Conditions: Neoplasms
Keywords: Urothelial Carcinomas Non-Squamous Non-Small Cell Lung Carcinomas Refractory Gastrointestinal Carcinomas Hsp90 Inhibitor Sarcomas
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
Background:

\- Some people have cancers that don't respond to standard treatments. In these cases, doctors may try to use drugs to slow the growth of the cancer.

Objectives:

\- To test the safety and efficacy of the drug combination of ganetespib and ziv-aflibercept.

Eligibility:

\- Adults age 18 and over with advanced cancer of the colon, lung, urinary tract, and sarcomas.

Design:

* Participants will be screened with medical history, blood tests, and scans to measure their tumors.
* Participants will have one or two eye exams, with dilating eye drops.
* Participants will get the study drugs at the clinic as an infusion in a vein. Ganetespib will be given once a week on the same day for 3 weeks in a row, followed by a 1-week rest period. Ziv-aflibercept will be given once every other week. The drugs will be given in 28-day cycles.
* Participants may have a small piece of their tumor collected once or twice. This is done using a small needle during computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound scan.
* Participants will have their blood pressure checked at each visit. They will check it at home every day of the study.
* Participants may have one or more whole-body positron emission tomography (PET) scans with 89Zr-panitumumab. A small amount of a radioactive chemical will be injected through a tube in an arm. Participants will lie on a bed that slides in and out of the donut-shaped PET scanner. They will have small amounts of blood drawn.
* Participants may stay in the study as long as they are tolerating the drugs and their tumor is not getting worse.

Detailed description:
BACKGROUND:

* Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 that has demonstrated activity against multiple cancer cell lines and tumor xenografts in preclinical models. Inhibiting the Hsp90 chaperone complex results in the recruitment of ubiquitin ligases, polyubiquination, and proteosomal degradation of Hsp90 client proteins, including transcription factors and proteins involved in angiogenesis vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), hypoxia-inducible factor 1 (HIF-1), signal transducers and activators of transcription protein 3 (STAT-3); growth factor independence rapidly accelerated fibrosarcoma (RAF), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), insulin-like growth factor 1 receptor (IGFR); resistance to anti-growth signals cyclin-dependent kinase 4 (CDK4); tissue invasion and metastases mesenchymal-epithelial transition factor (MET), matrix metalloproteinase-2 (MMP2); and avoidance of apoptosis protein kinase B (AKT), rat insulin promoter (RIP), Survivin, B cell lymphoma (Bcl-2).
* HIF-1-alpha activation has been implicated in mediating resistance to anti-angiogenic therapy; recent evidence implicates a greater role for Hsp90 in direct modulation of VEGF signaling.
* Combining Hsp90 inhibition with ganetespib and anti-angiogenic therapy with Ziv-Aflibercept, a soluble fusion protein with high binding affinity for vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placenta growth factor (PIGF), presents a rational novel strategy for improving upon and overcoming resistance to anti-angiogenic therapy

PRIMARY OBJECTIVE:

\- To establish the safety, tolerability, and maximum tolerated dose (MTD) of the combination of ganetespib and Ziv-Aflibercept in patients with refractory gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas

SECONDARY OBJECTIVE:

* To assess modulation of HIF-1-alpha as a pharmacodynamic marker of therapy with the combination of ganetespib and Ziv-Aflibercept
* To assess modulation of epidermal growth factor receptor (EGFR) expression using 89Zr-labeled, EGFR-targeting antibody panitumumab positron emission tomography (PET)/computed tomography (CT) imaging of tumor lesions prior to and following treatment with study drugs

ELIGIBILITY:

* Adult patients with histologically confirmed metastatic gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas with disease progression after at least one line of standard therapy
* Participants in the expansion phase must demonstrate EGFR expression on archival tumor samples and have disease amenable to biopsy with willingness to undergo pre- and post-treatment biopsies
* No major surgery within 4 weeks prior to study enrollment, no radiation or chemotherapy within 3 weeks prior to enrollment; patients must have recovered from toxicities of prior therapies to at least eligibility levels prior to enrollment.

STUDY DESIGN:

* Ganetespib will be administered intravenously weekly on days 1, 8, and 15 of a 28-day cycle. Ziv-Aflibercept will be administered intravenously every 2 weeks, on days 1 and 15, during a 28-day cycle.
* The escalation portion of the trial will follow a standard 3+3 design, whereby patients are dose-escalated in cohorts of 3 until dose-limiting toxicity is observed.
* Once the MTD is established, 10 additional patients will be enrolled to the expansion phase, at the MTD, and tumor biopsies will be obtained to assess pharmacodynamic endpoints. During cycle 1 of the expansion phase, ganetespib will be administered intravenously weekly, on days 8 and 15 with omission of day 1 treatment to accommodate a baseline biopsy pre-ganetespib but after administration of Ziv-Aflibercept. For all subsequent cycles, ganetespib will be administered days 1, 8, and 15. Ziv-Aflibercept will still be administered intravenously every 2 weeks, on days 1 and 15, of a 28-day cycle.
* PET/CT imaging with 89Zr-labeled panitumumab will be performed to evaluate tumor distribution prior to and following treatment with study agents.

Arms:
arm 1: Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m\^2 + ziv-aflibercept at 3 mg/kg or 4 mg/kg.

Interventions: intervention 1: Ziv-Aflibercept intervention 2: Ganetespib
Intervention descriptions: intervention 1: Ziv-aflibercept is a soluble fusion protein with high binding affinity for vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placenta growth factor (PIGF) and thus confers anti-angiogenic activity intervention 2: Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 with activity against multiple cancer cell lines and tumor xenografts in preclinical models.

Protocol document:
Prot_SAP_001.pdf: 
Amendment
Protocol Number:
14C0150-E
Principal Investigator: Alice Chen 
NCI 
DCTD 
301.435.0517 
chenali@mail.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
367158
Protocol Title:
Phase I Study of Ganetespib and Ziv-Aflibercept in Patients with Advanced Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell 
Lung Carcinomas, Urothelial Carcinomas, and Sarcomas
SIGNATURES
Principal Investigator (*): 
Alice Chen - applied signature on 03/01/2017 8:57 AM EST
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
Jim Doroshow - applied signature on 02/27/2017 5:11 PM EST
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 03/20/2017 1:25 PM EDT
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and
used solely for those purposes.  Questions may be addressed to the Protrak System Owner.
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
N/A
DEC Clearance Date:
N/A
Protocol Version Date:02/13/2017
Lemuel Clayborn                                                                               AM E                                                     03/30/2017


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
1
TITLE:  Phase I Study of Ganetespib and Ziv-aflibercept in Patients With Advanced 
Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial 
Carcinomas, and Sarcomas  
 
Abbreviated Title:  
 Ph I Ganetespib Ziv-aflibercept 
 
 
Coordinating Center: 
Developmental Therapeutics Clinic (NCIDTC) 
National Cancer Institute 
10 Center Drive 
Bethesda, MD 20892 
 
 
Principal Investigator: 
A.P. Chen, MDA-E 
 
31 Center Drive 
 
Bldg 31 Room 3A44 
 
Bethesda, MD 20892 
 
 
Phone: (301) 496-4291; Fax: (301) 496-0826 
 
 
chenali@mail.nih.gov 
 
 
NCI Associate 
Investigators: 
Peter Choyke, MDA-E 
Barbara Conley, MDA-E 
MIP/CCR 
DCTD 
 
James H. Doroshow, MDA-E 
DCTD 
 
Paula Jacobs, PhDE 
CIP/DCTC 
 
Karen Kurdziel, MDA-E 
Maria L. Lindenberg, MDA-E 
MIP/CCR 
MIP/CCR 
 
Richard Piekarz, MD, PhDA-E 
DCTD 
 
Howard Streicher, MDA-E 
Elad Sharon, MDA-E 
Geraldine O’Sullivan Coyne, MD, PhDA-E 
CTEP/DCTD 
CTEP/DCTD 
DCTD 
 
 
 
 
 
Non-NCI Associate 
Investigators: 
Lamin Juwara, CRNPA,B,E 
Robert Kinders, PhDE 
Leidos Biomed., FNLCR 
Leidos Biomed., FNLCR 
 
Statistician 
Larry Rubinstein, PhD, BRB, DCTDE 
 
9609 Medical Center Dr. Rm 5W106 
 
Phone: (240) 276-6026 
 
rubinsteinl@mail.nih.gov 
 
Responsible  
Research Nurse: 
Jennifer Zlott, RNA,B,E 
 
Building 10, Rm 13N214 
 
Phone: (301) 594-5664 
 
Fax: (301) 480-7281 
 
zlottjh@mail.nih.gov 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
2
 
CTEP Drug Monitor: 
Pamela Harris, MD 
 
Study Sponsor: 
CTEP 
 
 
 
NCI Supplied Agent:  
Ganetespib (NSC 777169) 
 
Ziv-aflibercept (NSC 724770) 
89Zr-Labeled, EGFR-targeting Antibody Panitumumab 
 (supplied by CIP/DCTD) 
 
 
IND Number: 
123037 
 
 
Version Date: 
February 13, 2017 
 
 
Roles: Aobtains information by intervening or interacting with living individuals for research 
purposes; Bobtains identifiable private information about living individuals; Cobtains the voluntary 
informed consent of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, 
interprets, or analyzes identifiable private information or data/specimens for research purposes 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
3
PRÉCIS 
Background: 
• 
Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 that has demonstrated activity against 
multiple cancer cell lines and tumor xenografts.  Inhibiting the Hsp90 chaperone complex results in 
the recruitment of ubiquitin ligases, polyubiquination, and proteosomal degradation of Hsp90 client 
proteins, including transcription factors and proteins involved in angiogenesis (VEGF, VEGFR, 
HIF-1, STAT-3); growth factor independence (RAF, EGFR, Her2, IGFR); resistance to anti-growth 
signals (CDK4); tissue invasion and metastases (MET, MMP2); and avoidance of apoptosis (AKT, 
RIP, Survivin, Bcl-2). 
• 
HIF-1α activation has been implicated in mediating resistance to anti-angiogenic therapy; recent 
evidence implicates a greater role for Hsp90 in direct modulation of VEGF signaling 
• 
Combining Hsp90 inhibition with ganetespib and anti-angiogenic therapy with ziv-aflibercept, a 
soluble fusion protein with high binding affinity for VEGF-A, VEGF-B, and PIGF, presents a 
novel rational strategy for improving on and overcoming resistance to anti-angiogenic therapy 
Primary Objective: 
• 
To establish the safety, tolerability, and maximum tolerated dose (MTD) of the combination of 
ganetespib and ziv-aflibercept in patients with refractory gastrointestinal carcinomas, non-
squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas 
Secondary Objectives: 
• 
To assess modulation of HIF1α as a pharmacodynamic marker of therapy with the combination of 
ganetespib and ziv-aflibercept 
• 
To assess modulation of EGFR expression using 89Zr-labeled, EGFR-targeting antibody 
panitumumab PET/CT imaging of tumor lesions prior to and following treatment with study drugs 
Eligibility: 
• 
Adult patients with histologically confirmed metastatic gastrointestinal carcinomas, non-squamous 
non-small cell lung carcinomas, urothelial carcinomas, and sarcomas with disease progression after 
at least one line of standard therapy 
• 
Participants in the expansion phase must demonstrate EGFR expression on archival tumor samples 
and have disease amenable to biopsy with willingness to undergo pre- and post-treatment biopsies 
• 
No major surgery within 4 weeks prior to study enrollment, no radiation or chemotherapy within 
3 weeks prior to enrollment; patients must have recovered from toxicities of prior therapies to at 
least eligibility levels prior to enrollment. 
Study Design: 
• 
Ganetespib will be administered IV weekly on days 1, 8, and 15 of a 28-day cycle.  Ziv-aflibercept 
will be administered IV on days 1 and 15 of a 28-day cycle. 
• 
The escalation portion of the trial will follow a standard 3+3 design, whereby patients are dose-
escalated in cohorts of 3 until dose-limiting toxicity is observed. 
• 
Once the MTD is established, 10 additional patients will be enrolled to the expansion phase at the 
MTD, and tumor biopsies will be obtained to assess pharmacodynamic endpoints.  During cycle 1 
of the expansion phase, ganetespib will be administered IV weekly, on days 8 and 15 with 
omission of day 1 treatment to accommodate a baseline biopsy pre-ganetespib but after 
administration of ziv-aflibercept.  For all subsequent cycles, ganetespib will be administered days 
1, 8, and 15.  Ziv-aflibercept will still be administered IV on days 1 and 15 of a 28-day cycle. 
• 
PET/CT imaging with 89Zr-labeled panitumumab will be performed to evaluate tumor distribution 
prior to and following treatment with study agents. 
 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
4
SCHEMA 
 
 
 
G 
A 
*Tumor  
  Biopsy 
 
#CTCs 
 
‡PET/CT 
G = Ganetespib 
A = Ziv-aflibercept 
C1D1 
D8  
D22  
D15  
C2D1 
D8  
D15  
D22  
* 
* Tumor biopsies (optional during the escalation phase, mandatory during the expansion 
phase) will be performed on C1D7 prior to administration of ganetespib on C1D8 and again 
on C2D7 prior to administration of ganetespib on C2D8.  If tumor biopsies are pursued, the 
first dose of ganetespib on C1D1 will be omitted. 
 
#Circulating tumor cells (optional) will be collected during the expansion phase only at 
baseline (pre-treatment), on C1D8 (+/- 1 day) prior to the administration of ganetespib, on 
C1D15 4 hours (+/- 1 hour) after completion of drug administration, on C2D8 (+/- 1 day) 
prior to the administration of ganetespib, on C2D15 4 hours (+/- 1 hour) after completion of 
drug administration, on day 1 of all subsequent cycles before drug administration, and at 
disease progression.   
‡ 89Zr-panitumumab PET/CT imaging will be performed in all patients during the expansion 
phase (optional during the escalation phase), prior to initiation of treatment.  If there is 
evidence of measurable uptake on baseline scans, patients will receive a second scan on 
C1D16 day to assess for evidence of EGFR target modulation.  If patients are unable to have a 
second scan on C1D16 + 1 day due to scheduling conflicts, scans may be done on C2D16 + 1 
day. 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
5
TABLE OF CONTENTS 
PRÉCIS ............................................................................................................................................3 
SCHEMA .........................................................................................................................................4 
1 
OBJECTIVES ......................................................................................................................7 
2 
BACKGROUND .................................................................................................................7 
2.1 
Role of Hsp 90 chaperone in Angiogenesis and Cancer ..........................................7 
2.2 
Ganetespib................................................................................................................9 
2.3 
Ziv-aflibercept........................................................................................................15 
3 
PATIENT SELECTION ....................................................................................................20 
3.1 
Eligibility Criteria ..................................................................................................20 
3.2 
Exclusion Criteria ..................................................................................................22 
3.3 
Inclusion of Women and Minorities ......................................................................23 
3.4 
Screening Evaluation .............................................................................................23 
4 
REGISTRATION PROCEDURES ...................................................................................24 
4.1 
Registration Process ...............................................................................................24 
5 
TREATMENT PLAN ........................................................................................................25 
5.1 
Agent Administration.............................................................................................25 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................26 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................28 
5.4 
Duration of Therapy ...............................................................................................30 
5.5 
Duration of Follow Up ...........................................................................................30 
5.6 
Criteria for Removal from Study ...........................................................................30 
6 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................30 
6.1 
Dose Modifications ................................................................................................31 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................34 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Ganetespib (NSC 777169) .....................................................................................34 
7.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Ziv-
aflibercept (VEGF-Trap, NSC 724770) .................................................................36 
7.3 
Adverse Event Characteristics ...............................................................................40 
7.4 
Expedited Adverse Event Reporting ......................................................................41 
7.5 
NCI-IRB Reporting ................................................................................................46 
7.6 
Secondary Malignancy...........................................................................................47 
7.7 
Second Malignancy ................................................................................................47 
8 
PHARMACEUTICAL INFORMATION ..........................................................................48 
8.1 
Ganetespib (NSC 777169) .....................................................................................48 
8.2 
Ziv-aflibercept (NSC 724770) ...............................................................................50 
8.3 
89Zr-labeled Panitumumab ....................................................................................51 
8.4 
Agent Ordering ......................................................................................................53 
8.5 
Agent Accountability .............................................................................................54 
9 
CORRELATIVE/SPECIAL STUDIES .............................................................................54 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
6
9.1 
Pharmacodynamic Assays .....................................................................................55 
10 
STUDY CALENDAR .......................................................................................................62 
11 
MEASUREMENT OF EFFECT........................................................................................64 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................64 
11.2 
Guidelines for Evaluation of Measurable Disease .................................................66 
11.3 
Response Criteria ...................................................................................................69 
11.4 
Duration of Response .............................................................................................71 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................71 
12.1 
Data Reporting .......................................................................................................71 
12.2 
CTEP Multicenter Guideline .................................................................................72 
12.3 
Collaborative Agreements Language .....................................................................72 
13 
STATISTICAL CONSIDERATIONS...............................................................................73 
13.1 
Study Design/Endpoints.........................................................................................73 
13.2 
Sample Size/Accrual Rate ......................................................................................74 
13.3 
Analysis of Secondary Endpoints ..........................................................................74 
14 
HUMAN SUBJECTS PROTECTIONS ............................................................................74 
14.1 
Justification for Subject Selection .........................................................................74 
14.2 
Evaluation of Benefits and Risks/Discomforts ......................................................75 
14.3 
Consent and Assent Process and Documentation ..................................................75 
14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks..................76 
14.5 
Patient Advocate ....................................................................................................76 
REFERENCES ..............................................................................................................................77 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................80 
APPENDIX B: POTENTIAL DRUG INTERACTIONS ..............................................................81 
APPENDIX C: DRUGS WITH RISK OF TORSADES DE POINTES .......................................83 
APPENDIX D: 89Zr-LABELED PANITUMUMAB ORDER FORM ..........................................86 
APPENDIX E - PATIENT STUDY CALENDAR .......................................................................88 
APPENDIX F: EXPANSION PHASE PD COLLECTION WORKSHEETS ..............................91 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
7
1 OBJECTIVES 
Primary Objective: 
• To establish the safety, tolerability, and the maximum tolerated dose of the combination of 
ganetespib and ziv-aflibercept in patients with refractory gastrointestinal carcinomas, non-
squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas 
 
Secondary Objectives: 
• To assess the modulation of HIF1α as a pharmacodynamic marker of therapy with the 
combination of ganetespib and ziv-aflibercept 
 
• To assess modulation of EGFR expression using 89Zr-labeled, EGFR-targeting antibody 
panitumumab PET/CT imaging of tumor lesions prior to and following treatment with 
study drugs as an exploratory non-invasive evaluation of Hsp90 client protein modulation 
 
 
2 
BACKGROUND 
2.1 
Role of Hsp 90 chaperone in Angiogenesis and Cancer 
Induction of angiogenesis is one of the hallmarks of carcinogenesis; malignant tumors are 
dependent upon angiogenesis for oxygen support, growth, and metastasis [1].  The central 
driving force behind angiogenesis is the interaction of pro-angiogenic signaling pathways 
with various endothelial cell signaling pathways.  Additionally, more recent evidence also 
implicates a role for the co-optation of cells in the tumor microenvironment for additional 
tumor support and progression [2].  The development of anti-angiogenic agents has brought 
to light new resistance mechanisms invoked by both tumor cells as well as cells in the 
tumor microenvironment, leading to the idea that simultaneous targeting of multiple 
resistance pathways will enhance anti-tumor activity.  
 
Hsp90 is a molecular chaperone involved in the folding and stabilization of newly 
synthesized or misfolded proteins, and accordingly involved in many signaling pathways 
important for tumor cell survival, proliferation, and metastasis [3].  More than 100 
individual Hsp90 client proteins have been identified.  These include transcription factors 
and proteins involved in angiogenesis (VEGF, VEGFR, HIF1, STAT-3); growth factor 
independence (RAF, EGFR, HER-2, IGFR); resistance to anti-growth signals (CDK4); 
tissue invasion and metastases (MET, MMP2); and avoidance of apoptosis (AKT, RIP, 
Survivin, Bcl-2).  Hsp90 inhibition results in ubiquination and proteosomal degradation of 
misfolded client proteins, providing an opportunity for effecting antitumor activity through 
inhibition of multiple oncogenic pathways.   
 
Extensive preclinical and clinical evidence supports the hypothesis that exposure to anti-
angiogenic therapy can, paradoxically, cause an adaptive-evasive response with induction 
of local invasiveness and distant metastases [4];  HIF1α has been implicated in mediating 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
8
this response and inducing resistance to anti-VEGF therapy [5].  Preclinical models in 
sarcomas confirm synergism of anti-VEGF inhibition and HIF1α-inhibition [6].  Based on 
recent evidence implicating a greater role for Hsp90 in angiogenesis, with direct 
modulation of VEGF signaling, vessel formation [7], and stabilization of the HIF1α 
dimerization complex required for Raf/Mek/Erk-mediated endothelial cell proliferation [8], 
the combination of Hsp90 inhibition with ganetespib and an anti-angiogenic agent such as 
ziv-aflibercept, present a rational novel strategy for improving upon and overcoming 
resistance to the inhibition of angiogenesis.  
 
Ganetespib is a non-geldamycin Hsp90 inhibitor which exerts its action by binding to the 
ATP pocket in the N-terminus of Hsp90.  Preclinical studies demonstrate potent Hsp90 
inhibition in multiple tumor models including colon, lung, and breast [9-12].  Ziv-
aflibercept is a soluble fusion protein comprised of the immunoglobulin domain of 
VEGFR1 and VEGFR2 fused to the Fc portion of human IgG1.  It acts as a high-affinity 
soluble VEGFR decoy receptor, and has high affinity for VEGF-A, VEGF-B, and PIGF.  
VEGF is central to endothelial cell survival and promotion of angiogenesis; PIGF is a 
chemotactic factor of endothelial cells and has been implicated in the mobilization of bone 
marrow-derived progenitor cells and response to VEGF-induced angiogenic signaling [13]. 
 
