseline   
 Cycle 1 Day 1    
 Cycle 2 Day 8/Day 9    
 Off Treatment (without progression)   
 Progression on 1st Regimen (Arm A or B)  
 Progression on 2nd Regimen (Arm C)   
 Off Study 
 
Specimen Type  
(indicate inclusion in shipment by checking box) 
Quantity submitted 
Date specimen obtained 
 Biopsy core(s) frozen in OCT 
 
 
 FNA samples 
 
 
 Fluid biopsy samples 
 
 
 Streck tubes 
 
 
 Blood in lavender top (EDTA) 
 
 
 Other, specify: 
 
 
 Other, specify: 
 
 
 
 
 
Responsible Contact: _______________________________  
 
Site: _____________________________________________ 
 
Email: ___________________________________________ 
 
Phone number: ___________________________________ 
 

STA-9090, a novel HSP90 inhibitor, for ER+ breast cancer                             Protocol version date: 4/29/2015  
152 
 
 
 
APPENDIX L: 11-477 SPECIMEN REQUISITION (PBMC Tubes) 
 
Complete this form and include with the specimen shipment.  Label ALL materials with DFCI participant study ID, collection time point and collection 
date and time.  
 
Ship specimen(s) to:   Luke Whitesell 
 
 
Whitehead Institute 
 
9 Cambridge Center  
 
 
Cambridge, MA 02142 
_____________________________________________________________________________________________________________________ 
 
Specimen Information 
DFCI Participant Study ID Number: _____________    Date specimen(s) shipped: ____________________ 
 
PBMC (PAXgene) Tube Time Point 
(indicate inclusion in shipment by checking box)
Quantity submitted 
Collection Date 
Collection Time 
(24 Hour Clock) 
 Pre-treatment/Cycle 1 Day 1  
 
 
 
 Cycle 2 Day 8 
 
 
 
 Cycle 2 Day 9 
 
 
 
 Progression on 1st Regimen (Arm A or B)   
 
 
 
 Progression on 2nd Regimen (Arm C) 
 
 
 
 Off Treatment (without progression) 
 
 
 
 Off Study 
 
 
 
 
 
 
Responsible Contact: _______________________________  
 
Site: _____________________________________________ 
 
Email: ___________________________________________ 
 
Phone number: ___________________________________ 
 
 

D: 2/10/2012 KAJ; F: 5/10/2012 PH; R: 10/10/2013 KAJ; 4/3/2014 KAJ; R: 4/13/2014 (AM#30); Revised  (AM#34)MRH 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
11-477 
Protocol Name: 
Randomized phase II study of fulvestrant with or without ganetespib in patients with 
hormone receptor-positive, metastatic breast cancer 
DFCI Site PI: 
Nancy Lin, MD 
DFCI Research Nurse: 
Myra St. Amand, RN; Kathleen Roche, RN; Elizabeth Kasparian, RN; Margaret Haldoupis, 
RN; Mary O’Driscoll, RN; Beth Tiani, RN 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
           SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study 
Design 
Ganetespib is an HSP90 inhibitor.   
Fulvestrant is a pure anti-estrogen which is thought to act by downregulating ER expression. 
Study Design – Section 1.1;   Study Rationale – Section 2.4;   A cycle is 28 days – Section 5.0 
Dose 
Calc. 
 
Ganetespid is in mg/m2, calculated by the weight obtained at each treatment visit per DFCI standard of 
practice. 
 
Fulvestrant is flat dosing. 
Study Drug &Administration 
Ganetespid administration guidelines are in Sections 5.2 and 7.1 
 
IV, diluted in D5W, administered over 1 hour using a 0.2µm inline filter – Section 7.1.7 
 
Pre-med with dexamethasone and diphenhydramine is required for Cycle 1 and 2.  Participants who have 
successfully tolerated at least 2 cycles of ganetespid ((on Arms B or C) without a hypersensitivity reaction are 
not required to take the pre meds  and is left to the discretion of the treating provider described in Section 5 – 
see alert page.  Loperamide is recommended – Section 5.2.1 
 
Use of vascular access devices (VADs) w/silicone catheters ONLY or peripheral IV is permitted. Use of VADs 
with catheters made of any other material is prohibited – Sect. 5.2 
 
Administered on Days 1, 8, and 15 of each cycle ( 3 weeks on, 1 week off) – Section 5.2 
 
See Section 5.5 for management of hypersensitivity reactions 
Fulvestrant administration guidelines are in Sections 5.2 and 7.2 
 
Administered via intramuscular injection into the buttocks on C1, D1; C1, D15; and Day 1 of each subsequent 
cycle; Sect. 5.2.2 & 7.2.4.  NOTE:  In Arm C, will only be administered on Day 1 of each cycle; see Alert Page
Dose Modifications and 
Toxicity 
Dose Modification for toxicity guidelines are in Section 6 
 
Definition of DLT is outlined in Section 5.3 
Ganetespib: See Section 6.2.1 for Dose Reduction Table and Dose Modification Guidelines Table 
 
Diarrhea is expected in most patients.  Please see Section 5.5 for diarrhea management guidelines (NOTE: 
These guidelines were updated on 10/2/2013). 
 
Toxicities must recover to ≤ Grade 1 or baseline to resume treatment after skipped doses 
 
Criteria to treat: ≤ Grade 2: ANC≥1000/mm3; Platelets ≥50,000/ mm3; Hgb≥8.0g/dL 
 
Participants may continue on fulvestrant alone if treatment with ganetespib must be discontinued 
Fulvestrant: There are no dose modifications for fulvestrant - See Section 6.2.2 
Concomitant 
Meds 
Concomitant therapy guidelines are in Sections 5.4 and 5.5 
 
Participants should receive full supportive care – Section 5.5 
 
For participants receiving ganetespib, medications that can cause QT prolongation should be avoided – Sect. 5.4
 
CYP3A4 substrates and CYP2C19 substrates should be used with caution – See Sect. 5.4 for common examples
 
 Biphosphonate treatment is allowed if the 1st dose was given PRIOR to initiation of protocol therapy – Sect. 5.5
Required   
Data  
Study assessments are in Section 9 (includes Study Calendars A-D); Appendix C 
 
Blood for Germline DNA will be collected in a lavender top tube on C1, D1 
 
A CPT tube will be collected for plasma & lymphocytes – See study calendars for cohort-specific time points 
 
Pharmacodynamic assays:  PMBC collection will occur in Arms A&B on C1D1, C2D8, C2D9 & progression 
 
Circulating tumor cells will be collected - See study calendars for cohort-specific time points 
 
EKGs are single & minimal - See study calendars for cohort-specific time points; Vital Signs are routine. 

D: 2/10/2012 KAJ; F: 5/10/2012 PH; R: 10/10/2013 KAJ; 4/3/2014 KAJ; R: 4/13/2014 (AM#30); Revised  (AM#34)MRH 
Charting 
Tips 
 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record 
 
If there is a discrepancy in the infusion time, delay in administration, or the infusion takes longer than permitted 
by the guidelines of the protocol, please document the reason for the discrepancy in the medical record. 
 
Please be sure to also DOCUMENT any required observation periods, any additional vital signs, routes of 
administration, or injection sites 
 

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