Rationale for Combination of Ganetespib and Ziv-aflibercept in Gastrointestinal 
Carcinomas: 
Epidermal growth factor receptor is a member of the ErbB family of receptors, and its 
expression is found in an estimated 60-80% of colorectal cases [14].  Events downstream of 
the EGFR pathway have been implicated in colon carcinogenesis, and include Ras-
mediated activation of the PI3K/Akt/mTOR and Raf/Mek/Erk pathways.  EGFR-mediated 
activation of the PI3K/Akt/mTOR pathway has also been implicated in upregulation of 
HIF1α and VEGF [15].  Additionally, both Akt and Raf are known client proteins 
modulated by Hsp90.  In vitro evidence supports antiangiogenic modulation by ganetespib 
in colorectal cancer cells, where significant inhibition of HIF1α and STAT-3 in addition to 
PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, and VEGF were observed in both KRAS wild-type 
and mutant cell lines.  Downregulation of mRNA transcripts for the same angiogenic 
factors previously mentioned were also seen in ganetespib-treated tumor samples [16].  
Antiangiogenic therapy with ziv-aflibercept is currently approved for use in patients with 
metastatic colorectal cancer [17]. 
 
Rationale for Combination of Ganetespib and Ziv-aflibercept in Lung Carcinomas: 
Extensive preclinical evidence exists for antitumor activity of Hsp90 inhibition in non-
small cell lung cancer (NSCLC) [18, 19].  Ganetespib has also previously been tested in 
combination with bevacizumab in preclinical models of NSCLC, with evidence of 
enhancement of in vitro and in vivo efficacy [16].  Based on results of the Phase 3 ECOG 
4599 trial [20] and AVAiL trial [21], bevacizumab is currently approved for the initial 
systemic treatment of patients with metastatic NSCLC.  A recent multicenter Phase 2 study 
of ganetespib in advanced non-small cell lung cancer has demonstrated significant single 
agent activity [22].  In this study, PFS rates at 16 weeks were 13.3% in patients with EGFR 
mutation, 5.9% in patients with KRAS mutation, and 19.7% in patients who had neither 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
9
mutation.  The combination of Hsp90 inhibition, with ganetespib, and anti-angiogenic 
inhibition, with ziv-aflibercept, allows for enhancement of antitumor efficacy. 
 
Rationale for Combination of Ganetespib and Ziv-aflibercept in Urothelial 
Carcinomas: 
EGFR and HER2/neu, both Hsp90 client proteins, are highly expressed in urothelial 
carcinoma cells and expression correlates with stage, grade, and survival [23, 24].  In case 
series studied, HER2/neu expression and amplification correlated with survival both alone 
and when co-expressed with other EGFR family members; median survival for those with 
HER2/neu-expressing tumors was 33 months compared with 50 months in HER2/neu-non-
expressing tumors [25].  Early preclinical data with the EGFR inhibitor cetuximab 
demonstrated a dose-dependent decrease in cell proliferation of the malignant urothelial 
cell line 253J [26].  Additionally, HIF1α overexpression has been implicated as a predictor 
of tumor recurrence and progression in urothelial carcinomas [27].  The combination of 
Hsp90 inhibition, with ganetespib and anti-angiogenic inhibition, with ziv-aflibercept, 
allows for the targeting of multiple poor-prognostic pathways, and amplification of 
antitumor activity. 
 
Rationale for Combination of Ganetespib and Ziv-aflibercept in Sarcomas: 
Angiogenesis is crucial to the growth and dissemination of sarcomas.  Microarray profiling 
of soft tissue sarcomas demonstrated 10-fold higher levels of VEGF compared to normal 
tissues controls [28].  More recent studies demonstrated a role for upregulation of HIF1α as 
a mechanism of resistance of soft tissue sarcomas to antiangiogenic therapies, and that 
inhibition of HIF1α can augment the destruction of tumor vasculature within sarcoma 
xenografts [29].  In addition to VEGF, overexpression of many receptor tyrosine kinases 
has also been implicated in the pathogenesis of soft tissue sarcomas, including HER2 and 
IGF-1R, both are client proteins of Hsp90 [30].  Recent proteonomic analyses of 
osteosarcomas also show overexpression of Hsp90 in all osteosarcomas, and 30 of 75 high-
grade sarcomas analyzed [31]. 
2.2 
Ganetespib 
Mechanism of Action 
Ganetespib is a non-geldamycin inhibitor of Hsp90 chaperone activity, exerting activity 
through binding at the N-terminal adenosine triphosphate (ATP) pocket of Hsp90, and 
inhibiting its function.  Hsp90 inhibition causes its client proteins to adopt aberrant 
conformations, which are then targeted for ubiquination and proteosomal degradation.  
Client protein degradation results in induction of cell cycle arrest and apoptosis, thereby 
inhibiting tumor growth [9].  Ganetespib has activity against a broad spectrum of cancer 
cell lines compared to first generation Hsp90 inhibitors [32] with an average IC50 value 
20-fold lower than 17-AAG [9]. 
 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
10
Preclinical Studies 
 
In Vitro Studies 
Reverse Phase protein arrays performed on lysates from four KRAS mutant NSCLC cell 
lines treated with for 24 hours show diminished expression of multiple receptor kinases 
(including EGFR, MET, HER2), signaling intermediates (CRAF, Src, STAT3, MAPK, 
GSK3), kinases involved in protein synthesis and growth (AKT/mTOR), resulting in the 
activation of apoptotic mediators and cell cycle arrest [33]. 
 
 
Table 1. Fold-changes in protein expression following Ganetespib Treatment (250 nM,  
24 hours) in KRAS- Mutant NSCLC Lines. 
 


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In Vivo Studies 
Pharmacodynamic analyses were performed in mice bearing H3122 xenografts, a non-
small cell lung carcinoma model with constitutively active ELM4-ALK fusion kinase.  
Animals were treated with a single-bolus injection of ganetespib (50 mg/kg) and tumors 
were harvested at 24, 48, 72, and 96 hours.  For comparison, animals were treated with a 
single injection of vehicle or crizotinib (50 mg/kg) and tumors were collected at 24 hours.  
Levels of Hsp90 client proteins were evaluated by immunoblotting, namely ERK, MET, 
EGFR, pSTAT3, and pAKT, and all showed evidence of degradation detectable at 24 
hours, and lasting up to 72 hours (Figure 1). 
 
 
Figure 1: In Vivo Effects of Ganetespib on Expression of Hsp90 Client Proteins in H3122 
Human NSCLC Xenograft Model SCID mice bearing H3122 tumors were treated with vehicle or 
a single bolus injection of ganetespib (50 mg/kg) at the indicated time points between 24 and 96 
hours.  Mice were also treated with a single bolus injection of crizotinib (50 mg/kg) for 24 hours.  
Tumors were resected and the levels of the indicated proteins determined by immunoblotting. 
 
Ganetespib was also shown to reduce the expression of HIF1α levels in NSCLC tumor 
xenografts, as far as 150 µM from the nearest blood vessel, suggesting ganetespib can 
penetrate deep into the hypoxic regions of tumor tissue [data not shown].  In addition, 
exposure to a single bolus of ganetespib also resulted in reduction of CD31 expression 
(endothelial cell marker) by 39%, coordinate with a reduction in cell proliferation and rise 
of apoptosis and hypoxia (Figure 2). 


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Figure 2: In Vivo Effect of Ganetespib on Tumor Vasculature, Proliferation, and Apoptosis in 
the NCI H1975 Xenograft Model.  Mice were injected sc with 5 million NCI-H1975 tumor cells 
in 50% Matrigel.  On D11, animals were treated with vehicle or a single bolus injection of 
ganetespib (125 mg/kg).  Tumors were excised 24 hours after dosing and subject to quantitative 
image analysis for markers of proliferation (BrdU), apoptosis (TUNEL), vasculature (CD31), 
hypoxia (pimonidazole), and perfusion (DiOC7). 
 
H3122 NSCLC tumor xenografts, with constitutively active ELM4-ALK fusion kinase, 
were also treated with ganetespib once weekly, with evidence of durable tumor regression, 
when compared with crizotinib (Figure 3). 
Figure 3: Anti-Tumor Activity 
of Ganetespib in the NCI H3122 
Human NSCLC Xenograft 
Model .  Mice (7/group) were 
injected sc with 5x106 NCI H3122 
tumor cells in 50% Matrigel.   
IV drug treatments (arrowheads) 
were performed starting on D24 
and continued once/week for 5 
weeks for ganetespib (150 mg/kg) 
and 5 times/week for crizotinib 
(200 mg/kg).  %Tumor/Control 
values for D59 are indicated on 
the right.  No excessive body 
weight loss (>20%) was observed 
in any animal.  Error bars 
represent SEM.  
 
 


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Non-Clinical Pharmacokinetics 
The pharmacokinetic (PK) profiles of ganetespib were evaluated in mice, rats, and 
monkeys following intravenous administration.  Ganetespib displayed dose proportional 
PK in all species over the dose ranges tested.  It is highly protein-bound and highly 
distributed throughout nearly all tissues, with limited distribution into the central nervous 
system.  It is extensively metabolized in the liver to mainly glucuronide conjugates.  The 
major route of excretion is in the feces.  Ganetespib was highly cleared in mice and rats, 
and moderately cleared in monkeys.  Mean terminal half-life (T1/2) values for ganetespib in 
the multiple dose studies were approximately 6 and 11 hours in rats and monkeys, 
respectively.  Ganetespib does not appear to accumulate after multiple dosing.  No marked 
sex differences were observed in the PK of ganetespib in either rats or monkeys. 
 
Preclinical Safety Pharmacology Studies and Toxicology Studies 
Ganetespib was evaluated for safety pharmacology effects in a panel of receptor-binding 
assays in vitro and in a rabbit Langendorff heart preparation ex vivo.  Rabbit hearts were 
perfused with vehicle (dimethylsulfoxide [DMSO] in Krebs solution) followed by 
escalating concentrations of ganetespib (10-8, 10-7, 10-6, 10-5, and 10-4 M) for 15 minutes 
each.  Ganetespib minimally decreased the rate of atrioventricular (AV) conductance at 10-6 
and 10-5 M.  At 10-4 M, the PQ interval was not measurable because of arrhythmia.  Also at 
10-4 M, the QRS duration increased, a second degree AV block was produced, and 
occasional supraventricular premature depolarization occurred.  Other cardiac parameters 
were not significantly altered by ganetespib.  The Cmax at 1 mg/kg in cynomolgus monkeys 
correlates to a concentration of 10-8 M, when corrected for plasma protein binding, and is 
100-fold lower than the minimum concentration of 10-6 M at which PQ interval increase 
was observed.  At this concentration, there were no ganetespib-related changes in the mean 
arterial blood pressures or heart rates and no qualitative or quantitative ganetespib-related 
electrocardiogram changes. 
To evaluate ocular toxicities, adult male Sprague Dawley rats received bolus IV injection 
of vehicle or 20 mg/kg/day ganetespib for 2 days.  Twenty-four hours after the last dose, 
ocular toxicity was assessed by TUNEL staining of retinal tissues to detect apoptotic cell 
death.  In subsets of animals, plasma and retinal tissues were collected to determine drug 
exposure.  Ganetespib, at an exposure (AUCt 36.1 µM*h) that exceeded the 216-mg/m3 
human exposure (AUCt 22.5 µM*h), did not elicit retinal photoreceptor injury with no 
increase in TUNEL-positive cells. 
In 3-month studies, ganetespib was administered on Days 1 and 15 of four 21-day cycles.  
Rats tolerated a dose of 20 mg/kg/dose, the NOAEL.  Transient decreases in weight gain 
occurred at 50 and 100 mg/kg/dose, and early deaths occurred at 100 mg/kg/dose.  
Cynomolgus monkeys on the same regimen tolerated doses up to 7 mg/kg/dose, the 
NOAEL.  
 


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Clinical Pharmacokinetic Studies 
 
Pharmacokinetic profiles in a Phase 1 study in solid tumors demonstrated that the 
concentration of ganetespib declined to approximately 10% of Cmax within one hour of 
infusion termination and 1% of Cmax within 8 to 10 hours.  The mean time to reach Cmax 
was 0.79 hours.  There was no apparent drug accumulation with once weekly dosing.  The 
mean ± SD terminal T1/2 was approximately 7.54 ± 2.64 h and plasma drug clearance was 
52.59 ± 17.80 L/h (28.55 + 9.33 L/h/m2).  Clearance and volume of distribution were 
approximately constant across doses.  AUC increased in proportion to dose (Figure 4) [34]: 
 
 
Figure 4. Pharmacokinetic linearity plots. (A) AUC vs. Dose and (B) Cmax vs. Dose.  Solid line 
represents linear regression of D1 (diamond) and D15 (triangle) data combined.  For D1 and 15 
combined, coefficients of determination for AUC and Cmax were 0.75 and 0.76, respectively [34].
 
 
 
 
 
 
  
Clinical Experience 
Ganetespib has been studied in 5 completed Synta-sponsored clinical trials and 3 
completed Synta-sponsored studies in normal healthy volunteers.  Ganetespib is currently 
being studied in 6 ongoing Synta-sponsored clinical trials and 17 investigator-sponsored 
clinical trials.  In Phase 1 studies, ganetespib was well tolerated as a weekly infusion for 3 
weeks of a 4 week cycle, with the maximum tolerated dose at 216 mg/m2 and 
recommended Phase 2 dose at 200 mg/m2.  A recent Phase 2 study of ganetespib 
monotherapy in previously treated patients with non-small cell lung cancer (NSCLC) 
demonstrated 4 objective responses of 99 enrolled patients, stratified by mutant EGFR, 
mutant KRAS, or neither mutation [22].  These 4 patients were found to harbor anaplastic 
lymphoma kinase (ALK) gene rearrangement on retrospective analysis.  PFS rates at 16 
weeks were 13.3% for the mutant EGFR cohort, 5.9% for the mutant KRAS cohort, and 
overall 19.7% for the remaining cohort which included the 4 patients who achieved a 
partial response [22].  Ganetespib has also been tested in combination with docetaxel 
(Synta-sponsored Study 9090-07) and was found to be tolerable at a dose of 150 mg/m2 on 
day 1 and 15, with docetaxel at 75 mg/m2 on day 1. 
 


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Potential Drug Interactions 
Inhibition and induction potentials of ganetespib were investigated in human liver 
microsomes and human hepatocytes.  Ganetespib is a substrate for P-gp but not BRCP.  
Ganetespib is an inhibitor of CYP2C19 and CYP3A4 (midazolam specific), but is not an 
inducer of CYP or UGT enzymes.  In liver microsomal studies, inhibition of CYP1A2, 
CYP2B6, CYP2D6 and CYP3A4 (testosterone-specific) by ganetespib was less than 50% 
at concentrations up to 10 µM (IC50 > 10 µM, maximum solubility conditions); ganetespib 
inhibited activities of CYP2C8, CYP2C9, CYP2C19 and CYP3A4 (midazolam-specific) 
with IC50 values of 9.8, 8.3, 1.0, and 1.1 µM, respectively.  Inhibition of CYP2C8, 
CYP2C9, and CYP2C19 were competitive with inhibition constant (Ki) values of 3.2, 4.1, 
and 0.28 µM, respectively, whereas inhibition of CYP3A4 (midazolam specific) was non-
competitive with a Ki value of 1.8 µM. Inhibition of CYP enzymes was reversible in all 
cases.  In human hepatocytes, ganetespib did not induce CYP1A2, CYP2B6, or CYP3A4 at 
concentrations up to 10 µM.  No increases in the levels of CYP1A2, CYP2B6, CYP3A4, 
UGTA1, and UGT1A6 were observed by Western Blot analyses after incubation of 
ganetespib in human hepatocytes. 
A panel of potential co-medications (atorvastatin, dexamethasone, fentanyl, furosemide, 
morphine, and warfarin) was evaluated for potential drug interactions with ganetespib via 
hepatic metabolism using human cryopreserved hepatocytes suspensions.  Ganetespib in 
vitro clearance was not affected by any of the co-medications tested at clinically relevant 
concentrations.  Ganetespib did not markedly affect the CYP3A4-mediated metabolism of 
atorvastatin, dexamethasone, fentanyl, or warfarin.  Ganetespib at 20 µM inhibited UGT 
mediated metabolism of potential co-medications, morphine (mainly UGT2B7), and 
furosemide (UGT1As), by approximately 30% in human hepatocytes at clinically relevant 
concentrations of these medications. 
Due to evidence of increase in QTc interval 24 hours after the dose of ganetespib in a 
pharmacology study of healthy volunteers (Investigator’s Brochure), certain drugs known 
to be associated with QTc prolongation (Appendix C) should not be used by patients 
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.  Ondansetron has been associated with 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 5HT3 antagonists is acceptable (e.g., 
palonosetron, granisetron, or tropisetron). 
2.3 
Ziv-aflibercept 
Mechanism of Action 
Angiogenesis is one of the hallmarks of carcinogenesis and malignant tumors are 
dependent upon angiogenesis for oxygen support, growth, and metastasis.  VEGF, the key 
growth factor in angiogenesis, is comprised of 5 isoforms (VEGF-A, -B, -C, -D, -E, and 
placental growth factor [PlGF]).  These growth factors exert their action through 3 tyrosine 
kinase receptors, VEGFR1, VEGFR2 and VEGF receptor 3 (VEGFR3).  Ziv-aflibercept is 
a recombinant fusion protein consisting of human vascular endothelial growth factor 


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(VEGF) receptor extracellular domains fused to the Fc portion of human immunoglobulin 
G1 (IgG1).  Ziv-aflibercept contains portions of the extracellular domains of 2 different 
vascular endothelial growth factor receptors (VEGFRs): VEGFR1 (also known as Flt-1) 
and VEGFR2 (also known as KDR or Flk-1).  It acts as a high-affinity soluble VEGFR 
decoy receptor, and has high affinity for VEGF-A, VEGF-B, and PIGF.  The affinity 
constants (KD) for binding to 2 human isoforms of VEGF, VEGF165 and VEGF121, are 
0.50 pmol/L and 0.36 pmol/L, respectively.  The KD for human PlGF2 is 39 pmol/L.  The 
binding of ziv-aflibercept to its ligands in vivo is expected to block tumor angiogenesis and 
vascular permeability. 
 
Nonclinical Toxicology Studies 
 
General toxicity studies were conducted in cynomolgus monkeys and based on weekly and 
every two week intravenous administration of ziv-aflibercept for up to 6 months, and 
consistent with inhibition of the VEGF pathway previously reported with other anti-VEGF 
agents.  Target organs indentified in these studies included bone (interference with growth 
plate maturation of long bones and osteocartilaginous exostoses of vertebrae), kidney 
(frequently increased glomerular mesangial matrix, occasionally hyperplasia of parietal 
epithelium, and periglomerular fibrosis), adrenals (decreased vacuolation with 
inflammation), nasal cavity (atrophy/loss of the septum and/or turbinates), kidney 
(glomerulopathy with inflammation), ovary (decreased number of maturing follicles, 
granulosa cells, and/or theca cells).  Other microscopic findings in the 6-month chronic 
toxicity study included vascular alterations in the choroid plexus and digestive tract, 
vascular degeneration and fibrosis in several tissues including the heart, and hepatic portal 
inflammation and periportal necrosis. 
 
Ziv-aflibercept was shown to alter fertility parameters in sexually mature male and female 
monkeys treated for 6 months.  These effects were noted at plasma exposures of free ziv-
aflibercept that were close to exposures in patients at the recommended pharmacological 
doses and were considered to impact fertility in both males and females.  Inhibition of the 
female reproductive function by anti-VEGF drugs is related to the key role of VEGF-
mediated angiogenesis in follicular and luteal development.  The effects of ziv-aflibercept 
on sexually mature male and female fertility were reversible.   
 
The safety pharmacology studies showed that ziv-aflibercept reduced vascular density in 
certain normal tissues in mice, increased blood pressure in rats and mice and delayed 
wound repair and healing in rabbits.  Detectable effects these parameters were noted at 
doses that were lower than the optimal pharmacologic doses determined in tumor bearing 
mice.  Maximal effects on wound healing and blood pressure were noted only at doses in 
the same range as pharmacologically active doses.  The increase in blood pressure reported 
in rodents was reversible and was reported in patients treated with ziv-aflibercept.  The 
reversibility of the effect on wound repair and healing was not evaluated.  In full-thickness 
excisional and incisional skin wound models, ziv-aflibercept administration reduced 
fibrous response, neovascularization, epidermal hyperplasia/re-epithelialization, and tensile 


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strength.  Ziv-aflibercept had no effects on respiratory function in rats or on thrombus 
formation in rabbits. 
 
Pharmacokinetic Studies 
 
Plasma concentration of free and VEGF-bound ziv-aflibercept were measured using 
specific enzyme-linked immunosorbent assays (ELISA).  Free ziv-aflibercept 
concentrations exhibited linear pharmacokinetics in the dose range of 2-9 mg/kg.  
Following 4 mg/kg every two week administration schedule, the elimination half-life of 
free ziv-aflibercept was approximately 6 days (range 4-7 days).  Steady state concentrations 
of free ziv-aflibercept were reached by the second dose.  The accumulation ratio for free 
ziv-aflibercept was approximately 1.2 after an administration of 4 mg/kg every 2 weeks.  
Based on population pharmacokinetic analyses in patients with mild and moderate hepatic 
impairment, there was no effect of total bilirubin, aspartate aminotransferase, and alanine 
aminotransferase on the clearance of free ziv-aflibercept.  There are currently no data 
available for patients with severe hepatic impairment (defined as total bilirubin >3 times 
upper limit of normal and any SGOT/AST).  Based on population pharmacokinetic 
analyses of patients with mild, moderate, and severe renal impairment, there was no 
clinically observed effect of creatinine clearance on the clearance of free ziv-aflibercept. 
 
Summary of Clinical Studies 
To date, the clinical development of ziv-aflibercept encompasses a total of 41 clinical 
oncology trials (25 Sanofi trials and 16 NCI trials) in more than 3700 cancer patients 
mostly with advanced solid malignancies as well as 2 clinical trials in 76 healthy subjects 
(PDY6655 and PDY6656).  Doses have been administered up to 800 μg/kg SC twice 
weekly, 7 mg/kg IV every 2 weeks (q2w), and 9 mg/kg IV every 3 weeks (q3w). 
 
Based on combination Phase I dose-escalation studies conducted to evaluate safety, PK, 
and antitumor activity in patients with solid malignancies, the recommended Phase II dose 
(RP2D) of ziv-aflibercept was established at 4 mg/kg administered intravenously every 2 
weeks when combined with chemotherapy. 
 
In Phase III combination studies, ziv-aflibercept at a dose of 4 mg/kg administered 
intravenously every 2 weeks was combined with standard doses of the following cytotoxic 
agents: oxaliplatin/5-fluorouracil/leucovorin (FOLFOX4), [TCD6117]), 
irinotecan/leucovorin/5-fluorouracil (irinotecan/LV5FU2, [TCD6118]), and gemcitabine or 
gemcitabine and erlotinib (TCD6121), gemcitabine (EFC10547/VANILLA), and 
irinotecan/5-FU/leucovorin (FOLFIRI, [EFC10262/VELOUR]).  Additional Phase III 
studies have also combined ziv-aflibercept at a dose of 6 mg/kg every 3 weeks in 
combination with standard doses of docetaxel (Taxotere®)/cisplatin/5-fluorouracil (TCF, 
[TCD6119]), docetaxel or docetaxel/cisplatin or pemetrexed (TCD6120), and docetaxel 
(EFC10261/VITAL). 
 
FDA Approval was obtained based on results of Study EFC10262/VELOUR, a 
multinational, randomized, double-blind study, comparing the efficacy of ziv-aflibercept 


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administered at a dose of 4 mg/kg intravenously every 2 weeks versus placebo in patients 
with metastatic colorectal cancer treated with irinotecan /5-FU combination (FOLFIRI) 
after failure of an oxaliplatin based regimen.  The efficacy conclusion from 
EFC10262/VELOUR was that ziv-aflibercept administered at a dose of 4 mg/kg over 1 
hour, every 2 weeks, in combination with the FOLFIRI regimen demonstrated a 
statistically and clinically significant improvement in overall survival (OS), progression 
free survival (PFS) duration and a significantly higher overall response rate (ORR) 
compared to placebo/FOLFIRI.  The addition of ziv-aflibercept to FOLFIRI gave no new 
toxicity signals but did enhance some toxicities of FOLFIRI, namely diarrhea, asthenia, 
decrease appetite, weight decrease, palmar plantar erythrodysesthesia syndrome, and 
hematological abnormalities (with the exception of anemia).  Grade 3 or 4 events occurred 
with >2% higher incidence in the ziv-aflibercept/FOLFIRI arm compared to 
placebo/FOLFIRI arm, and included neutropenia, hypertension, diarrhea, asthenia, 
leucopenia, stomatitis and ulceration, infection, neutropenic complications and 
gastrointestinal (GI) and abdominal pain. 
 
The risk of treatment-emergent adverse events identified as possible anti-VEGF class 
specific adverse events were significantly increased and these were more frequently all 
grade hypertension and hemorrhage.  Analyses of pre-specified subgroups during 
EFC10262/VELOUR, showed no statistically significant differences across subgroups 
(gender, race, age, of body weight, creatinine clearance, ECOG PS at baseline) with regard 
to incidences of hypertension, hemorrhage, venous thromboembolic events, arterial 
thromboembolic events, wound healing complications, renal failure events, acute drug 
reactions.  The safety profile (either VEGF-blockade adverse events or chemotherapy 
induced toxicities) in patients with renal or liver function impairment did not significantly 
differ when compared to that observed in patients with normal renal or liver function at 
baseline.  The safety profile of ziv-aflibercept in combination with FOLFIRI was also 
comparable between patients with or without prior bevacizumab. 
 
Since this current study (14-C-0150) opened, there have been two dose limiting toxicities 
in patients on DL1.  The first patient, who had a history of peptic ulcer disease, had grade 3 
recurrent epigastric pain despite optimal management.  The second patient had abdominal 
pain with colon cancer; a CT scan showed progressive disease and bowel perforation.  This 
patient died on cycle 1 day 22.  Because bowel perforation has been seen with ziv-
aflibercept, it may have contributed to the toxicity.  In response to these events the protocol 
was amended to add lower dose levels. 
 
 
2.4 
89Zr-labeled, EGFR-targeting Antibody Panitumumab PET/CT 
 
Panitumumab is a fully human monoclonal antibody (mAb) that targets EGFR and is 
approved for use by the FDA for the treatment of EGFR-expressing metastatic colorectal 
cancer with disease progression [35].  Panitumumab competes with endogenous ligands 
such as epidermal growth factor and tumor growth factor α (TGF-α) to block stimulation 
of the EGF receptor.   


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89Zr has emerged as a promising positron-emitting radionuclide [36-39] for diagnostic 
immune-PET imaging.  The half-life (78.4 h) provides a good match with the biological 
half-life of an intact mAb.  Based on findings from recent clinical trials in Europe, 89Zr-
labeled mAbs are safe for human use [39].  It is also being used for imaging in NCI 
Protocol # 06-C-0164 with no adverse events.  We anticipate that 89Zr-immuno-PET with 
panitumumab as targeting ligand will prove to be an ideal imaging modality to quantify 
EGFR expression as a biomarker to guide patient selection, therapy, and dosing in the 
future.  No clinical decisions will be made based on the 89Zr-panitumumab imaging 
findings in this study.  Use of 89Zr-panitumumab as an investigational agent is covered by a 
cross-reference letter from IND 116,229, held by DCTD/CIP. 
 
89Zr-panitumumab has been prepared with high radiochemical purity and specific activity 
at the Frederick National Laboratory for Cancer Research.  The immunoconjugate was 
found to be stable with respect to loss of the radio-isotope in human serum.  Immuno-PET 
experiments indicated that 89Zr-panitumumab shows excellent potential as a PET tracer for 
specific noninvasive delineation of EGFR-positive tumors in vivo. 
 
Human cell lines with low, medium, and high levels of EGFR (BT-474, MDA-MB-231, 
and MDA-MB-468, respectively) were implanted subcutaneously as xenografts in athymic 
nude mice (Figure 5)[40]. 89Zr-panitumumab was administered intravenously, and a CT 
scan followed by a static PET scan was performed at 96 hours.  EGFR protein expression 
correlated well with the PET tracer present in tumors. 
 
Figure 5. Tumor uptake of 89Zr-
panitumumab in sc xenograft 
models with different levels of 
EGFR expression.  10.18 ±1.24 
MBq of 89Zr-panitumumab were 
administered IV via tail-vein, and 
a 5 min CT scan followed by a 
30min static PET scan were 
performed 96-h post-injection 
[40]. 
 
 
 
 
 
 
 
Biodistribution studies of 89Zr-panitumumab were performed in male and female mouse 
cohorts, which were injected with ~100 µCi of agent via tail vein injection.  A fraction of 
the animals were sacrificed daily up until 6-days post injection.  The organs, blood, and 
carcass activity was measured and recorded as %ID/g.  For the hollow organs (i.e., gut, 


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urinary bladder) the total activity within the organ was recorded.  Minimal radiotracer was 
excreted from the body over the entire 6-day period; the loss via urinary excretion was 
likewise minimal.  Human dose estimates were made using appropriate correction factors 
(to account for the differences in percent total body weight of each solid organ) to calculate 
residence times for each organ.  OLINDA/EXM 1.1 software was used to calculate human 
dose estimates (Table below).  Based on these figures, we intend to administer a dose of 
not more than 1.0 mCi (mass dose <1 mg) to patients in this protocol.   
 
89Zr-labeled, EGFR-targeting antibody panitumumab human dosimetry estimates for the 
organs receiving the highest dose: 
 
Target Organ 
89Zr-panitumumab male/female 
(rads/mCi) 
Heart 
10.1/12.7 
Lungs 
3.14/3.77 
Liver 
2.74/3.47 
Red marrow 
2.57/3.15 
Spleen 
2.61/2.87 
Effective Dose (rem/mCi) 
1.92/2.47 
 
We have early human experience with 89Zr-panitumumab imaging in the ongoing Phase II 
Study of BAY 43-9006 (Sorafenib) in Combination with Cetuximab (ErbituxTM) in EGFR 
Expressing Metastatic Colorectal Cancer (CRC) Protocol 06-C-0164.  So far, two patients 
have undergone imaging with good tolerability and no adverse side effects. 
 
3 PATIENT SELECTION 
3.1 
Eligibility Criteria 
3.1.1 Patients must have histologically confirmed recurrent or metastatic gastrointestinal 
carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, 
and sarcomas with disease progression after at least one line of standard therapy.  
Disease should have progressed following all treatments known to prolong survival, 
unless a given treatment is contraindicated. 
• Patients with colorectal carcinoma must have progressed through at least two 
lines of standard chemotherapy in the metastatic setting.   
• Patients with non-small cell lung cancer with known sensitizing EGFR mutation 
and/or ALK rearrangement should have received prior erlotinib and/or 
crizotinib, respectively.   
• Patients with urothelial carcinoma will have progressed on prior platinum-based 
therapy or for which platinum-based therapy is contraindicated.   
• Patients enrolled on the expansion phase of the protocol must demonstrate 
EGFR expression by immunohistochemistry on archival tumor samples prior to 
undergoing 89Zr-panitumumab PET/CT scans. 


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3.1.2 Age ≥18 years of age.  
3.1.3 ECOG performance status < 2 (see Appendix A). 
3.1.4 Life expectancy > 3 months. 
3.1.5 Patients must have normal organ and marrow function as defined below: 
− absolute neutrophil count  
≥1,500/mcL 
− platelets  
 
 
 
 
 
≥100,000/mcL 
− total bilirubin 
 
 
 
 
≤1.5 X institutional upper limit of normal 
− AST(SGOT)/ALT(SGPT)  
≤3 X institutional upper limit of normal 
− creatinine 
 
 
 
 
 
≤1.2X institutional upper limit of normal 
 
OR 
 
− creatinine clearance  
 
 
≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal 
− urine protein/creatinine  
 
< 1 mg/mg 
− INR  
 
 
 
 
 
 
< 1.5 
3.1.6 Cardiac function within institutional normal limits on echocardiogram. 
3.1.7 Patients must have blood pressure no greater than 140 mmHg (systolic blood 
pressure) and 90 mmHg (diastolic blood pressure) for eligibility.  Initiation or 
adjustment of antihypertensive medications is permitted prior to study entry 
provided that the average of three blood pressure measurements at enrollment visit 
is less than 140/90 mmHg. 
3.1.8 The effects of ganetespib on the developing human fetus are unknown.  For this 
reason and because anti-angiogenic agents similar to ziv-aflibercept are known to 
be teratogenic, women of child-bearing potential and men must agree to use two 
forms of contraception (hormonal or barrier method of birth control; abstinence; 
sterilization) prior to study entry, for the duration of study participation, and for 3 
months after completing study treatment.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately.  Men treated or enrolled on this 
protocol must also agree to use two forms of contraception prior to the study, for 
the duration of study participation, and for 3 months after completion of 
administration of both ganetespib and ziv-aflibercept. 
3.1.9 Ability to understand and the willingness to sign a written informed consent 
document. 
3.1.10 During the escalation phase of the protocol, patients may have evaluable or 
measurable disease.  During the expansion phase of the protocol, patients must have 
1) measurable disease, 2) disease amenable to biopsy and 3) willingness to undergo 
pre- and post-treatment biopsies. 


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3.2 
Exclusion Criteria 
3.2.1 Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not 
recovered from adverse events due to agents administered more than 3 weeks 
earlier.   
3.2.2 Patients who are receiving any other investigational agents. 
3.2.3 Patients with known active brain metastases or carcinomatous meningitis are 
excluded from this clinical trial.  Patients whose brain metastatic disease status has 
remained stable for ≥ 4 weeks following treatment of brain metastases are eligible 
to participate at the discretion of the principal investigator. 
3.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
untreated infection, or psychiatric illness/social situations that would limit 
compliance with study requirements.  
3.2.5 Patients with known serious cardiac illness or medical conditions, including but not 
limited to: 
• Clinically unstable cardiac disease, including unstable atrial fibrillation, 
symptomatic bradycardia, unstable congestive heart failure, unstable angina or 
history of myocardial infarct within 6 months prior to enrollment, or indwelling 
temporary pacemaker 
• Ventricular tachycardia or a supraventricular tachycardia that requires treatment 
with antiarrhythmic agents 
• Second- or third-degree atrioventricular block unless treated with a permanent 
pacemaker 
• Complete left bundle branch block 
• History of long QT syndrome or a family member with this condition 
3.2.6 No major surgery within 4 weeks prior to enrollment or history of gastrointestinal 
bleeding within 3 months prior to enrollment. No signs or symptoms of active 
bleeding or nonhealing ulcer will be permitted at study entry. Patients with central 
pulmonary tumors with evidence of bronchial invasion, or presenting with 
hemoptysis will be excluded. 
3.2.7 QTc > 470 msec on electrocardiogram (by Bazett’s; average of triplicate recordings 
at the discretion of the PI) will exclude patients from entry on study.  Medications 
that are known to cause QTc interval prolongation are prohibited for patients 
entering on trial.  Patients for whom a given medication that may cause QTc 
interval prolongation cannot be discontinued, may be eligible at the discretion of the 
study PI, provided QTc interval criteria is met at enrollment.  A comprehensive list 
of agents with the potential to cause QTc prolongation can be found in Appendix C 
and at http://crediblemeds.org. 


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3.2.8 Pregnant women and women who are breastfeeding are excluded from this study 
because the effects of the study drugs on the developing fetus are unknown.  
3.2.9 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with ganetespib and ziv-
aflibercept.  In addition, these patients are at increased risk of lethal infections when 
treated with marrow-suppressive therapy.  Appropriate studies will be undertaken in 
patients receiving combination antiretroviral therapy when indicated. 
3.2.10 Substrates of CYP3A4 or CYP2C19 
Preliminary results of a clinical drug-drug interaction study, examining the effect of 
ganetespib on the pharmacokinetics of the CYP2C19-sensitive probe omeprazole, 
show a modest (20%) increase in omeprazole exposure when coadministered with 
ganetespib.  In vitro data implies expectation of greater interaction with CYP2C19 
substrates than with CYP3A4 substrates.  Caution is advised when sensitive narrow 
therapeutic range CYP3A4 or CYP2C19 substrates are concomitantly administered. 
Inhibitors of P-Glycoprotein Efflux Transporters 
Concomitant medications that are strong inhibitors of P-glycoprotein efflux 
transporters should be used with caution during the study; examples of these 
medications include ritonavir, cyclosporine, verapamil, erythromycin, ketoconazole, 
itraconazole, quinidine, and elacridar. 
3.2.11 Concurrent anticoagulation will be permitted providing the patient is receiving a 
stable dose of anticoagulants before study entry.  Patients receiving anticoagulants 
will be eligible for this trial.  Evidence of clinically significant bleeding diathesis or 
underlying coagulopathy (e.g., INR > 1.5 without vitamin K antagonist therapy) 
will not be permitted  
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
3.4 
Screening Evaluation 
3.4.1 Histologic confirmation of primary tumor tissue or of known recurrence will be 
required from each participant to confirm diagnosis.  Additionally, EGFR 
expression by immunohistochemistry on archival tissue will be required for patients 
undergoing 89Zr-panitumumab scans. 
3.4.2 History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, and performance score) will be conducted 
within 72 hours prior to enrollment.  


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3.4.3 Imaging Studies (Baseline): Every participant should have an evaluation of known 
sites of disease as part of the baseline evaluation.  All patients will be required to 
undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of disease within 
28 days prior to enrollment.  MRI evaluation of site of disease may be performed in 
lieu of CT evaluation at the discretion of the principal investigator if it is the 
opinion of the investigator that this modality would provide a more accurate 
assessment of disease than a CT would, for a given site. 
3.4.4 Electrocardiogram within 1 week prior to enrollment.  Echocardiogram evaluation 
to assess cardiac function must be performed within 4 weeks of enrollment. 
3.4.5 Laboratory Evaluation: Baseline laboratory data are to be obtained within 72 hours  
prior to enrollment: 
• Hematological Profile: CBC with differential. 
• Biochemical Profile: albumin, total bilirubin, BUN, calcium, creatinine, 
SGOT [AST], SGPT [ALT], amylase, lipase, magnesium, potassium, and 
sodium. 
• Coagulation Profile: PT, PTT, INR.  
• Serum pregnancy test for female participants of childbearing potential. 
 
3.4.6. All study participants must have a baseline eye exam by a qualified ophthalmologist 
within 4 weeks prior to enrollment and as clinically indicated thereafter. 
 
 
4 REGISTRATION PROCEDURES 
4.1 
Registration Process 
Authorized staff must register an eligible candidate with NCI Central Registration Office 
(CRO) within 24 hours of signing consent.  A registration Eligibility Checklist from the 
Web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and 
sent via encrypted email to:  NCI Central Registration Office (HOIS) 
(ncicentralregistration-l@mail.nih.gov).  After confirmation of eligibility at Central 
Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the 
patient on the protocol prior to the release of any investigational agents.  Verification of 
Registration will be forwarded electronically via e-mail to the research team.  A recorder is 
available during non-working hours. 
 
Off-Study Procedure: Authorized staff must notify the Central Registration Office (CRO) 
when a patient is taken off-study.  An off-study form from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed 
and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
(ncicentralregistration-l@mail.nih.gov). 
 
 


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5 TREATMENT PLAN 
This is an open-label Phase I trial evaluating the combination of ganetespib, Hsp90 inhibitor, 
and ziv-aflibercept, VEGF-trap, in patients with refractory gastrointestinal carcinomas, non-
squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas, whose disease 
has progressed following at least one line of standard therapy.  
 
Reported adverse events and potential risks for ganetespib and ziv-aflibercept are described in 
Section 7.  Appropriate dose modifications for ganetespib and ziv-aflibercept are described in 
Section 6. 
 
History and physical examination can be done up to 3 days before the start of a new cycle.  
Patients will be examined at the Clinical Center on days 1, 8, and 15 of each cycle, prior to 
treatment.  Each cycle is 28 days (± 1 day due to scheduling conflicts).   
 
Labs (CBC with differential; serum chemistries) will be performed on days 1, 8, and 15 of each 
cycle (+/- 1 day during the cycle and up to 3 days before start of a new cycle). 
 
Electrocardiogram will be done before each ganetespib administration and approximately 
24 hours after drug administration during each week of treatment of the first cycle.  For 
subsequent cycles, electrocardiogram will be done before each ganetespib administration with 
post-treatment electrocardiogram as clinically indicated. 
 
All study participants must have a baseline eye exam by a qualified ophthalmologist within 
4 weeks prior to enrollment and as clinically indicated thereafter. 
 
CT scans will be performed at baseline, and repeat-imaging scans will be performed every 
2 cycles.  MRI evaluation of site of disease may be performed in lieu of CT evaluation at the 
discretion of the principal investigator if it is the opinion of the investigator that this modality 
would provide a more accurate assessment of disease than a CT would for a given site. 
 
The starting dose will start at dose level 1 per dosing schema below.  Ganetespib will be dosed 
based on body surface area (mg/m2).  Ziv-aflibercept will be dosed based on body weight 
(mg/kg). 
5.1 
Agent Administration 
5.1.1 Ganetespib Administration 
Ganetespib will be administered intravenously, over one hour, weekly, on days 1, 8, 
and 15 of each 28-day cycle.  During the expansion phase, for cycle 1 only, 
ganetespib will be administered intravenously on days 8 and 15 of the 28-day cycle, 
with omission of day 1 treatment in order to accommodate tumor biopsies (*see 
dosing schema below). 


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5.1.2 Ziv-aflibercept administration 
Ziv-aflibercept will be administered intravenously, over one hour, every 2 weeks, 
on days 1 and 15 of each 28-day cycle. 
 
Dosing Schema: 
Dose 
Level 
Ganetespib (IV)  
days 1, 8, and 15* 
Ziv-aflibercept (IV) 
days 1 and 15 
-2 
80 mg/m2 
3 mg/kg 
-1 
100 mg/m2 
3 mg/kg 
1 
100 mg/m2 
4 mg/kg 
2 
150 mg/m2 
4 mg/kg 
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient’s malignancy. 
 
Due to evidence of increase in QTc interval 24 hours after the dose of ganetespib in a 
pharmacology study of healthy volunteers (Investigator’s Brochure), certain drugs known 
to be associated with QTc prolongation (Appendix C) should not be used by patients 
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.  Ondansetron has been associated with 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 5HT3 antagonists is acceptable 
(e.g., palonosetron, granisetron, tropisetron). 
 
5.2 
Definition of Dose-Limiting Toxicity 
Determination of dose-limiting toxicity will be based on toxicities observed in the first 
cycle of therapy.  Dose escalation will proceed within each cohort according to the 
following scheme.  Dose-limiting toxicity (DLT) is defined below: 
 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be declared 
the maximally administered dose (highest dose administered).  
Three (3) additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously at that dose. 


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1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the next 
dose level. 
• If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered 
dose.  Three (3) additional patients will be entered at the next 
lowest dose level if only 3 patients were treated previously at 
that dose. 
≤1 out of 6 at highest dose level 
below the maximally 
administered dose 
This is generally the recommended phase 2 dose.  At least 6 
patients must be entered at the recommended phase 2 dose. 
 
Dose limiting toxicity (DLT) is defined as an adverse event that is related (possibly, 
probably, or definitely) to administration of study drugs and fulfills one of the following 
criteria. 
5.2.1 Grade ≥ 3 Non-Hematological Toxicity 
Grade ≥ 3 non-hematological toxicity felt to be related to study medications will be 
considered dose-limiting with the following clarifications: 
5.2.1.1 Diarrhea Grade 3 will only be considered dose-limiting if it is refractory to 
treatment as outlined in Section 5.3.2, Supportive Care Guideline, and 
unable to be corrected to Grade 2 or less within 24 hours.  Bloody or Grade 
4 diarrhea will be dose-limiting. 
5.2.1.2 Nausea and vomiting Grade 3 will only be considered dose-limiting if it is 
refractory to anti-emetic therapy and unable to be corrected to Grade 1 or 
less within 24 hours as outlined in Section 5.3.1. 
5.2.1.3 Rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 
hours with IV fluids will be considered dose-limiting.  All Grade 4 rises in 
creatinine will be dose limiting. 
5.2.1.4 Grade ≥ 3 metabolic toxicities unable to be corrected to Grade 1 or baseline 
within 48 hours (hypocalcemia or hypercalcemia, hypomagnesemia or 
hypermagnesemia, and hyponatremia) will be considered dose limiting.  For 
hypokalemia or hyperkalemia, grade ≥ 2 toxicities unable to be corrected to 
grade 1 or less within 48 hours will be considered dose limiting.  Grade 4 
metabolic toxicities that are symptomatic will be considered dose limiting 
regardless of duration or ability to correct. 
5.2.1.5 Any Grade 4 QTc prolongation will be considered dose limiting and will 
require treatment discontinuation 
5.2.2 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding. 


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5.2.3 Grade 4 neutropenia ≥ 5 days or febrile neutropenia. 
5.2.4 Any degree or anemia, leukopenia in the absence of grade 4 neutropenia ≥ 5 days, 
or lymphopenia will not be considered dose limiting. 
5.2.5 Any degree of alopecia will not be considered dose limiting. 
5.2.6 Grade 3 fatigue of greater than 1 week duration. 
5.2.7 Failure to tolerate 100% of the dosing in the first cycle. 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
The predominant toxicity observed in clinical and non-clinical toxicology studies was 
diarrhea, nausea, vomiting, and abdominal pain.  Anemia was more commonly seen with 
ziv-aflibercept.  Weekly blood counts and chemistry panels will be obtained prior to 
treatment each week.  If any weekly evaluation demonstrates grade ≥ 2 neutropenia or 
thrombocytopenia, treatment will proceed but a repeat hematology assessment will be 
obtained prior to the next treatment or within a week if the last treatment received was on 
Day 15 of the cycle.  Platelet count must improve to Grade 1 or better and neutrophil count 
must improve to Grade 2 or better prior to dosing. 
 
All patients will be provided with the best available supportive care.  All concurrent 
medications should be documented prior to initiation of treatment, and be periodically 
reviewed with the patient. 
 
Based on in vitro and in vivo data, ganetespib is primarily metabolized (glucuronidated) by 
UGT1A9 and to a lesser extent by UGT1A1, UGT1A3, and various P450 enzymes.  It is 
also a substrate for P-glycoprotein, but is primarily eliminated through glucuronidation.  In 
in vitro studies, ganetespib is a moderate inhibitor of CYP2C19 and CYP3A4.  No 
dedicated drug-drug interaction studies have been conducted for ziv-aflibercept.  Due to the 
potential for drug-drug interactions with study agents, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, and alternative therapies.  
Concurrent use of strong P450 inducers or inhibitors will not be permitted.  Concurrent use 
of moderate or strong UGT1A9 inhibitors (e.g., efavirenz and propofol) should be avoided.  
Concurrent use of inducers of UGTs (e.g., rifampin, phenobarbital, phenytoin, and St. 
John’s Wort) may significantly increase ganetespib clearance, resulting in reduced plasma 
concentration and should be avoided.  Concurrent use of weak P450 inducers, inhibitors, or 
substrates will be permitted at the discretion of the Principal Investigator. 
 
The QTc study in healthy volunteers has reported a modest increase in QT interval 
24 hours post ganetespib dose.  To date, clinical experience with ganetespib does not 
support 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, patients should avoid concomitant drugs that may 
cause QTc prolongation, see Appendix C. 


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5.3.1 Nausea/Vomiting 
Anti-emetics will not be administered routinely prior to either ganetespib or ziv-
aflibercept (VEGF-Trap).  However, if a patient develops nausea/vomiting, anti-
emetics such as but not limited to prochlorperazine, metoclopramide, 5-HT3 
antagonists (except for ondansetron), or aprepitant may be given.  In addition, if a 
patient develops nausea and/or vomiting that is Grade 2 or greater, antiemetics may 
be instituted prophylactically at the discretion of the investigator with subsequent 
treatments.  Nausea and vomiting will be considered refractory if it does not resolve 
to ≤ Grade 1 within 24 hours. 
5.3.2 Diarrhea 
Prophylactic anti-motility agents will be permitted with treatment as diarrhea is a 
known toxicity of both agents and the established recommended dose of ganetespib 
was established based on prophylactic administration of anti-motility agents.  
Prophylactic treatment will start 1-2 hours before ganetespib administration.  If 
diarrhea develops despite prophylactic treatment with anti-motility agents and does 
not have an identifiable cause other than study drug administration, addition of anti-
motility agents such as tincture of opium (deodorized 10%), Lomotil (diphenoxylate 
HCl 2.5 mg + atropine sulfate 0.025 mg/tablet) dosed according to package insert, 
or loperamide 4 mg po after the first unformed stool with 2 mg po with every 2 
hours as long as unformed stools continue (4 mg every 4 hours while asleep) may 
be used.  No more than 16 mg of loperamide should be taken during a 24-hour 
period).  This regimen can be repeated for each diarrheal episode and will continue 
for 12 hours after the first formed stool.  Diarrhea will be considered refractory if it 
does not resolve within 24 hours ≤ to Grade 2 with the above measures.  If the 
patient develops blood or mucus in the stool, dehydration, or hemodynamic 
instability, or fever along with the diarrhea, anti-diarrheals will be discontinued and 
the patient will be treated with IV fluids and antibiotics as medically indicated. 
5.3.3 Neutropenia 
To reduce the risk of severe myelosuppression events, a complete blood count 
(CBC) should be performed prior to each weekly treatment.  Febrile neutropenia is 
a life-threatening complication requiring hospitalization and urgent broad-spectrum 
antibiotics, as well as an aggressive search for the source and microbial cause of the 
episode.  Growth factors to prevent neutropenia will not be administered 
prophylactically.  If necessary, they may be administered according to accepted 
American Society of Clinical Oncology (ASCO) guidelines to allow re-treatment. 
5.3.4 Anemia 
Symptomatic anemia should be treated with red blood cell transfusion and is 
recommended if the hemoglobin falls below 8 g/dL.  The initiation of erythropoietic 
therapy for the management of chemotherapy-induced anemia follows the 
American Society of Hematology/ASCO clinical practice guidelines 
(http://www.asco.org). 


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5.3.5 Thrombocytopenia 
Thrombocytopenia will be treated conservatively.  In the absence of bleeding, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet 
count ≤10,000/mm3.  If invasive procedure(s) is (are) planned, or the patient 
develops bleeding, platelet transfusions should be administered in accordance with 
the standard of practice, usually maintaining a platelet count above 50,000/mm3. 
5.4 
Duration of Therapy 
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 
• 
Significant toxicity occurs despite 2 dose reductions as described in Section 6  
• 
Pregnancy 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
5.5 
Duration of Follow Up 
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of  care, or 
death, whichever comes first.  The follow-up will consist of a phone call between Days 27-
30 after the last dose to evaluate adverse events that were ongoing and any new events that 
might be deemed related to the therapy.  Toxicities felt to be possibly, probably, or 
definitely related to the study drugs that have not resolved or stabilized by Day 30 post-
treatment will be followed until stabilization or resolution via phone calls as clinically 
indicated. 
5.6 
Criteria for Removal from Study 
Patients will be removed from study for one of the following reasons: completed 30-day 
follow up period or toxicities are unresolved but stabilized, patient enrolls on another 
protocol, or patient receives standard of care.  The reason for study removal and the date 
the patient was removed must be documented in the medical record and communicated by 
fax to Central Registration per Section 4. 
 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
Toxicities should have resolved to ≤ Grade 2 prior to starting the next cycle.  Treatment may 
be delayed for a maximum of 2 weeks beyond the actual cycle length of 28 days for toxicities 
that develop and do not resolve as defined above.  Beyond two weeks, the patient may remain 
in the study at the discretion of the PI.  Treatment may be delayed for a maximum of ± 1 day 


CTEP #9605 
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during a cycle due to unavoidable scheduling conflicts.  If treatment is held during a cycle, that 
week’s treatment will be omitted for the cycle and treatment will proceed with the following 
week’s treatment as scheduled (e.g., if Day 8 ganetespib treatment is held, the next treatment 
will be Day 15 treatment with both agents). 
 
Dose Modification Schema: 
 
Baseline Dosing Schema 
 
Dose Level 
Ganetespib (IV) 
Ziv-aflibercept (IV) 
-2 
80 mg/m2 
3 mg/kg 
-1 
100 mg/m2 
3 mg/kg 
1 
100 mg/m2 
4 mg/kg 
2 
150 mg/m2 
4 mg/kg 
 
DLT attributed to Ganetespib  
alone 
 
Schema A 
 
DLT attributed to  
Ziv-Aflibercept alone 
 
Schema C 
Dose 
Level 
Ganetespib 
(IV) 
Ziv-aflibercept 
(IV) 
 
Dose 
Level 
Ganetespib 
(IV) 
Ziv-aflibercept 
(IV) 
-1a 
80 mg/m2 
3 mg/kg 
-1c 
100 mg/m2 
2 mg/kg 
 
DLT attributed to both agents 
Schema B 
Dose Level 
Ganetespib (IV) 
Ziv-aflibercept (IV) 
-1b 
80 mg/m2 
2 mg/kg 
 
 
6.1 
Dose Modifications 
Dose modifications are defined below: 
6.1.1 Grade 2 Drug-related toxicity: No changes will be made to the dose of either 
ganetespib or ziv-aflibercept for Grade 2 toxicities.  Therapy will not be interrupted 
for Grade 2 hematologic toxicities. 
6.1.2 Grade 3-4 Drug-related non-hematologic toxicities attributed to both drugs: Doses 
of both ganetespib and ziv-aflibercept will be held until toxicities recover to  
≤ Grade 2 or baseline prior to re-initiating treatment at the next lower dose level.  
Electrolyte abnormalities will not require dose reduction if resolution to Grade 2 or 
less is documented within 72 hours.  Dose modifications (per dosing Schema B) for 
nausea, vomiting, and diarrhea will be made only if they are refractory to treatment 
(See Section 5.2). 
6.1.3 Grade 3 Drug-related hematologic toxicities: Both ganetespib and ziv-aflibercept 
 
 


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will be held until hematologic toxicities, except anemia, lymphopenia, or 
leucopenia in the absence of Grade 3 or higher neutropenia, have resolved to  
≤ Grade 2 prior to re-initiating treatment at the same dose level. 
6.1.4 Grade 4 Drug-related Hematologic Toxicities: Both ganetespib and ziv-aflibercept 
(VEGF-Trap) will be held until hematologic toxicities, except anemia, 
lymphopenia, or leucopenia in the absence of Grade 4 neutropenia, have resolved to 
≤ Grade 2 prior to re-initiating treatment at the next lower dose level (per dosing 
Schema B). 
6.1.5 Diarrhea attributed to both ganetespib and ziv-aflibercept: As diarrhea is an 
expected toxicity for both agents, and as the recommended dose of ganetespib was 
established in the setting of prophylactic loperamide, prophylactic anti-motility 
agents will be given 1 to 2 hours before ganetespib administration, and will be 
repeated every 4 hours for the first 12 hours.  If diarrhea occurs despite prophylactic 
administration of anti-motility agents, supportive care guidelines will follow 
Section 5.3.2. 
6.1.6 Ocular toxicities attributed to ganetespib: Dose of ganetespib will be held until 
toxicities recover to < Grade 2 or baseline prior to re-initiating treatment at the next 
lower dose level per Schema A (above). 
6.1.7 QTc interval prolongation ≥ 500 msec (by Bazett’s formula) attributed to 
ganetespib: Dose of ganetespib will be held until QTc interval is <500 msec or 
baseline prior to re-initiating treatment at the next lower dose level per Schema A 
(above). Dose of ziv-aflibercept will not be modified.  
6.1.8 Proteinuria attributed to ziv-aflibercept: For proteinuria ≥ 1 grams/24 hours, dose of 
ziv-aflibercept will be held until proteinuria is < 1 grams/24 hours prior to re-
initiating treatment at the same dose level.  Dose reduction will occur for 
proteinuria ≥ 3 grams/ 24 hours or for recurrent proteinuria of ≥ 1 grams/24 hours 
per Schema C (above). Ziv-aflibercept will be discontinued for proteinuria with 
gross hematuria.  Dose of ganetespib will not be modified for proteinuria.  
6.1.9 Hypertension toxicity attributed to ziv-aflibercept:  
CTCAE V4.0 Grade 
Action to be taken: 
Grade 1 
(SBP 120-139 mmHg or 
DBP 80-89 mmHg) 
Consider increased BP monitoring; 
Start anti-hypertensive medication if persistent. 
For patients without prior antihypertensive therapy, at the 
time of the hypertensive episode the initiation of calcium-
channel blockers should be considered as a first-intent 
treatment.  A close monitoring of the BP should be initiated 
for further adjustment in treatment, as needed.  
 
For patients already under anti-hypertensive therapy, efforts 
should be done to optimize the existing therapy before adding 
other agents as required to control the BP. 


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CTCAE V4.0 Grade 
Action to be taken: 
Grade 2 asymptomatic 
(SBP 140-159 mmHg or 
DBP 90-99 mmHg) 
Start or add an additional anti-hypertensive agent and continue 
ziv-aflibercept per recommendations below.   
Close monitoring of BP for further adjustment, as needed. 
No dose modification and no delay. 
Grade 3 
(SBP ≥ 160 mmHg or 
DBP ≥ 100 mmHg) 
Hold ziv-aflibercept for a maximum of 2 weeks, until recovery 
to < Grade 2. 
• 
If BP is controlled within 2 weeks delay: 
-First episode: re-administer ziv-aflibercept at the same 
dose 
-Subsequent episode: re-administer ziv-aflibercept with 
dose reduction as per Schema C (above).  
• 
If BP is still uncontrolled despite appropriate anti-
hypertensive treatment and after 2 weeks delay, ziv-
aflibercept will be discontinued and patient will go off 
study. 
Grade 4 
(Hypertensive crisis or  
Malignant hypertension) 
Discontinue ziv-aflibercept.  Patient will go off study. 
6.1.10 For any Grade 3-4 arterial thromboembolic event, Grade 3-4 hemorrhage, Grade 3-
4 venous thromboembolic event, GI perforation, reversible posterior 
leukoencephalopathy syndrome attributed to ziv-aflibercept, ziv-aflibercept will be 
discontinued and the patient will go off study. 
6.1.11 Infusional reaction attributed to either ganetespib or ziv-aflibercept: Ganetespib 
contains a surfactant (polysorbate 80) which has been associated with 
hypersensitivity reactions with other medications administered by infusion.  Ziv-
aflibercept has also been associated with an antibody-associated infusional reaction.  
Symptoms have included pruritis, flushing, shortness of breath, chest tightness, 
dizziness, headache, increased systolic blood pressure and heart rate. 
Severity of Symptoms 
 
Mild transient reaction 
Give diphenhydramine HCl 25 mg to 50 mg IV, 
continue treatment, close monitoring of vitals  
q 5 min. for 15 min. after onset of symptoms.   
Mild to moderate persistent reaction 
Stop treatment; give dexamethasone 10 mg IV and 
diphenhydramine HCl 25 mg to 50 mg IV; may 
resume treatment after recovery of symptoms; pre-
medication indicated for subsequent drug 
administration: pre-medication indicated prior to re-
initiation: dexamethasone 12 mg PO and 
diphenhydramine HCl 25 mg to 50 mg PO 
approximately 4 to 6 hours prior to re-challenge 
Severe symptoms (e.g., hypotension 
requiring pressor therapy or IV fluids, 
angioedema, respiratory distress 
requiring bronchodilator therapy, or 
generalized urticaria) 
Stop treatment; give dexamethasone 10 mg IV and 
diphenhydramine HCl 25 mg to 50 mg IV; add 
bronchodilators as needed; patients may not receive 
further treatment. 


CTEP #9605 
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7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting. 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Ganetespib 
(NSC 777169) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.   
Below is the CAEPR for ganetespib.  Frequency is provided based on 423 patients. 
Version 2.0, January 27, 20141 
 Adverse Events with Possible  
 Relationship to Ganetespib 
 (CTCAE 4.0 Term) 
[n= 423] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Cardiac arrest 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 


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HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Sepsis 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase increased 
 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
 
Hypokalemia 
 
  
 
Hyponatremia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
 Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash acneiform 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail. 
 
Also reported on Ganetespib trials but with the relationship to Ganetespib still 
undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
EYE DISORDERS - Blurred vision; Eye disorders - Other (transient visual impairment) 
GASTROINTESTINAL DISORDERS - Colonic fistula; Gastrointestinal disorders - Other 
(gastroenteritis) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; 
Infusion related reaction 
INVESTIGATIONS - Blood bilirubin increased; Cardiac troponin I increased; Electrocardiogram 
QT corrected interval prolonged; GGT increased; Investigations - Other (blood lactate 
dehydrogenase increased); Lipase increased; Lymphocyte count decreased; Neutrophil count 
decreased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia; 
Hypophosphatemia 


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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (muscle spasms); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Syncope 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough 
VASCULAR DISORDERS - Hypertension 
 
Note: Ganetespib in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Ziv-
aflibercept (VEGF-Trap, NSC 724770) 
Frequency is provided based on 811 patients. Below is the CAEPR for Ziv-aflibercept (VEGF-
Trap, AVE 0005). 
 
 
 Version 2.6, November 24, 20151 
 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 811] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
 
 
Hemolytic uremic syndrome 
  
 
 
Thrombotic thrombocytopenic 
purpura 
  
CARDIAC DISORDERS 
  
 
 
Chest pain - cardiac 
  
 
 
Myocardial infarction 
  
 
 
Restrictive cardiomyopathy 
  
 
 
Cardiac disorders - Other 
(intracardiac thrombus) 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 2) 
 
Anal mucositis 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal perforation3 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 


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 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 811] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
  
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Wound complication 
 
  
 
Wound dehiscence 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
Lymphocyte count decreased 
 
 
 Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
  
 
White blood cell decreased 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Headache 
 
 
 Headache (Gr 3) 
 
 
Ischemia cerebrovascular 
 Ischemia cerebrovascular (Gr 2) 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
 
Transient ischemic attack 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Proteinuria 
 
 Proteinuria (Gr 3) 
 
 
Renal disorders - Other 
(nephrotic syndrome) 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Genitourinary system fistula5 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Pharyngolaryngeal pain 
 
  
Voice alteration 
 
 
 Voice alteration (Gr 2) 


CTEP #9605 
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 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 811] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Respiratory, thoracic, and 
mediastinal disorders - Other 
(rhinorrhea) 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Palmar-plantar erythrodysesthesia 
syndrome 
 
  
 
Rash maculo-papular 
 
  
 
Skin hyperpigmentation 
 
  
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 3) 
 
Vascular disorders - Other 
(hemorrhage)6 
 
 Vascular disorders - Other (hemorrhage)6 
(Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
2Gastrointestinal fistulas may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Gastrointestinal perforation imay include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small 
intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
5Genitourinary fistulas may include: female genital tract fistula, uterine fistula, and vaginal fistula. 
 
6The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a critical 
area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and nervous system 
[including fatal intracranial hemorrhage and cerebrovascular accident] have been reported. 
 
Adverse events reported on Ziv-aflibercept (VEGF-Trap, AVE 0005) trials but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Ziv-aflibercept (VEGF-Trap, 
AVE 0005) caused the event. 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemoglobin increased); Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (left ventricular diastolic 
dysfunction); Heart failure; Left ventricular systolic dysfunction; Pericarditis; Supraventricular tachycardia 


CTEP #9605 
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EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eye disorders - Other (blindness 
transient); Eye disorders - Other (diplopia); Vitreous hemorrhage 
GASTROINTESTINAL DISORDERS - Abdominal distension; Colitis; Dental caries; Dry mouth; 
Dyspepsia; Dysphagia; Esophageal pain; Flatulence; Gastritis; Gastrointestinal disorders - Other (early 
satiety); Gastrointestinal disorders - Other (enteric fistula); Gastrointestinal disorders - Other (eructation); 
Gastrointestinal disorders - Other (gastrointestinal necrosis); Gastrointestinal disorders - Other (hiatal 
hernia);Gastrointestinal disorders - Other (intestinal ischemia); Gastrointestinal disorders - Other 
(pneumatosis intestinalis); Gastrointestinal disorders - Other (peritonitis); Gingival pain; Hemorrhoids; 
Ileus; Oral pain; Rectal mucositis; Rectal ulcer; Small intestinal mucositis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema 
trunk; Facial pain; Infusion related reaction; Injection site reaction; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Biliary anastomotic leak; Gastric 
anastomotic leak; Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; 
Creatinine increased; Ejection fraction decreased; GGT increased; Investigations - Other (elevated LDH) 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; 
Chest wall pain; Generalized muscle weakness; Head soft tissue necrosis; Joint range of motion decreased; 
Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (muscle spasms); 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness); Musculoskeletal and 
connective tissue disorder - Other (rotator cuff tear); Myositis; Neck pain; Osteonecrosis of jaw; Pain in 
extremity; Pelvic soft tissue necrosis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage) 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Dysgeusia; 
Encephalopathy; Extrapyramidal disorder; Leukoencephalopathy; Memory impairment; Paresthesia; 
Peripheral sensory neuropathy; Seizure; Syncope; Vagus nerve disorder 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Psychiatric disorders - Other 
(mental status change); Psychosis 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Laryngeal mucositis; 
Nasal congestion; Pharyngeal mucositis; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary fibrosis; 
Respiratory, thoracic and mediastinal disorders - Other (nasal dryness); Respiratory, thoracic and 
mediastinal disorders - Other (tracheal fistula); Respiratory, thoracic and mediastinal disorders - Other 
(septal perforation); Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (hyperemia); Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Peripheral ischemia; Phlebitis 
 
Note: Ziv-aflibercept (VEGF-Trap) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 


CTEP #9605 
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Safety monitoring for 89Zr-panitumumab PET/CT:  
Panitumumab was well tolerated in previous clinical trial studies where doses were much higher.  The 
most common adverse events related to panitumumab at doses of 6 mg/kg every 14 days were skin 
rash with variable presentation, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and 
diarrhea.  The most serious events that have been reported were fibrosis, severe dermatologic toxicity 
complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, 
hypomagnesemia, nausea, vomiting, and constipation. 
No adverse events are expected for the 89Zr-panitumumab PET/CT imaging study.  The dose of 
panitumumab anticipated for this study will be <1 mg for a single injection.  The radiation 
exposure associated with this study is comparable to the dose for the other widely used clinical 
nuclear medicine procedures. 
Subjects will be monitored for adverse events during each 89Zr-panitumumab PET/CT imaging 
session and for one month post injection.  Adverse events are defined as any signs of illness or 
symptoms that have appeared or worsened since the infusion of the 89Zr-panitumumab.  The 
infusion and imaging procedure will be terminated in any patient who exhibits anaphylaxis, 
significant hypotension (systolic blood pressure less than 80 mmHg on 2 measurements obtained 
within 1-2 minutes of each other), dyspnea, or chest pain.  At the beginning and end of the imaging 
session, subjects will be questioned regarding any appearance or change in signs and symptoms.  
The adverse events to be specifically monitored during the infusion include localized discomfort at 
the IV injection site, pain, respiratory difficulties, flushing, dizziness, itching/rash, and any other 
symptoms that could be secondary to anaphylactic reaction.  If one participant develops any grade 
≥ 2 AE reaction attributable to the imaging agent, the 89Zr-panitumumab study will be placed on 
hold and discussed with the study sponsor. 
Injection site monitoring will be performed prior to administration of the imaging agent and at 
various time points post-injection over a 24-hr period.  Any abnormal findings during this period 
will be recorded as an AE on the research record.  Abnormal injection site findings include, but are 
not limited to, radiopharmaceutical extravasation, bleeding, hematoma, redness, and infection.  
Any abnormal finding that is new or represents a worsening from baseline is an AE.  Once AE 
notification is decided upon, the procedure for AE notification will be followed, as described 
below. 
7.3 
Adverse Event Characteristics 
• CTCAE term (AE description) and grade: 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 Web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Attribution of the AE: 
 
1. Definite – The AE is clearly related to the study treatment. 
 
2. Probable – The AE is likely related to the study treatment. 
 
3. Possible – The AE may be related to the study treatment. 


CTEP #9605 
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4. Unlikely – The AE is doubtfully related to the study treatment. 
 
5. Unrelated – The AE is clearly NOT related to the study treatment. 
7.4 
Expedited Adverse Event Reporting 
7.4.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Expedited Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in 
the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for 
DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from 
the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly 
outlined in the tables below (Section 7.3.2). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, the 24-hour notification phoned in must be entered electronically into 
CTEP-AERS by the original submitter at the site. 
7.4.2 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment or 
other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) – Other (Progressive 
Disease)” under the system organ class (SOC) of the same name.  Evidence that the 
death was a manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  


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6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4.3 Protocol-specific expedited AE reporting exclusions 
For this protocol only, certain AEs/grades are exceptions to the Expedited 
Reporting Guidelines and do not require expedited reporting (i.e., CTEP-AERS).  
These are any grade lymphopenia, any grade alopecia, Grade 2 electrolyte (sodium, 
potassium, phosphorous, magnesium) abnormalities, Grade 2 anemia, Grade 2 
hypoalbuminemia, Grade 2 hyperglycemia, Grade 2 INR, Grade 2 PTT, and Grade 
2 hyperuricemia will NOT be reported through CTEP-AERS but will be reported in 
the routine data submissions. 
7.4.4 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed for 
patients who became pregnant on study, and faxed along with any additional 
medical information to 301-230-0159.  The potential risk of exposure of the fetus to 


CTEP #9605 
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the investigational agent(s) or chemotherapy agent(s) should be documented in the 
“Description of Event” section of the CTEP-AERS report. 
7.4.4.1 Pregnancy 
• Because patients who become pregnant on study risk intrauterine exposure of 
the fetus to agents which may be teratogenic, DCTD/DCP is requesting that 
pregnancy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal conditions 
SOC. 
• The pregnancy outcome for patients on study should be reported via CTEP-
AERS at the time the outcome becomes known, accompanied by the same 
Pregnancy Report Form used for the initial report. 
7.4.4.2 Fetal Death 
• Fetal death is defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of respiration, 
heartbeat, or definite movement of a voluntary muscle after expulsion from 
the uterus, without possibility of resuscitation.” 
• Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions – Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC. 
• A fetal death should NOT be reported as “Fetal death,” a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEP-AERS recognizes this event as a patient death. 
7.4.4.3 Death Neonatal 
• Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by the 
investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
• A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the General 
disorders and administration SOC. 
• Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event.  If reported as 
such, the CTEP-AERS interprets this as a death of the patient being treated. 


CTEP #9605 
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7.4.5 NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths 
7.4.5.1 Definitions 
 
Adverse event 
An adverse event is defined as any reaction, side effect, or untoward event that 
occurs during the course of the clinical trial associated with the use of a drug in 
humans, whether or not the event is considered related to the treatment or clinically 
significant.  For this study, AEs will include events reported by the patient, as well 
as clinically significant abnormal findings on physical examination or laboratory 
evaluation.  A new illness, symptom, sign or clinically significant laboratory 
abnormality or worsening of a pre-existing condition or abnormality is considered 
an AE.  All AEs must be recorded on the AE case report form unless otherwise 
noted above in Section 7.3.3. 
 
All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until satisfactory resolution.  
AEs should be reported up to 30 days following the last dose of study drug.   
 
An abnormal laboratory value will be considered an AE if the laboratory 
abnormality is characterized by any of the following: 
 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms 
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including 
hospitalization 
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the 
test drug and about the patient’s outcome. 
 
Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
 
Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, is 


CTEP #9605 
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not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application.  “Unexpected” also refers to adverse events 
or suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition 
of a Serious Adverse Event or if it compromises the safety, welfare or rights of 
subjects or others. 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view 
of the investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 
Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, 
in the view of the investigator or sponsor, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that had it occurred in a 
more severe form, might have caused death. 
 
Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
 


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Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program 
(HRPP) policies, IRB requirements, or regulatory requirements for the protection of 
human research subjects. 
 
Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to 
(a) the research risks that are described in the IRB-approved  
 
research protocol and informed consent document; Investigator’s  
 
Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
 
7.5 
NCI-IRB and NCI Clinical Director Reporting Requirements 
7.5.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI 
Clinical Director: 
• All deaths, except deaths due to progressive disease 
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
 
Reports must be received within 7 days of PI awareness via iRIS. 
7.5.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
For reporting of adverse events at time of continuing review, the NCI-IRB requires 
a summary report of adverse events that have occurred on the protocol since the 
previous continuing review and in aggregate.  The method of presentation should 
provide the NCI-IRB with the information necessary to clearly identify risks to 
participants and to make a risk:benefit determination.  Please sort the events by the 
system organ class and by grade.  The summary report is based on the following 
guidance: any unexpected severity and/or unexpected frequency of expected events 
needs to be reported and interpreted in relation to the risk:benefit of study 
participants in the narrative. 
Please use following table for reporting adverse events at time of CR: 


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System 
Organ Class 
CTCAE 
Term 
Grade 
# of Events 
since last CR 
Total # 
of Events 
Attribution 
to Research 
Serious? 
Unexpected? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The protocol PI will report to the NCI-IRB:  
 
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely 
related to the research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to 
the research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
 
7.5.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that require a sponsor recommended change to the 
protocol or the consent form or in the opinion of the PI increase risks to study 
participants will need to be reported to the NCI IRB. 
 
7.6 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy).  A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS.  Three options are available to 
describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.7 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.  


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8 PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational administered 
in this study can be found in Section 7. 
8.1 
Ganetespib (NSC 777169) 
Other Names: 
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 
Classification: 
Hsp90 inhibitor 
CAS Registry No.  
888216-25-9 
Mode of Action: 
Ganetespib inhibits heat shock protein 90 (Hsp90) chaperone activity 
by binding to its N-terminal adenosine triphosphate pocket resulting 
in the proteosomal degradation of oncogenic client proteins.  Client 
protein degradation results in induction of cell cycle arrest and 
apoptosis, thereby inhibiting tumor growth.   
Mol. Formula: 
C20H20N4O3 
Mol. Weight: 
364.40 g/mol 
Description: 
Ganetespib is a novel triazolone heterocyclic compound, provided as a 
concentrate solution and is a clear, colorless-to-pale-yellow solution. 
How Supplied: 
Synta Pharmaceuticals supplies ganetespib and PMB, CTEP, DCTD 
distributes as 300 mg vials, 25 mg/mL, (total volume is 12.84 mL 
with 0.84 mL overfill).  The solution is a clear, colorless-to-pale 
yellow solution free of visible particles in a polyethylene glycol 300, 
polysorbate 80 and dehydrated alcohol cosolvent-surfactant system. 
Storage: 
 
 
The 300 mg vials 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), protected from light.   
Stability: 
Stability of the intact vials is ongoing. 
If not used immediately, store the prepared IV solution at controlled 
room temperature, protect from light.  Do not refrigerate the IV 
solution.  The IV solution is to be administered over 1 hour and must 
be completed within 4 hours of finishing the preparation.   
Preparation: 
 
Use an empty non-PVC and non-DEHP IV bag to prepare ganetespib IV 
solution to a final concentration between 0.1 and 1.1 mg/mL. For 
consistency, 500 mL D5W should be the final volume of the prepared IV


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1. Add the calculated volume (mL) of D5W into the non-PVC, non-
DEHP empty IV bag  
2. Next, add the calculated amount (mL) of ganetespib. Note: 
ganetespib solution is viscous.  Use a 16G or 18G needle to 
withdraw the calculated amount of ganetespib.  
3. Gently invert the IV bag approximately 10 times to completely mix 
the IV solution  
4. Visually inspect the final IV solution.  The solution must be clear 
and free of visible particles.  Do not use it if the IV solution is not 
clear. 
Route of 
Administration: 
Intravenous.   
Method of 
Administration: 
1. Set up the infusion pump to deliver the 500 mL 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 material other 
than silicone 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. 
 
Potential Drug 
Interaction: 
In vitro and in vivo, ganetespib is primarily metabolized (glucuronidated) 
by UGT1A9 and to a lesser extent by UGT1A1, UGT1A3, and various 
P450 enzymes.  It is also a substrate for P-glycoprotein, but is primarily 
eliminated through glucuronidation.  In vitro, ganetespib is a moderate 
inhibitor of CYP2C19 and CYP3A4, but has not demonstrated any 
clinically significant drug interactions to date, including a study of its effect 
on omeprazole (a sensitive CYP2C19 substrate) pharmacokinetics in 
healthy human volunteers.  Avoid concomitant administration with 
moderate or strong UGT1A9 inhibitors, which include efavirenz and 
propofol.  The concomitant use of inducers of UGTs (e.g., rifampin, 
phenobarbital, phenytoin, various herbal preparations including St. John 
Wort) might significantly increase ganetespib clearance, resulting in 
reduced plasma concentrations.   


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The QTc study in healthy volunteers has reported a modest increase in QT 
interval 24 hours post ganetespib dose.  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, patients should avoid concomitant drugs that 
may cause QTc interval prolongation while receiving ganetespib, see 
Appendix C. 
Availability 
Ganetespib is an investigational agent supplied to investigators by 
DCTD, NCI.  Ganetespib is provided to the NCI under a Collaborative 
Agreement between the Pharmaceutical Collaborator and DCTD, NCI. 
8.2 
Ziv-aflibercept (NSC 724770) 
Other Names: 
AVE0005; Zaltrap 
Classification: 
Recombinant humanized fusion protein (Chinese hamster ovary 
source) 
Mode of Action: 
The cytokine VEGF binds to and activates VEGFR1 and VEGFR2 on 
the vascular endothelium, promoting new vessel formation.  VEGF 
Trap is a soluble recombinant decoy receptor that binds and inactivates 
extravascular and hematologic VEGF.  It reduces tumor vasculature 
density, available nutrient supply, and tissue matrix components 
escaping from leaky tumor vessels. 
Molecular Weight: 
115 kDa 
Approximate 
Solubility: 
At least 100 mg/mL water (with 5mM Na phosphate, 5 mM Na citrate, 
100 mM NaCl, 0.004-0.08% Polysorbate 20) at 5°C and 25°C. 
Description: 
The fusion protein ziv-aflibercept (VEGF Trap) is comprised of 
2 portions of human VEGF receptor extracellular domains, VEGFR1 
and VEGFR2, fused to the Fc portion of human IgG1. 
How Supplied: 
Ziv-aflibercept (VEGF Trap) is supplied by Sanofi-Aventis 
Pharmaceuticals and distributed by CTEP, DCTD, NCI.  Ziv-
aflibercept (VEGF Trap) is a sterile, nonpyrogenic, colorless to pale 
yellow solution in vials of 200 mg (8 mL) at a concentration of 25 
mg/mL.  The solution contains the following excipients: sucrose, 
sodium chloride, sodium citrate dehydrate, citric acid monohydrate, 
polysorbate 20, sodium phosphate dibasic heptahydrate, sodium 
phosphate monobasic monohydrate, and water for injection.  The pH of 
ziv-aflibercept (VEGF Trap) is 6.2.  The product is packaged in a type 
1, clear borosilicate glass vial closed with a flanged cap with tear-off 
lid and inserted sealing disc, Flurotec® (PTFE) coated. 
Preparation: 
Prior to infusion, the VEGF Trap dosage form must be diluted directly 


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into infusion bags of 0.9% sodium chloride solution or 5% dextrose.  
The concentration of the diluted solution can range between 0.6 and 8 
mg/mL.  The pH of the diluted solution is about 6.2. 
Storage: 
Intact vials are stored at 2°C to 8°C (Refrigerated condition). 
Stability: 
Shelf-life stability studies of intact vials are ongoing.  Ziv-aflibercept’s 
provisional shelf-life is up to 36 months at 2°C to 8°C. 
Caution: The sterile single use vials contain no antibacterial 
preservatives.  Discard remaining agent 8 hours after initial entry. 
Ziv-aflibercept (VEGF Trap) diluted to a concentration of 0.6 to 8 
mg/mL in 0.9% NaCl or 5% dextrose has demonstrated chemical and 
physical stability for up to 24 hours under refrigerated conditions (2°C 
to 8°C) or up to 8 hours at ambient temperature (approximately 25°C) 
in infusion bags made of polyvinyl chloride (PVC) containing di(2-
ethylhexyl)phthalate (DEHP) or polyolefin (PVC free DEHP free), or 
polyethylene. 
Route of 
Administration: 
Intravenous 
Method of 
Administration: 
Administer ziv-aflibercept (VEGF Trap) intravenously over 1 hour into 
a peripheral vein or central venous catheter using gravity, an infusion 
pump, or syringe pump.  The infusion should not exceed two hours at 
room temperature (approximately 25°C).   
Ziv-aflibercept (VEGF Trap) may be administered using infusion 
tubing made of PVC containing DEHP, polyethylene lined PVC, 
DEHP free PVC containing tris (2-ethylhexyl) trimellitate (TOTM), 
polypropylene, or polyurethane, or polybutadiene. 
The infusion set must contain a 0.2 micron polyethersulfone inline 
filter.  Polyvinylidene fluoride (PVDF) filters or Nylon filters should 
not be used. 
Availability 
Ziv-aflibercept is an investigational agent supplied to investigators by 
DCTD, NCI.  Ziv-aflibercept is provided to the NCI under a 
Collaborative Agreement between the Pharmaceutical Collaborator and 
DCTD, NCI. 
8.3 
 89Zr-labeled Panitumumab 
Other Names: 
[89Zr]-DFO-panitumumab or 89Zr-panitumumab 
Classification: 
Radiopharmaceutical for imaging 
IND#: 
Cross reference support from IND 116229, held by DCTD/CIP 
Composition: 
Fully human IgG2 monoclonal antibody 


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Mechanism of 
Action: 
Panitumumab competes with endogenous ligands such as 
epidermal growth factor and tumor growth factor α (TGF α) to 
block stimulation of the EGF receptor.  By blocking the ligand-
receptor interaction, critical signaling cascades are prohibited from 
occurring which would otherwise result in downstream activation 
of signaling pathways involved in the progression of metastatic 
disease.  Some of these processes include: cell growth, survival, 
motility, proliferation, and transformation. 
How Supplied: 
89Zr-panitumumab is a sterile, IV injectable solution with a 
volume of ≤10 mL containing 0.9% saline and <5 mg gentistic 
acid. 
Storage: 
Vials are stored at 2°C to 8°C (36°C to 46°F) (refrigeration 
conditions) until time of use.  Protect from direct sunlight 
exposure.  Do not freeze. 
Route of 
Administration: 
The agent is administered by intravenous injection, not to exceed 
1.0 mCi, of 89Zr-panitumumab.  Appropriate shielding to meet 
Radiation Safety Guidelines will be used. 
Toxicity:  Panitumumab was well tolerated in previous clinical trials studies where doses were 
much higher.  The most common adverse events related to panitumumab, at doses of 6mg/kg 
every 14 days, were skin rash with variable presentation, hypomagnesemia, paronychia, fatigue, 
abdominal pain, nausea, and diarrhea.  The most serious events that have been reported were 
fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, 
infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. 
NOTE: For PET imaging purpose we will be using panitumumab labeled with 89Zr.  89Zr-labeled, 
EGFR-targeting antibody panitumumab is expected to be administered as a microdose.  A 
microdose is defined as less than 1/100th of the dose calculated to yield a pharmacological effect 
of a test substance, or, for proteins, not more than 30 nanomoles.  In this trial, we propose 
administering <1 mg of panitumumab, which is approximately 1/500th (0.2%) of the 
recommended therapeutic (pharmacologic) dose of 6 mg/kg, less than 7 nmol.  Microdose studies 
are designed to evaluate the pharmacokinetics or imaging of specific targets and are not designed 
to induce pharmacological effects.  Thus, the potential risk is very low and information adequate 
to support the initiation of such limited studies can be derived from limited pre-clinical safety 
studies. 
Safety monitoring for 89Zr-panitumumab PET/CT: Panitumumab was well tolerated in 
previous clinical trial studies where doses were much higher.  The most common adverse events 
related to panitumumab at doses of 6 mg/kg every 14 days were skin rash with variable 
presentation, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea.  The 
most serious events that have been reported were fibrosis, severe dermatologic toxicity 
complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, 
hypomagnesemia, nausea, vomiting, and constipation. 
No adverse events are expected for the 89Zr-panitumumab PET/CT imaging study.  The dose 
of panitumumab anticipated for this study will be <1 mg for a single injection.  The radiation 


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exposure associated with this study is comparable to the dose for the other widely used clinical 
nuclear medicine procedures. 
A 5-mL blood sample will be drawn for immunogenicity testing prior to initial 89Zr 
panitumumab administration and during Cycle1 Day 16.  Samples will be delivered at room 
temperature to Building 10/IB54 for appropriate testing. 
Drug Interactions: There are no formal evaluations regarding drug-food, drug-lab, or drug-
disease interaction that are currently available. 
Production of the Radiopharmaceutical: The 89Zr-panitumumab used in this study is 
prepared locally by the Leidos Biomedical Research Radiopharmacy, Frederick, MD.  The 
precursors for the radiosynthesis include panitumumab, deferoxamine-NCS, and 89Zr-oxalate.  
The other reagents used in the synthesis are sodium carbonate, water, gentisic acid, HEPES, 
and USP saline for injection.  The radiopharmaceutical product is a clear and colorless liquid 
that is stored at room temperature in a sterile serum vial.  89Zr-panitumumab has an expiration 
time of 48 hours after sterile filtration. 
8.4 
Agent Ordering  
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Ordering for 89Zr-panitumumab: 89Zr-panitumumab will be ordered from the 
Leidos Biomedical Radiopharmacy using the form supplied in Appendix D; orders should 
be placed 5 business days prior to the scheduled scan date and time. 
 


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George Afari, PharmD, BCNP 
Clinical Radiopharmacist 
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc. 
Frederick National Laboratory for Cancer Research 
Phone: 301 846 7391 
Fax: 301 846 5935 
E-mail: george.afari@nih.gov 
8.5 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the 
CTEP Web site at http://ctep.cancer.gov for Procedures for Drug Accountability and 
Storage and to obtain a copy of the DARF Clinical Drug Request form.) 
 
Agent Accountability for 89Zr-panitumuab: The organic precursor for 89Zr-panitumumab 
is purchased commercially in single-use, 200-mg vials that are delivered to the custody of 
Dr. George Afari, the lead nuclear radiopharmacist for this project.  They are stored in a 
controlled temperature refrigerator in a locked and secure room and they are inventoried 
with a chain of custody maintained from the time of receipt.  Each radiosynthesis is done 
by Dr. George Afari or his designee and, after passing all required quality control assays, 
the product 89Zr-panitumumab dose is drawn up under the supervision of Dr. George Afari 
or the nuclear medicine physician investigators Dr. Peter Choyke, Dr. Karen Kurdziel, or 
Dr. Liza Lindenberg. 
The quality control tests that must be passed prior to release of the product 89Zr-labeled, 
EGFR targeting antibody panitumumab for injection include radioactive purity, 
radiochemical purity, pH, sterilizing filter integrity, and tests for endotoxin and 
particulates.  The dose is drawn up into a syringe, assayed for mCi at time of injection, 
labeled, and administered to the research subject. 
 
Agent Returns:  If for any reason the study imaging is unable to be completed, sites will 
allow the radioactivity of the 89Zr-panitumumab solution to decay and then discard it 
appropriately per site’s policies and procedures, making a record of the event as required.  
A copy of the policy should be available upon request. 
 
 
9 CORRELATIVE/SPECIAL STUDIES 
We plan to evaluate the effect of modulation of HIF1α inhibition and additional Hsp90 client 
proteins as a result of combination therapy with ganetespib and ziv-aflibercept.  We also plan 
to pursue 89Zr-panitumumab PET/CT imaging to evaluate tumor distribution of EGFR prior to 
and following treatment with both agents as an exploratory correlation for evidence of 
modulation of EGFR, as an indirect biomarker of Hsp90 inhibition, as EGFR is a known 
Hsp90 client protein. 


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Two core biopsies will be obtained, one on C1D7 prior to administration of ganetespib on 
C1D8, and 7 days after administration of ziv-aflibercept on C1D1; and again on C2D7, 7 days 
after treatment with the combination of ganetespib and ziv-aflibercept on C2D1, but before 
administration of ganetespib on C2D8.  One core will be immediately flash frozen for analysis 
of HIF1α, a second core will be stored and later analyzed for Hsp90 client proteins based on 
the availability of tissue and various histologies, and availability of assays. 
 
Circulating tumor cells (CTCs) will be isolated from whole blood samples collected at baseline 
and then throughout the study for assessment of DNA damage response markers such as 
γH2AX.  These samples will be optional and will be collected from patients on the MTD 
expansion phase only.  We will also evaluate whether we can measure changes in the number 
and phenotype (epithelial-mesenchymal transition) of CTCs in patients over time to explore any 
correlation with response to treatment or disease progression.  This analysis will be performed 
in Dr. Kinders’ lab with the ApoStream instrument, which uses antibody-independent CTC 
isolation technology that can isolate viable CTCs from epithelial and non-epithelial cancers.   
The enriched cells are then stained with a panel of antibodies targeting MUC1 (tumor marker) 
and CEA (tumor marker), CK (epithelial marker), EpCAM (epithelial marker) and β-catenin 
(CTNNB1; epithelial-mesenchymal transition marker) and CD45 (PTPRC; leukocyte marker), 
as an exclusion marker.   
 
9.1 
Pharmacodynamic Assays 
Assessment of HIF1α protein expression in tumor biopsies: 
 
To determine whether the combination of ganetespib and ziv-aflibercept modulates intra-
tumoral HIF1α expression, tumor biopsies will be analyzed for change in HIF1α expression by 
immunofluorescence assay (IFA).  Cores will be normalized against the percentage of tumor 
within the sample.  Paired pre- and post-combination treatment samples will be compared for 
qualitative changes in levels of HIF1α expression. 
 
Figure 6. IFA showing HIF1α expression in A375 
xenograft tumors treated for 2 hours with topotecan 
and counterstained with DAPI. 
 
 
 
 
 
 
 
 
 
 


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Assessment of EGFR modulation by 89Zr-panitumumab PET/CT imaging: 
 
To evaluate for tumor distribution of EGFR, patients will undergo 89Zr-immuno-PET imaging 
with 89Zr-labeled EGFR-targeting panitumumab antibody in all patients as a non-invasive 
exploratory correlative to evaluate modulation of EGFR client protein prior to and after 
treatment with the combination of ganetespib and ziv-aflibercept.  Immunohistochemistry 
staining to confirm EGFR expression in archival tumor biopsies will be performed prior to 
pursuing scans.  Panitumumab is a fully human monoclonal antibody that targets EGFR and 
competes with endogenous ligands to block stimulation of EGFR.  89Zr-immuno-PET imaging 
with panitumumab as a targeting ligand allows for quantification of EGFR expression within 
tumors.  Changes in 89Zr-panitumumab PET/CT avidity (as measured by SUV) can therefore 
serve as a surrogate biomarker of Hsp90 inhibition, as EGFR is a known Hsp90 client protein. 
 
 
Figure 7 Example of Zr89 Panitumumab scan from a patient with 
colon cancer metastasis to the liver.  Note the high physiologic 
radiotracer activity in the liver with decreased uptake in metastatic 
lesions. 
 
 
 
 
 
 
 
 
 
 
9.1.1 Laboratory Contact 
At least 24 hours prior to tumor biopsy or blood sample collection, the research 
nurse will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10:  
E-mail NCIPK-PDsupportgroup@mail.nih.gov, Pager: 102-12798 Phone:  
301-451-1169 Fax: 301-480-5871.  For biopsies, tubes pre-labeled with the 
information specified in Section 9.1.4, biopsy date, and site of tissue biopsy will be 
provided.  Initial processing and shipping of the samples will be completed as 
described below. 
9.1.2 Tumor Biopsies 
9.1.2.1 Timing of tumor biopsies 
Biopsies will be mandatory during the expansion phase.  Biopsies will be 
collected at the following time points: 
• On C1D7 before ganetespib administration on C1D8 (baseline) 


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• On C2D7 after combination of ganetespib and ziv-aflibercept on C2D1, 
and before ganetespib administration on C2D8  
 
 
If tumor biopsies are pursued, the first dose of ganetespib on C1D1 will be omitted. 
9.1.2.2 Biopsy Procedure 
Serial tumor biopsies will be obtained by the Interventional Radiology team by a 
percutaneous approach.  It is preferred that 2-3 core biopsies 18-gauge in diameter 
and ≥1 cm in length will be obtained during each procedure.  It is estimated that 
there will be between 2 million–5 million cells from each biopsy.  If a site is 
deemed appropriate for biopsy with minimal risk to the participant by agreement 
between the investigators and Interventional Radiology team, an attempt for biopsy 
will be made. 
 
The use of imaging to facilitate biopsies will be decided by members of the 
Interventional Radiology team and may include ultrasound, CT scan, or MRI.  
Should a CT scan be needed for biopsy, the number of scans for each procedure 
will be limited to the minimum number needed to safely obtain a biopsy.  Tumor 
biopsies and local anesthesia will be administered only if they are considered to be 
of low risk to the participant, as determined by the investigators and Interventional 
Radiology. 
 
If the participant chooses not to undergo tumor biopsy, he/she will still remain in 
the study and receive study medication, and all the other correlative studies will be 
performed. 
 
Tumor biopsies are optional during the escalation phase and mandatory during the 
expansion phase.  Baseline biopsies will be performed following patient enrolling 
on study.  If an initial attempt at percutaneous biopsy is unsuccessful, the patient 
will be given an option to proceed with a repeated attempt at percutaneous biopsy.  
A separate consent form must be signed for each biopsy procedure, so patients may 
choose not to undergo subsequent biopsies.  If the baseline biopsy is unsuccessful 
or the patient refuses to undergo subsequent biopsies, no further biopsies will be 
performed but the patient will remain on study, receive study medication, and other 
correlative studies will be performed.  
9.1.2.3 Solid Tumor Biopsy Processing 
At least two tissue cores will be collected.  The cores will be transferred into a  
1.5-mL pre-chilled cryovial and then flash frozen in liquid nitrogen per DCTD 
SOP340507 (http://dctd.cancer.gov/ResearchResources/biomarkers/ 
docs/par/SOP340507_Biopsy_Frozen.pdf).  Samples will be submitted to 
Dr. Kinders' laboratory for evaluation of DNA damage markers, and H&E 
pathology evaluation.  The frozen biopsy specimens are transferred to PADIS on 
dry ice, where the core biopsy samples are stored at -80°C, or colder, and 


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subsequently processed within 7-10 days for analysis or as directed by the Principal 
Investigator.  Biopsy samples will be analyzed for HIF1α expression as described 
above; any additional cores will be flash-frozen and kept for future analysis in the 
Frederick National Laboratories CR Biorepository in liquid nitrogen freezers. 
 
Biopsies for PD analysis will be shipped on dry ice to Dr. Kinders’ laboratory: 
 
 
Dr. Robert Kinders (PADIS/LHTP/FNLCR) 
 
Bldg. 431, Rm. 129 
 
Frederick, MD 21702-1201 
 
Phone: 301-846-6410 
 
kindersr@mail.nih.gov 
 
9.1.3 Circulating Tumor Cells 
Whole blood for CTCs will be collected aseptically by venipuncture or from a 
venous port into two K3 EDTA 4 mL tubes.  Samples will be collected at the 
following times from patients on the expansion cohort only:  
• cycle 1 prior to drug administration 
• cycle 1 day 8 (+/- 1 day, i.e., prior to the administration of ganetespib on C1D8) 
• cycle 1 day 5, 4 hours (+/- 1 hour) after completion of drug administration 
• cycle 2 day 8 (+/- 1 day, i.e., prior to the administration of ganetespib on C2D8) 
• cycle 2 day 15, 4 hours (+/- 1 hour) after completion of drug administration 
• on day 1 of all subsequent cycles before drug administration 
One additional blood sample will be collected at time of disease progression.  All 
CTC samples will be shipped to Dr. Kinders’ lab. 
9.1.4 Sample Collection and Processing 
Biospecimens will be collected and processed using validated SOPs that will ensure 
both specimen quality and patient confidentiality pursuant to informed consent 
provisions.  Information about each specimen (e.g., blood, tumor biopsy, circulating 
tumor cells, per specific protocol) will be recorded on a PK/PD collection 
worksheet. 
 
Using a computerized inventory system and a backup hardcopy process, all 
specimen collection and processing steps will be documented and the specific 
location of each specimen will be tracked.  Each new specimen collected will be 
assigned a unique barcode identifier that can be linked to the original specimen 
collected and other relevant information within the inventory system.  To ensure 
patient confidentiality, only containers used for the initial specimen collections will 
be labeled with patient identifiers.   
 
Only the barcode identifier will be applied to all subsequent specimen containers.  
When specimens are processed and aliquoted, no patient information will be 


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included on the new containers.  Original specimen containers will be discarded.  
Only barcode-labeled specimens without patient identifiers will be shipped for 
analysis and/or storage.  Specimen labels will indicate: CTEP protocol number, 
unique patient accession number, 3-digit sample number (see list below), collection 
time, and total volume collected, as appropriate.  Samples from sets of at least three 
patients will be grouped for scientific analysis. 
 
Standardized 3-digit sample collection numbers: 
400 series: blood for circulating tumor cells (CTCs) 
500 series: tumor biopsies 
 
The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality.  Access to the inventory system and associated 
documents will be restricted to appropriate individuals.  Requests to use specimens 
stored in the repository must be approved.  The only patient information available 
in the inventory system will be the patient sex, diagnosis, and level of informed 
consent given.  SOPs ensure that any changes in informed consent made by a 
patient and relayed to the PI will be reflected in the inventory system to ensure that 
specimens are destroyed as appropriate.  All laboratory personnel will be trained to 
adhere to SOPs and will be monitored for high-quality performance. 
 
Any new use of these samples will require prospective IRB review and approval.  
Access to these samples will only be granted following IRB approval of an 
additional protocol, granting the rights to use the material. 
 
If at any time, a patient withdraws from the study and does not wish for their 
existing samples to be utilized, the individual must provide a written request.  
Following receipt of this request, the samples will be destroyed (or returned to the 
patient, if so requested), and reported as such to the IRB.  Any samples lost (in 
transit or by a researcher) or destroyed due to unknown sample integrity (i.e., 
broken freezer allows for extensive sample thawing, etc.) will be reported as such to 
the IRB. 
 
9.1.5 Immunohistochemistry 
Patients undergoing 89Zr-panitumumab PET/CT scans will be required to submit a 
minimum of 2 unstained slides from archival tumor biopsies to the Laboratory of 
Pathology, CCR, NCI for confirmation of EGFR expression by 
immunohistochemistry (IHC) to determine eligibility prior to undergoing scans.  
IHC staining for EGFR will be performed using the commercially available mouse 
anti-EGFR antibody from Zymed Laboratories, (Zymed Laboratories, Inc., 
Invitrogen Immunodetection, South San Francisco, CA) according to the 
manufacturer’s instructions.  Positivity will be defined as any membrane staining 
for EGFR in tumor cells.  For enrollment purposes the archival material will be 
scored solely as positive or negative.  Only those patients whose tumors are scored 


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as positive will be eligible for 89Zr-panitumumab scans; scans are optional during 
the escalation phase and mandatory during the expansion phase of this trial. 
9.1.6 Imaging Studies 
We are conducting 89Zr-immuno-PET imaging with panitimumab as a targeting 
ligand in the 10 patients enrolled in the expansion cohort, scans are optional during 
the escalation phase.  89Zr-panitumumab will be administered at baseline (prior to 
cycle 1 day 1 of treatment) and PET/CT imaging will be performed 2-6 hours 
following 89Zr-panitumuab injection.  If uptake into tumors is shown to be 
measurable, a second 89Zr-panitumumab infusion and scan will be performed at the 
end of cycle 1.  Uptake of 89Zr-panitumumab in normal tissue and tumors will be 
evaluated and human dosimetry values will be calculated.   
 
89Zr-panitumumab PET/CT will be performed in the NCI Molecular Imaging Clinic 
(B3B). The injectable dose of 89Zr-panitumumab for this study will be 1.0 mCi 
(37 MBq), with an allowable range of 0.75 to 1.0 mCi (28-37 MBq), and with a 
specific activity greater than 200 Ci/mmol at the time of injection.  The injected 
mass dose is less than or equal to 1 mg (7 nmol).  Ordering instructions for 89Zr-
panitumumab are provided in Appendix D.  Participants with severe claustrophobia 
not relieved by oral anxiolytic medication or patients weighing >136 kg (weight 
limit for scanner table) may not undergo 89Zr-panitumumab imaging.  89Zr-
panitumumab is a sterile, IV injectable solution that will be administered to subjects 
over 1 minute by intravenous bolus injection.   
 
The infusion and imaging procedure will be terminated in any patient who exhibits 
anaphylaxis, significant hypotension (systolic blood pressure less than 80 mmHg on 
2 measurements obtained within 1-2 minutes of each other), dyspnea, or chest pain. 
 
9.1.6.1 Scanning Procedure 
The scanning acquisition should include the patient torso, from the mid-ears to the 
mid-thighs.  A corresponding low energy transmission CT will be acquired 
immediately before each emission scan for attenuation correction and localization 
purposes.  The acquisition time for each PET/CT image is estimated at one hour.  
The injected dose of 89Zr-panitumumab will not exceed 1.0 mCi.  The minimum 
injected dose will be 0.75 mCi, although the total dose administered may be 
reduced at the discretion of the principal investigator on a case-by-case basis due to 
unpredictable delays.  The reasoning for a reduction in the dose will be clearly 
documented. 
9.1.6.2 Image Analysis 
• Preliminary analysis will be performed to define human dosimetry and evaluate 
tumor uptake/image quality (as determined by an experienced nuclear imaging 
physician). 


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• The uptake within an EGFR positive tumor us expected to be greater than mean 
background activity + 2X the standard deviation of the background tissue. 
• Regions/Volumes of interest (VOIs) will be drawn within the tumor focus/foci 
and normal solid organs, which will be identified on the transmission CT scan.  
For the tumor foci, an estimated smoothed maximum standard uptake value 
(SUV; SUVmax) will be reported as the mean SUV value of an automated 80% 
maximum pixel value threshold based on volume of interest (i.e., the average 
SUV of the :hottest” 20% of pixels in the user defined lesion).  This method 
reduces the chances of the SUVmax value being dominated by one or more 
“noisy” pixel values.  Additional VOIs will include an anatomic value based on 
the transmission CT and a metabolic volume using an absolute SUVmax 
threshold.  For the normal solid organs, VOIs will also be drawn and SUVmean 
will be reported. 
• A small VOI will also be defined within the left ventricular or atrial cavity or 
over the aorta to obtain the blood pool and SUVmean will be reported. 
• A normal tissue “background” VOI will be drawn by establishing a 50% 
maximum pixel value volume of interest (VOI), drawn within a homogeneous 
non-tumor-involved region within the organ in which the tumor resides.  This 
VOI will be used to determine tumor:background ratios. 
• All regions/volumes of interest will be saved.  Region volumes, and SUV values 
will be output to an Excel spreadsheet using MIM imaging software 
(www.mimsoftware.com) 
• Image data will be used to calculate the dosimetry using OLINDA (Organ Level 
Internal Dose Assessment Code, sopyright Vanderbilt University, 2003) 
software and to obtain preliminary tissue uptake variability measurements 
 
9.1.6.3 Data Analysis 
SUVmax and SUVmean within the tumor and non-tumor areas, and tumor:background 
will be analyzed.  Percent change of SUV between baseline and after the first cycle 
will be assessed.  Based on published PET/CT reproducibility data, a percent 
change >20% in SUV values will be considered significant. 
9.1.7 Human Data Sharing Plan 
What data will be shared?  
We will share human data generated in this research for future research as follows: 
X De-identified data in an NIH-funded or approved public repository  
X Identified data in BTRIS (automatic for activities in the Clinical Center)  
X De-identified or identified data with approved outside collaborators under 
appropriate agreements  
 
How and where will the data be shared?  
Data will be shared through:  
X An NIH-funded or approved public repository: clinicaltrials.gov 


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X BTRIS (automatic for activities in the Clinical Center)  
X Approved outside collaborators under appropriate individual agreements  
X Publication and/or public presentations  
 
When will the data be shared?  
X At the time of publication or shortly thereafter 
 
10 STUDY CALENDAR 
Baseline evaluations are to be conducted within 72 hours prior to start of protocol therapy.  
Scans and x-rays must be done ≤4 weeks prior to the start of therapy.  Start of next cycle may 
be delayed for up to 1 week to accommodate scheduling conflicts.  Treatments within a cycle 
may be delayed up to +/- 1 day to accommodate scheduling conflicts.  History and physical 
examination and laboratory evaluations can be performed up to 3 days before the start of the 
next cycle.  


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Study Procedure 
Screen 
Study Treatment  
Cycle 1  
Cycle 2 and subsequent 
cycles 
Off 
Treatment 
W1 
W2 
W3 
Wk 4 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
 
Ganetespiba 
 
Xb 
X 
X 
 
X 
X 
X  
 
 
Ziv-Aflibercept 
 
X 
 
X 
 
X 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-----------------------------------------------------------------------X 
 
Physical examd 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Vital signsd 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Heightd 
X 
 
 
 
 
 
 
 
 
 
Weightd 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Performance statusd 
X 
 
X 
X 
 
X 
X 
X 
 
X 
CBC w/diff, pltse 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Serum chemistrye 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Urine 
protein/creatininee 
X 
 
 
X 
 
X 
 
X 
 
X 
PT, INR, PTTf 
X 
 
X 
 
 
 
X 
 
 
 
β-HCGg 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogramh 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Echocardiogrami 
X 
 
 
 
 
 
 
 
 
 
Ophthalmologic 
examj 
X 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
X 
X----------------------------------------------------------------------X 
 
Tumor  
measurements 
X 
Tumor measurements are repeated every 2 cycles.  Documentation 
(radiologic) must be provided for patients removed from study for 
progressive disease. 
X 
Tumor biopsyk 
 
 
X 
 
 
 
X 
 
 
 
89Zr-panitumumab 
PET/CT scanl 
 
X 
 
X 
 
 
 
 
 
 
PD blood collectionm 
X 
X 
X 
 
 
X 
X 
 
 
 


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a. Ganetespib will be administered intravenously on D1, 8, and 15 of a 28-day cycle. 
b. In order to accommodate biopsies, D1 administration of ganetespib may be omitted during cycle 1 only. 
c. Ziv-aflibercept will be administered intravenously on D1 and 15 of a 28-day cycle. 
d. Physical examination, including vitals, weight, and performance status, will be performed at the Clinical 
Center at the start of each cycle or treatment (up to 3 days before start of a new cycle or treatment). 
Height will be performed at enrollment and will not need to be repeated prior to each treatment. 
e. Serum chemistry (albumin, total bilirubin, calcium, creatinine, phosphorus, magnesium, potassium, 
sodium, SGOT [AST], SGPT [ALT], amylase, lipase); CBC w/diff,  and platelets should be performed 
within 72 hours of enrollment and weekly thereafter on weeks of treatment, prior to the first treatment 
of that week.  If clinically indicated, labs may be obtained with more frequency with subsequent cycles.  
Urine protein/creatinine ratio will be checked prior to treatment with ziv-aflibercept. 
f. PT/INR, PTT prior to biopsy. 
g. Serum pregnancy test (women of childbearing potential) within 1 week prior to enrollment and as 
clinically indicated. 
h. Electrocardiogram will be performed prior to each ganetespib treatment and approximately 24 hours 
after each treatment during the first cycle, and will be repeated as indicated until QTc is less than 
500 msec.  With subsequent cycles, electrocardiogram will be performed prior to each treatment, and 
repeated after treatment if clinically indicated. 
i.  Echocardiogram must be performed within 4 weeks prior to enrollment and as clinically indicated 
thereafter. 
j.  Ophthalmologic exams must be performed within 4 weeks prior to enrollment and as clinically indicated 
thereafter. 
k. Tumor biopsies will be obtained on Cycle 1 D7 prior to administration of ganetespib on C1D8, and again 
on C2D7 before administration of ganetespib on C2D8.  Tumor biopsies are optional during the 
escalation phase and mandatory during the expansion phase.  If tumor biopsies are collected, the first 
dose of ganetespib on C1D1 will be omitted. 
l. 89Zr-panitumumab scan will be performed in patients with confirmed EGFR expression on archival tumor 
tissue prior to initiation of treatment on C1D1.  If there is evidence of measurable uptake on baseline 
scans, patients will receive a second 89Zr-panitumumab PET/CT scan after completion of C1D15 
treatment, on C1D16 ± 1 day.  If patients are unable to have a second scan during cycle 1 due to 
scheduling conflicts, scans may be performed during C2D16 ± 1 day.  Scans will be optional during the 
escalation phase and mandatory during the expansion phase. 
m.  Blood for circulating tumor cells (optional) will be collected on the expansion phase only per Section 
9.1.3  
 
11 MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
Although response is not the primary endpoint of this trial, patients with measurable 
disease will be assessed by standard criteria.  For the purposes of this study, patients should 
be re-evaluated for response every 8 weeks (every 2 cycles).  In addition to a baseline scan, 
confirmatory scans should also be obtained at least 4 weeks following initial 
documentation of objective response. 
 


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Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with the combination of ganetespib and ziv-
aflibercept. 
 
Evaluable for objective response.  Only those patients who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT scan, MRI, or 
calipers by clinical exam.  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. 
 
Non-measurable disease.  All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥10 to <15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 


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abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above.  However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
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.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
11.2 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment 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 unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 


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Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease.  Furthermore, as 
with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of 
the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 


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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 patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
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 stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 


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11.3 Response Criteria 
11.3.1 Evaluation of Target Lesions 
Complete Response (CR): 
 Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-
target) 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 (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions). 
 
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. 
11.3.2 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). 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Non-CR/Non-PD:  
 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase.     


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Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
11.3.3 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 
patient'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 
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 
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 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients 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. 
 


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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 
Non-CR/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 as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
11.4 
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 recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive 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, including the baseline measurements.  
 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
12.1.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS). 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31 and October 31.  
 
 
Note: All adverse events that have occurred on the study, including those reported 
through CTEP-AERS, must be reported via the monitoring method identified 
above. 
12.1.2 Responsibility for Data Submission 
N/A 


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12.2 
CTEP Multicenter Guideline 
N/A 
12.3 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.   Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators.  The protocol 
documents for studies utilizing Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement.  A suitable model 
agreement can be downloaded from http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as “Multi-Party Data”):  
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, the 
design of the proposed combination protocol, and the existence of any obligations 
that would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
 
clinical trial by any other Collaborator solely to the extent necessary to allow said  
 
other Collaborator to develop, obtain regulatory approval or commercialize its  
 
own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 


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described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must 
also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
 
E-mail: ncicteppubs@mail.nih.gov 
 
 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
13 STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Endpoints 
This Phase I study will use a standard 3+3 design.  The MTD dose for the combination of 
ganetespib and ziv-aflibercept is defined as the dose level at which no more than 1 of 6 
patients experience a DLT during the first cycle of the treatment, and the dose level below 
that at which at least 2 (of < 6) patients have DLT as a result of the drug.  Patients will 


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receive ganetespib intravenously on a weekly basis, on days 1, 8, and 15, for 3 weeks out of 
4, every 28 days, and ziv-aflibercept intravenously every 2 weeks, on days 1 and 15, during 
a 28-day cycle.  Once the MTD is established, 10 additional patients will be enrolled to the 
expansion phase of the trial, at the MTD and tumor biopsies will be obtained to assess for 
pharmacodynamic endpoints.  Patients will also undergo an 89Zr-panitumumab PET/CT 
scan to evaluate tumor distribution of EGFR prior to and following treatment with both 
study agents.   
 
13.2 
Sample Size/Accrual Rate 
We plan to accrue a total of 22 patients in this study.  To allow for some patients who may 
have only evaluable and not measurable disease, the accrual ceiling is set at 26.  It is 
anticipated that 2-3 patients may be enrolled per month onto this study.  It is expected that 
14-21 months will be required to accrue the number of patients necessary to complete the 
trial. 
13.3 
Analysis of Secondary Endpoints 
At the maximal tolerated dose (MTD), we will enroll an additional 10 patients, with 
mandatory tumor biopsies, for further assessment of pharmacodynamics and imaging 
endpoints.  HIF1α expression and EGFR expression (as measured by SUV, using 89Zr-
labeled, EGFR-targeting panitumumab antibody PET/CT imaging) will all be assessed 
similarly, in an exploratory fashion.  For each endpoint, the mean difference (or mean log-
difference, if such a transformation appears appropriate) between pre- and post-treatment 
values, paired by patient, will be assessed by the 1-sample paired t-test, at the 1-sided .05 
significance level, if the differences (or log-differences) appear distributed in 
approximately normal (uni-modal) fashion.  This test will have 90% power to detect a 
treatment related change, in any individual endpoint, equivalent to approximately 0.92SD 
associated with the natural variation over repeated measures in the absence of treatment.  If 
the differences are not distributed in approximately normal (uni-modal) fashion, the non-
parametric sign test will be used to assess whether the observed treatment related changes 
are in a reliably negative direction (this test will have low power, since it requires that at 
least 8 of the 10 changes be in the negative direction, to achieve statistical significance at 
the 1-sided .05 level). 
 
 
14 HUMAN SUBJECTS PROTECTIONS 
14.1 
Justification for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race, provided 
that the aforementioned inclusion and exclusion criteria are met.  Patients for this study will 
be recruited through internal referral, our physician referral base, and through various 
cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer).  To 
date, there is no information that suggests that differences in drug metabolism or effect on 


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tumor would be expected in one ethnic group compared to another.  Efforts will be made to 
extend accrual to each representative population, but a balance must be struck between 
participant safety considerations and limitations on the number of individuals exposed to 
potentially ineffective treatments on the one hand and the need to explore racial/ethnic 
aspects of clinical research on the other hand.  If differences in outcome that correlate to 
ethnic identity are noted, a follow-up study may be written to investigate those differences 
more fully. 
 
Due to lack of knowledge of the effects of the combination of ganetespib and ziv-
aflibercept on the fetus or infants, as well as the possibility of teratogenic effects, pregnant 
and nursing women will be excluded from this trial.  Patients with unstable or serious 
medical conditions are excluded due to the possibility that the combination of ganetespib 
and ziv-aflibercept may worsen their condition and the likelihood that the underlying 
condition may obscure the attribution of adverse events to ganetespib and ziv-aflibercept.  
HIV-positive patients on combination antiretroviral therapy are excluded from the study 
because of possible PK interactions with the combination of ganetespib and ziv-aflibercept. 
14.1.1 Participation of Children 
This study includes patients 18 years of age and older.  Because insufficient dosing 
or adverse event data are currently available on the use of combination of 
ganetespib and ziv-aflibercept in patients <18 years of age, children are excluded 
from this study, but may be eligible for future pediatric trials.  Studies will be 
performed in patients <18 years of age when it is appropriate to do so. 
14.2 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  
Their participation will benefit future cancer patients.  Potential risks include the possible 
occurrence of any of a range of side effects that are listed in the consent document.  The 
procedure for protecting against or minimizing risks will be to medically evaluate patients 
as described in Section 5 and Section 6.  Although no compensation is available, any injury 
will be fully evaluated and treated in keeping with the benefits or care to which participants 
are entitled under applicable regulations. 
14.3 
Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, 
alternatives, drug administration plan, research objectives, and follow-up of this trial.  The 
patient will be provided an IRB-approved consent for review and signature and his/her 
questions will be answered.  After a decision is made to enroll into the study, a signature 
will be obtained from the patient.  The original signed consent goes to Medical Records; a 
copy will be placed in the research record. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on 
study. 


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14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All 
patients will be monitored for side effects from taking study medication.  This research 
represents a greater than minimal risk to participants, but presents the prospect of direct 
benefit to individual subjects. 
 
The research component of this study required to obtain 2 CT tumor biopsies confers 
radiation exposure at an effective dose of 0.29 rem.  This dose is below NIH RSC 
guidelines of less than 5.0 rem per year in adults, and represents a slightly greater than 
minimal risk to patients.  The imaging component of the study using 89Zr-panitumumab 
PET/CT confers an effective dose up to 6.9 rem, and adds a radiation risk which is slightly 
greater than minimal risk to subjects and offers no direct benefit to individual subjects. 
 
14.5 
Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this 
protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical 
Research Center, Room 1-3521, on the Bethesda NIH campus.  Patients will be informed 
that they can contact the study PI or RN at any time with questions about their medical 
care, and that the patients’ rights representative is also available to answer non-medical 
questions about the study. 


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REFERENCES 
1. 
Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 
144(5): p. 646-74. 
2. 
Bottsford-Miller, J.N., R.L. Coleman, and A.K. Sood, Resistance and escape from 
antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol, 2012. 30(32): p. 
4026-34. 
3. 
Stravopodis, D.J., L.H. Margaritis, and G.E. Voutsinas, Drug-mediated targeted disruption 
of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr 
Med Chem, 2007. 14(29): p. 3122-38. 
4. 
Mancuso, M.R., et al., Rapid vascular regrowth in tumors after reversal of VEGF 
inhibition. The Journal of Clinical Investigation, 2006. 116(10): p. 2610-2621. 
5. 
Casanovas, O., et al., Drug resistance by evasion of antiangiogenic targeting of VEGF 
signaling in late-stage pancreatic islet tumors. Cancer Cell, 2005. 8(4): p. 299-309. 
6. 
Pàez-Ribes, M., et al., Antiangiogenic Therapy Elicits Malignant Progression of Tumors to 
Increased Local Invasion and Distant Metastasis. Cancer Cell, 2009. 15(3): p. 220-231. 
7. 
Ebos, J.M.L., et al., Accelerated Metastasis after Short-Term Treatment with a Potent 
Inhibitor of Tumor Angiogenesis. Cancer Cell, 2009. 15(3): p. 232-239. 
8. 
Rini, B.I. and M.B. Atkins, Resistance to targeted therapy in renal-cell carcinoma. Lancet 
Oncol, 2009. 10(10): p. 992-1000. 
9. 
Ying, W., et al., Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits 
potent antitumor activity and a superior safety profile for cancer therapy. Mol Cancer Ther, 2012. 
11(2): p. 475-84. 
10. 
Sang, J., et al., Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK 
inhibitor resistance in non-small cell lung cancer. Cancer Discov, 2013. 3(4): p. 430-43. 
11. 
Friedland, J.C., et al., Targeted inhibition of Hsp90 by ganetespib is effective across a 
broad spectrum of breast cancer subtypes. Invest New Drugs, 2013. 
12. 
Ganji, P.N., et al., Antiangiogenic effects of ganetespib in colorectal cancer mediated 
through inhibition of HIF-1alpha and STAT-3. Angiogenesis, 2013. 16(4): p. 903-17. 
13. 
Carmeliet, P., et al., Synergism between vascular endothelial growth factor and placental 
growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat 
Med, 2001. 7(5): p. 575-83. 
14. 
Messa, C., et al., EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta 
Oncol, 1998. 37(3): p. 285-9. 
15. 
Karar, J. and A. Maity, PI3K/AKT/mTOR Pathway in Angiogenesis. Front Mol Neurosci, 
2011. 4: p. 51. 
16. 
Blackman, R.K., et al., Abstract 2637: Hsp90 inhibitor STA-9090 enhances the activity of 
standard of care therapies in erlotinib-sensitive and -resistant NSCLC models. Cancer Research, 
2011. 70(8 Supplement): p. 2637. 
17. 
Van Cutsem, E., et al., Addition of aflibercept to fluorouracil, leucovorin, and irinotecan 
improves survival in a phase III randomized trial in patients with metastatic colorectal cancer 
previously treated with an oxaliplatin-based regimen. J Clin Oncol, 2012. 30(28): p. 3499-506. 
18. 
Shimamura, T., et al., Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has 
potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer. Clin Cancer 
Res, 2012. 18(18): p. 4973-85. 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
78
19. 
Ko, J.C., et al., HSP90 inhibition induces cytotoxicity via down-regulation of Rad51 
expression and DNA repair capacity in non-small cell lung cancer cells. Regul Toxicol Pharmacol, 
2012. 64(3): p. 415-24. 
20. 
Sandler, A., et al., Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell 
lung cancer. N Engl J Med, 2006. 355(24): p. 2542-50. 
21. 
Reck, M., et al., Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as 
first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III 
trial (AVAiL). Ann Oncol, 2010. 21(9): p. 1804-9. 
22. 
Socinski, M.A., et al., A multicenter phase II study of ganetespib monotherapy in patients 
with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res, 2013. 19(11): p. 
3068-77. 
23. 
Chow, N.H., et al., Significance of urinary epidermal growth factor and its receptor 
expression in human bladder cancer. Anticancer Res, 1997. 17(2B): p. 1293-6. 
24. 
Chow, N.H., et al., Expression profiles of ErbB family receptors and prognosis in primary 
transitional cell carcinoma of the urinary bladder. Clin Cancer Res, 2001. 7(7): p. 1957-62. 
25. 
Jimenez, R.E., et al., Her-2/neu overexpression in muscle-invasive urothelial carcinoma of 
the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. 
Clin Cancer Res, 2001. 7(8): p. 2440-7. 
26. 
Bellmunt, J., M. Hussain, and C.P. Dinney, Novel approaches with targeted therapies in 
bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor 
family. Crit Rev Oncol Hematol, 2003. 46 Suppl: p. S85-104. 
27. 
Theodoropoulos, V.E., et al., Evaluation of hypoxia-inducible factor 1alpha overexpression 
as a predictor of tumour recurrence and progression in superficial urothelial bladder carcinoma. 
BJU Int, 2005. 95(3): p. 425-31. 
28. 
Yoon, S.S., et al., Angiogenic profile of soft tissue sarcomas based on analysis of 
circulating factors and microarray gene expression. J Surg Res, 2006. 135(2): p. 282-90. 
29. 
Kim, Y.J., et al., Overcoming evasive resistance from vascular endothelial growth factor a 
inhibition in sarcomas by genetic or pharmacologic targeting of hypoxia-inducible factor 1alpha. 
Int J Cancer, 2013. 132(1): p. 29-41. 
30. 
Mahalingam, D., et al., Targeting sarcomas: novel biological agents and future 
perspectives. Curr Drug Targets, 2009. 10(10): p. 937-49. 
31. 
Staufer, K. and O. Stoeltzing, Implication of heat shock protein 90 (HSP90) in tumor 
angiogenesis: a molecular target for anti-angiogenic therapy? Curr Cancer Drug Targets, 2010. 
10(8): p. 890-7. 
32. 
Proia, D.A., et al., Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090) 
in cancer cells with activated JAK/STAT signaling. PLoS One, 2011. 6(4): p. e18552. 
33. 
Acquaviva, J., et al., Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 
inhibitor ganetespib. Mol Cancer Ther, 2012. 11(12): p. 2633-43. 
34. 
Goldman, J.W., et al., A first in human, safety, pharmacokinetics, and clinical activity 
phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in 
patients with solid malignancies. BMC Cancer, 2013. 13: p. 152. 
35. 
Argiles, G., et al., Panitumumab: a summary of clinical development in colorectal cancer 
and future directions. Future Oncol, 2012. 8(4): p. 373-89. 
36. 
Verel, I., et al., 89Zr immuno-PET: comprehensive procedures for the production of 89Zr-
labeled monoclonal antibodies. J Nucl Med, 2003. 44(8): p. 1271-81. 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
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37. 
Holland, J.P., Y. Sheh, and J.S. Lewis, Standardized methods for the production of high 
specific-activity zirconium-89. Nucl Med Biol, 2009. 36(7): p. 729-39. 
38. 
Perk, L.R., et al., Preparation and evaluation of (89)Zr-Zevalin for monitoring of (90)Y-
Zevalin biodistribution with positron emission tomography. Eur J Nucl Med Mol Imaging, 2006. 
33(11): p. 1337-45. 
39. 
Borjesson, P.K., et al., Performance of immuno-positron emission tomography with 
zirconium-89-labeled chimeric monoclonal antibody U36 in the detection of lymph node 
metastases in head and neck cancer patients. Clin Cancer Res, 2006. 12(7 Pt 1): p. 2133-40. 
40. 
Bhattacharyya, S., et al., Zirconium-89 labeled panitumumab: a potential immuno-PET 
probe for HER1-expressing carcinomas. Nuclear Medicine and Biology, 2013. 40(4): p. 451-457. 
 
 


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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on 
all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but ambulatory 
and able to carry out work of a light or 
sedentary nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed 
or chair. 
5 
Dead. 


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APPENDIX B: POTENTIAL DRUG INTERACTIONS 
 


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CYP2C19 INHIBITORS 
Chloramphenicol 
Cimetidine 
Esomeprazole 
Felbamate 
Fluoxetine 
Fluvoxamine 
Indomethacin 
Ketoconzaole 
Lansoprazole 
Modafinil 
Omeprazole 
Oxcarbazepine 
Pantoprazole 
Probenicid 
Rabeprazole 
Ticlodipine 
Topiramate 
 
 
CYP2C19 INDUCERS 
Carbamazepine 
Norethindrone 
Prednisone 
Rifampicin 
 
 
 
 
CYP2C19 SUBSTRATES 
Amitriptyline 
Carisoprodol 
Citalopram 
Chloramphenicol 
Clomipramine 
Clopidogrel 
Cyclophosphamide 
N-DeME 
Diazepam 
Hexobarbital 
Imipramine 
Indomethacin 
Lansoprazole 
S-mephenytoin 
R-mephobarbital 
Moclobemide 
Nelfinavir 
Nilutamide 
Omeprazole 
Pantoprazole 
Phenobarbitone 
Phenytoin 
Primidone 
Progesterone 
Proguanil 
Propanolol 
Rabeprazole 
Teniposide 
R-warfarin 
 
Because the lists of these agents are constantly changing, frequently-updated lists available at 
http://medicine.iupui.edu/clinpharm/ddis/table.asp will be consulted. 
 


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APPENDIX C: DRUGS WITH RISK OF TORSADES DE POINTES 
 
Obtained from the Arizona Center for Education and Research on Therapeutics (AZCERT) 
website http://crediblemeds.org, last revised May 4, 2015. 
 
 
 


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Next page:  
APPENDIX D: 89Zr-LABELED PANITUMUMAB ORDER FORM


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*Please place 89Zr-Panitumumab orders 5 business days prior to scheduled scan date and time. 
  Site Contact Information 
Site Name: 
 
Principal Investigator: 
 
Study Coordinator: 
 
NCI Protocol Number: 
 
Shipping Information 
Account Name: 
 
Contact Name: 
 
Contact Phone & Email 
or Fax: 
 
Shipment Address: 
 
2.  Leidos Radiopharmacy Section: Confirm receipt of Request Form and fax or e-mail to 
Clinical Site 
89Zr-Panitumumab Request Form received on ___  ___ ________  by _________________________ 
                                                                           DD MM YYYY                     Print Name 
3. Leidos Radiopharmacy Section   
Date request received: 
 
Leidos Radiopharmacy Shipment Number: 
 
Tracking Number: 
 
Mode of Transportation: 
 
Batch Number: 
 
Attachments:   
Please affix copy of the syringe label below  
 
 
 
 
Checked by: 
 
Packed by: 
Date Shipped: 
89Zr-panitumumab Order Form 
Site  
 
Subject / Patient ID 
 
Date of Request * 
 
DD           MM       YYYY 
Scheduled 89Zr-Panitumumab Scan 
 
DD         MM       YYYY 
Time 
 
24 hr clock 
Dose Activity 
 
 mCi 
1.  Site Section : Complete and fax to Leidos Radiopharmacy at 301-228-4624 


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APPENDIX E - PATIENT STUDY CALENDAR 
 
The study drugs are given over a 28-day period of time called cycles.  The 28-day treatment 
cycle will be repeated as long as you are tolerating the medications and your cancer is either 
stable or getting better.   
The chart below shows what will happen to you during cycle 1 and future cycles after you sign 
the consent form and start the study.  Each cycle is numbered.  The left-hand column shows the 
day in the cycle, and the right-hand column tells you what will happen on that day.   
 
Day 
What to do and what will happen to you 
Before 
starting 
study drug 
• Check in at the Outpatient Clinic 
• Get routine blood tests and electrocardiogram of your heart (EKG) 
• Urine tests to check for protein in your urine 
• Pregnancy test for women who are able to become pregnant 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• CT or MRI scan will be done 
• Echocardiogram or MUGA scan will be done to check your heart 
• Eye exam 
• Blood draws for research will be obtained from some patients  
• For patients who agree to undergo 89Zr-panitumumab PET/CT, baseline scans 
will be done prior to the start of cycle 1. 
Cycle 1,  
Day 1  
• Get routine blood tests and EKG (does not need to be repeated if done within 
3 days before starting treatment) 
• Urine tests to check for protein in your urine (does not need to be repeated if 
done within 3 days before starting treatment) 
• Receive the first dose of ziv-aflibercept through a vein 
• Receive the first dose of ganetespib through a vein; for patients who have 
tumor biopsies, this dose of ganetespib will not be given 
Cycle 1,  
Day 2 
• An electrocardiogram of your heart will be done approximately 24 hours after 
receiving ganetespib 
Cycle 1,  
Day 7 
• For patients who have agreed to undergo tumor biopsies, the first tumor 
biopsy will take place on this day  
Cycle 1,  
Day 8 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Blood draws for research will be obtained from some patients.  Get routine 
blood tests and EKG 
• Ganetespib will be given through a vein 
 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
89
Day 
What to do and what will happen to you 
Cycle 1,  
Day 9 
• An electrocardiogram of your heart will be done approximately 24 hours after 
receiving ganetespib 
Cycle 1,  
Day 15 
• Check in at the Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests and EKG 
• Urine tests to check for protein in your urine 
• Ziv-aflibercept will be given through a vein 
• Ganetespib will be given through a vein   
• Blood draws for research will be obtained from some patients 
Cycle 1, 
Day 16 
• An electrocardiogram of your heart will be done approximately 24 hours after 
receiving ganetespib 
• For patients who agree to undergo 89Zr-panitumumab PET/CT, post-treatment 
scans will be done on this day.  If there are scheduling conflicts, scans may be 
done during Cycle 2, Day 16. 
Cycle 1, 
Day 22 
• No drug is given 
Cycle 2, 
Day 1 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests and EKG 
• Urine tests to check for protein in your urine 
• Ziv-aflibercept will be given through a vein 
• Ganetespib will be given through a vein 
Cycle 2, 
Day 7 
• For patients who having tumor biopsies, the second tumor biopsy will take 
place on this day prior to treatment with ganetespib. 
Cycle 2, 
Day 8 
• Check in at the Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider  
• Blood draws for research will be obtained from some patients  
• Get routine blood tests and EKG 
• Ganetespib will be given through a vein   
Cycle 2, 
Day 15 
• Check in at the Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests and EKG 
• Urine tests to check for protein in your urine 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
90
Day 
What to do and what will happen to you 
• Ziv-aflibercept will be given through a vein 
• Ganetespib will be given through a vein   
• Blood draws for research will be obtained from some patients 
Cycle 2, 
Day 16 
• For patients who agree to undergo 89Zr-panitumumab PET/CT, post-treatment 
scans not performed during cycle 1, day 16 can have scans rescheduled to this 
day. 
Cycle 2, 
Day 22 
• No drug is given 
Cycle 3, 
Day 1 and 
15, and 
onward 
• Check in at the Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests and EKG 
• Urine tests to check for protein in your urine 
• CT scan to determine how your tumor is responding to the treatment will be 
done every 8 weeks (every 2 cycles) 
• Ziv-aflibercept will be given through a vein 
• Ganetespib will be given through a vein   
• Blood draws for research will be obtained from some patients on day 1 of 
every cycle 
Cycle 3, 
Day 8, and 
onward 
• Check in at the Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider  
• Get routine blood tests and EKG 
• Ganetespib will be given through a vein   


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
91
APPENDIX F: EXPANSION PHASE PD COLLECTION WORKSHEETS 
 
 
Date:  
PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 1 
CTEP Protocol P9605 
 
 
Page 102-12798 for Sample Pick-up  
Lab phone: 301-451-1169 
Research Nurse:  
Dose level: 
 
Phone:  
Patient ID: 
 
Lead AI/PI:  
  Phone:                          
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual Time 
Record comments (i.e., if collection missed), 
and sign each time you collect a sample 
Day 1 
Prior to drug 
administration 
PD 400 2x 4 mL K3 EDTA 
Label tube: sample number, date and time 
 
  
 
 
Date:  
PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 8 
CTEP Protocol P9605 
 
 
Page 102-12798 for Sample Pick-up  
Lab phone: 301-451-1169 
Research Nurse:  
Dose level: 
 
Phone:  
Patient ID: 
 
Lead AI/PI:  
  Phone:                          
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual Time 
Record comments (i.e., if collection missed), 
and sign each time you collect a sample 
Day 8 
Prior to drug 
administration* 
PD 401 2x 4 mL K3 EDTA 
Label tube: sample number, date and time 
 
  
*No drugs administered on Day 7; Ganetespib administered on Day 8 
 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
92
 
Date:  
PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 15 
CTEP Protocol P9605 
 
 
Page 102-12798 for Sample Pick-up  
Lab phone: 301-451-1169 
Research Nurse:  
Dose level: 
 
Phone:  
Patient ID: 
 
Lead AI/PI:  
  Phone:                          
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual Time 
Record comments (i.e., if collection missed), 
and sign each time you collect a sample 
Day 15 
Completion time of Ziv-aflibercept and Ganetespib IV administration: 
Day 15 
4 hr after 
completion of drug 
administration 
PD 402  2x 4 mL K3 EDTA 
Label tube: sample number, date and 
time 
 
  
 
 
 
Date:  
PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 2 DAY 8 
CTEP Protocol P9605 
 
 
Page 102-12798 for Sample Pick-up  
Lab phone: 301-451-1169 
Research Nurse:  
Dose level: 
 
Phone:  
Patient ID: 
 
Lead AI/PI:  
Phone:                          
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual Time 
Record comments (i.e., if collection missed), 
and sign each time you collect a sample 
Day 8 
Prior to drug 
administration* 
PD 403  2x 4 mL K3 EDTA 
Label tube: sample number, date and 
time 
 
  
*No drugs administered on Day 7; Ganetespib administered on Day 8 
 
 
 
 


CTEP #9605 
Clinical Center #14-C-0150 
 
 
 
93
Date:  
PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 2 DAY 15 
CTEP Protocol P9605 
 
 
Page 102-12798 for Sample Pick-up  
Lab phone: 301-451-1169 
Research Nurse:  
Dose level: 
 
Phone:  
Patient ID: 
 
Lead AI/PI:  
  Phone:                          
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual Time 
Record comments (i.e., if collection missed), 
and sign each time you collect a sample 
Day 15 
Completion time of Ziv-aflibercept and Ganetespib IV administration: 
Day 15 
4 hr after 
completion of drug 
administration 
PD 404  2x 4 mL K3 EDTA 
Label tube: sample number, date and 
time 
 
  
 
 
 
Date:  
PD BLOOD SAMPLE COLLECTION SHEET: DAY 1 EACH CYCLE/PER PI 
CTEP Protocol P9605 
 
 
Page 102-12798 for Sample Pick-up  
Lab phone: 301-451-1169 
Research Nurse:  
Dose level: 
 
Phone:  
Patient ID: 
 
Lead AI/PI:  
  Phone:                          
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual Time 
Record comments (i.e., if collection missed), 
and sign each time you collect a sample 
Day  
Before drug 
administration 
PD 40X  2x 4 mL K3 EDTA 
Label tube: sample number, date and 
time 
 
  
 

ICF_000.pdf: 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
MEDICAL RECORD 
• Adult Patient or     •  Parent, for Minor Patient
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
 14-C-0150        
   PRINCIPAL INVESTIGATOR:  A.P. Chen, M.D. 
STUDY TITLE: 
Phase I Study of Ganetespib and Ziv-Aflibercept in Patients with Advanced 
Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, 
Urothelial Carcinomas, and Sarcomas 
Continuing Review Approved by the IRB on 05/18/15 
Amendment Approved by the IRB on 02/03/16 (D) 
 
  Date Posted to Web: 02/04/16 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or
•
Parent, for Minor Patient
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
The purpose of this study is to test the safety of the combination of ganetespib and ziv-
aflibercept, and to find out the doses of these drugs that can be safely given to humans.  We are 
trying to understand how these drugs work in humans.  Although we hope this experimental 
therapy will decrease the size of your tumor, we cannot promise or predict the benefits of the 
treatment at this time.  The drugs used in this study have known side effects that will be 
reviewed with you by your medical team before you sign the consent form. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 2 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Why are you being asked to take part in this study? 
You are being asked to take part in this research study because you have advanced cancer that 
has progressed after receiving standard treatment, or for which no effective therapy exists.  We 
hope that this combination of study drugs will slow down the growth of your cancer. 
How many people will take part in this Study?  
Up to 26 patients will take part in this study. 
Description of Research Study 
What will happen if you take part in this research study?   
If you are accepted and you choose to take part, you will begin receiving ganetespib and ziv-
aflibercept.  Both drugs are given as an infusion through a vein.  Ganetespib is given once a 
week on the same day for three weeks in a row, followed by a one week rest period.  Ziv-
aflibercept is given once a week every other week.  The drugs are given in cycles; each cycle is 
28 days (4 weeks) long.  Each patient may receive a different dose based on when he or she 
entered the study.  Your dose of study drugs may be decreased by the study doctor if you are not 
tolerating it well.  Study doctors have already seen some serious side effects on this study that 
are related to the agents and so new patients will be receiving a lower dose of the combination.  
 
Most of the exams, tests, and procedures you will have are part of your regular care such as a 
complete medical history, blood tests, and scans to measure your tumors.  We would also do a 
pregnancy test in women who are able to become pregnant.  The team will also give you a chart 
describing the tests and procedures that will be done each day during the study. 
 
While you are at the Clinical Center we will perform study tests and procedures to see how the 
study drugs are affecting your body.  If you develop any side effects, you may be asked to visit 
more often. 
 
How long will I be in this study?  
You will stay in the study as long as you are tolerating the drugs and your tumors are either 
stable or getting better, but you can choose to leave the study at any time. 
 
Tests and procedures that are either being tested in this study or being done to see how the 
drug is affecting your body: 
• Eye exam by a qualified eye doctor that involves adding eye drops to dilate, or widen, your 
eyes so that we can tell during the study if your eyes or vision have been affected by the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 3 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
study drugs.  We may do another eye exam during the study to find out if your eyes or 
vision have changed.   
• Blood cells for research: We will also be collecting blood samples from some patients to 
find out the effects of the drugs on any tumor cells in your blood.  Giving these samples is 
optional.  Each blood collection is about 2 teaspoons (8 mL).   
• Tumor Biopsy: You may be asked to undergo imaging-directed biopsy of your tumor 
(removal of a small bit of tissue for microscopic examination) once in the first cycle and a 
second time in the second cycle.  We are collecting biopsy samples to study the effects of 
study drugs on your tumor.  Biopsies are an important part of this trial and are done for 
research purposes.  Biopsies are optional in the early part of this study (called the dose 
escalation phase).  
If you decide not to have biopsies collected, you will still receive study drugs and other tests 
that are part of the study and detailed above.  However, at a certain point in the study 
called the expansion phase, willingness to undergo tumor biopsies will be required for 
taking part in this study.  We will tell you if biopsies are required before you decide to 
take part in the study.  No more than two biopsy procedures will be performed during the 
study.  After the first biopsy, if you decide not to have further biopsies, you will still receive 
study drugs and have other tests that are part of the study.  You will be asked to sign a 
separate consent form for each biopsy procedure. 
Tumor biopsies are only collected by trained personnel.  Biopsies are collected using a small 
needle under imaging guidance (CT, MRI, or ultrasound as deemed appropriate by the 
interventional radiologist performing the biopsy).  Imaging helps the specialized radiologist 
know that the needle has been placed into the tumor mass.   
Typical risks of biopsy collection include, but are not limited to, bleeding, infection, pain, 
and scarring.  If you experience any complications from the biopsy, medical care will be 
offered to you.  You will be counseled in more detail about biopsies, and you will be asked 
to sign a separate consent form that will describe the procedures and risks at that time.  Your 
safety is the most important thing at all times.  If upon attempting the first biopsy, no tissue 
can be obtained or it has caused you harm, further biopsies will not be done.  After you are 
enrolled in this study, if for any reason the biopsies cannot be done safely, you may still 
receive the study drugs but the biopsies will not be done. 
The biopsies are for research purposes and will not benefit you.  They might help other 
people in the future.  Even if you sign “yes” to have biopsies, you can change your mind at 
any time.  Please read the sentence below and think about your choice.  After reading the 
sentence, circle the initial answer that is right for you: 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 4 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
1) Have you been informed that you will be in the dose escalation phase in this study? 
 
Yes              No               Initials_________ 
I agree to have the tumor biopsies for the escalation phase of the research study 
(optional). 
 
Yes              No               Initials_________ 
2) Have you been informed that you will be in the expansion phase in this study? 
 
Yes              No               Initials_________ 
I agree to have the tumor biopsies for the expansion phase of the research study 
(mandatory). 
 
Yes              No               Initials_________ 
• 
89Zr-Panitumumab PET/CT: You may be asked to participate in a whole-body imaging 
study with 89Zr-panitumumab.  PET/CT is a type of scan that uses low dose x-rays to 
detect small amounts of radioactive chemicals (tracer), which allow us to see where the 
body tracer is going.  We are doing this to learn whether the study drugs ganetespib and 
ziv-aflibercept reduce how much of a protein called EGFR is made by your cancer cells 
without needing to collect a biopsy sample to measure EGFR directly in your tumor.  The 
amount you will be given for imaging is much lower than the dose given to treat cancer, 
and this dose is not expected to help treat your cancer.  For the PET scan, a small amount 
of a radioactive chemical will be injected through an intravenous (IV) catheter into your 
arm.  89Zr-panitumumab imaging will take place before you start treatment and again 
during the third week of the first cycle of treatment.  This imaging is optional for patients 
on the dose escalation phase but required in the expansion phase.  We will tell you if 
89Zr-panitumumab imaging is required before you decide to take part in the study.  
Your study team will explain 89Zr-panitumumab injections and PET/CT scans to you in 
more detail, and you will be asked to sign a separate consent.  
The PET scanner is shaped like a doughnut.  You will lie on your back on a bed that 
slides in and out of the scanner.  Each scan is expected to last approximately 70 minutes.  
After the scan, you will receive instructions about drinking fluids and urinating to limit 
your exposure to radioactivity.  The amount of radioactivity in your blood will be 
measured from a small amount of blood (about 2 teaspoons) drawn before 89Zr-
panitumumab injection and before each image is collected.   
This scan is for research purposes only.  The results of this scan will not affect or benefit 
you, but it will help researchers learn whether the 89Zr-panitumumab imaging is useful 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 5 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
for patients who have tumors that make too much EGFR.  If you choose to not undergo 
89Zr-panitumumab PET/CT imaging, this will not affect your care.  You may still take 
part in the study and receive the study drugs and other tests that are part of the study. 
 
I agree to undergo 89Zr-panitumumab PET/CT scans for research purposes:  
 
Yes              No               Initials_________ 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• you may choose to have the usual approaches described above  
• you may choose to take part in a different study, if one is available 
• you may continue your standard care as usual (see table below), and not take part in this 
study 
• or you may choose not to be treated, but you may want to receive comfort care to relieve 
symptoms  
 
Examples of treatments which are indicated for your particular cancer include: 
 
Colorectal cancer 
oxaliplatin- and irinotecan- based chemotherapy 
Non-squamous non-small 
cell lung cancer 
erlotinib for patients who have an EGFR mutation, crizotinib for 
patients who have ALK rearrangement, pemetrexed, paclitaxel, or 
platinum-based chemotherapy 
Urothelial cancer 
platinum-based chemotherapy 
 
Please talk to your doctor about these and other options. You should have received at least one of 
the treatments above (or both treatments in the case of colorectal cancer) before you may be 
eligible for this study.  Your doctor may decide that it is not safe for you to receive a particular 
treatment or you have the right to refuse a treatment, but before you decide to take part in this 
study you should discuss all available treatment options with your local doctor. 
 
Risks or Discomforts of Participation 
If you choose to take part in this study, there is a risk that: 
• 
You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• 
You may be asked sensitive or private questions which you normally do not discuss 
The agents used in this study may affect how different parts of your body work such as your 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 6 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
liver, kidneys, heart, and blood.  The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drugs/study approach. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
• The study doctor will provide you with information about other drugs you may need to 
avoid while receiving the study drug. 
The table below shows the most common and the most serious side effects that researchers know 
about.  There might be other side effects that researchers do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
High blood pressure is one common side effect of ziv-aflibercept.  Your blood pressure will be 
closely watched while you are receiving ziv-aflibercept.  This will include having your blood 
pressure checked at each clinic visit prior to your treatment for that week.  You will also be 
asked to check your blood pressure at home at least once a day for the entire length of the study.  
If you have high blood pressure while receiving ziv-aflibercept, your study doctor may 
recommend follow-up with your primary care physician and/or start or increase medications to 
lower your blood pressure.  Eye problems, including blurred vision, have also been reported in 
patients taking the study drugs.  Please tell us if you have any problems with your vision or eyes.   
Risks and side effects related to ganetespib may include: 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving ganetespib, more than 20 may have: 
• Diarrhea 
• Nausea 
• Tiredness 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 7 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving ganetespib, from 4 to 20 may have: 
• Anemia (low red blood cell count) which may require blood transfusion 
• Pain in belly, constipation, vomiting 
• Weight loss, loss of appetite 
• Dehydration 
• Dizziness, headache 
• Difficulty sleeping 
• Shortness of breath 
• Acne 
 
RARE, AND SERIOUS 
In 100 people receiving ganetespib, 3 or fewer may have: 
• Abnormal heart beat 
• Heart stops beating 
• Liver damage which may cause yellowing of the eyes and skin, swelling 
• Severe blood infection 
• Kidney damage which may require dialysis 
 
Risks and side effects related to ziv-aflibercept may include: 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving ziv-aflibercept, more than 20 and up to 100 may have: 
• Anemia which may require blood transfusion 
• Pain 
• Nausea 
• Tiredness 
• Loss of appetite 
• Headache 
• Changes in voice 
• High blood pressure which may cause blurred vision 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving ziv-aflibercept, from 4 to 20 may have: 
• Constipation, diarrhea, vomiting  
• Sores in mouth which may cause difficulty swallowing 
• Swelling of arms, legs 
• Fever 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 8 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Infection, especially when white blood cell count is low 
• Non-healing surgical site 
• Bruising, bleeding 
• Weight loss 
• Dehydration 
• Dizziness 
• A tear or hole in internal organs that may require surgery 
• Cough, shortness of breath 
• Runny nose 
• Hair loss, rash, skin changes 
• Redness, pain or peeling of palms and soles 
• Blood clot which may cause swelling, pain, shortness of breath, confusion, paralysis 
 
 
RARE, AND SERIOUS 
In 100 people receiving ziv-aflibercept, 3 or fewer may have: 
• Anemia, kidney problems which may require dialysis 
• Chest pain 
• Heart attack, Heart failure which may cause shortness of breath, swelling of ankles, cough 
or tiredness 
• A blood clot in the heart  
• Stroke which may cause weakness 
• Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 
• Mini stroke 
• Kidney damage which may require dialysis 
 
No side effects are expected from the 89Zr-panitumumab imaging study because the dose of drug 
is so low.  You will be monitored closely during this study for any new signs and symptoms.  
The side effects most likely during the 89Zr-panitumumab infusion are discomfort at the injection 
site, pain, respiratory difficulties, flushing, dizziness, itching/rash, and any other symptoms that 
could be secondary to an allergic reaction.  You will need to keep very still under the PET 
scanner for a period of 70 minutes, which you may find slightly uncomfortable.  You may need 
to keep your arms over your head for some of the imaging procedures, which may make your 
shoulders sore.  There is also the possibility that there may be unforeseen risks associated with 
this agent, about which nothing is yet known.  Any new findings that may affect your decision to 
remain in the study will be provided to you and your doctor. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 9 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Potential Risks Related to Blood Samples 
Possible side effects from drawing the blood sample include mild pain, bleeding, bruising, and 
infection at the site of the needle insertion.  Fainting or light-headedness can sometimes occur, 
but usually last only a few minutes.  
Potential Risks Related to Research-Related Imaging Studies:  
This research study involves exposure to radiation from up to 2 CT scans (used in biopsy 
collections) as well as from participation in 89Zr-panitumumab PET/CT imaging.  This radiation 
exposure is not required for your medical care and is for research purposes only.   
The total amount of radiation you may receive in this study is 7.2 rem, which exceeds the 
radiation dose permitted to research subjects at NIH, but the NIH Radiation Safety Committee 
has approved the higher dose in view of the value of the scientific information to be obtained.  
The radioactivity of each injected dose of 89Zr-panitumumab is less than 1 mCi (2 mCi in total).   
The radiation dose from CT scans used for biopsy collection only is 0.29 rem, which is below the 
guideline of 5 rem (or 0.5 rem in children) per year allowed for research subjects by the NIH 
Radiation Safety Committee.  The average person in the United States receives a radiation 
exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the earth's 
air and soil.  If you would like more information about radiation, please ask the investigator for a 
copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation.  Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study.   
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child.  If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
and your partner will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 3 months after you finish study treatment.  If you think 
that you or your partner is pregnant, you should tell your study doctor or nurse at once.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 10 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Effective forms of birth control include using at least two of the following:  
• abstinence  
• intrauterine device (IUD) 
• tubal ligation 
• vasectomy 
• barrier methods (condoms) 
 
• hormonal (birth control pills, injections, or implants) 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  
We do not know if you will receive personal, medical benefit from taking part in this study.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  Because there is not much information about the 
drugs’ effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• You will receive study treatment at no charge to you.  This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done outside the 
Clinical Center, NIH if the study related treatment is not available at the NIH.  
• There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs if they are not 
covered by your insurance company. 
• Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH. 
• Once you have completed taking part in the study, medical care will no longer be provided 
by the Clinical Center, NIH. 
• The study agents ganetespib and ziv-aflibercept, will be provided free of charge while you 
are participating in this study.  Even though it is unlikely, there is a possibility that at some 
point the supply of study agents may run out, necessitating taking you off-study.   
Will your medical information be kept private?  
Your privacy is very important to us and the researchers will make every effort to protect it.  
Your information may be given out if required by law.  For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis.  However, the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 11 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
researchers will do their best to make sure that any information that is released will not identify 
you.  Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research.   
 
There are organizations that may inspect your records.  These organizations are required to make 
sure your information is kept private, unless required by law to provide information.  Some of 
these organizations are: 
• The National Cancer Institute (NCI), which is sponsoring this study 
• NCI’s pharmaceutical partners  
• The Institutional Review Board (IRB), a group of people who review the research with 
the goal of protecting the people who take part in the study 
• The Food and Drug Administration (FDA), which regulates the testing of experimental 
drugs 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
 
Stopping Therapy  
You can decide to stop at any time.  If you decide to stop for any reason, it is important to let 
your study doctor know as soon as possible so you can stop safely.  If you stop, you can decide 
whether or not to let the study doctor continue to include your medical information in the study. 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
Your study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB, or FDA 
 
Conflict of Interest  
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  The following link contains details on this process 
http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf.  You may ask your 
research team for a copy of the Protocol Review Guide or for more information.  Members of the 
research team who do not work for NIH are expected to follow these guidelines but they do not 
need to report their personal finances to the NIH. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 12 of 14 pages  
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
Optional Studies 
We would like to keep some of the specimens and data that are collected for future research.  
These specimens and data will be identified by a number and not your name.  The use of your 
specimens and data will be for research purposes only and will not benefit you.  It is also 
possible that the stored specimens and data may never be used.  Results of research done on 
your specimens and data will not be available to you or your doctor.  It might help people who 
have cancer and other diseases in the future.   
If you decide now that your specimens and data can be kept for research, you can change your 
mind at any time.  Just contact us and let us know that you do not want us to use your 
specimens and data.  Then any specimens that remain will be destroyed and your data will not 
be used for future research.  
Please read each sentence below and think about your choice.  After reading each sentence, 
circle and initial the answer that is right for you.  No matter what you decide to do, it will not 
affect your care. 
1. My specimens and data may be kept for use in research to learn about, prevent, or treat 
cancer or other health problems.   
Yes              No               Initials_________ 
 
2. Someone may contact me in the future to ask permission to use my specimen(s) and data in 
new research not included in this consent.   
Yes              No               Initials_________ 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•  Adult Patient       or       •  Parent, for Minor Patient 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 13 of 14 pages  
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Dr. Alice Chen, 31 Center Drive, Building 31, Room 3A44, Telephone:  
301-496-4291.  You may also call the Clinical Center Patient Representative at 301-496-2626.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•  Adult Patient       or       •  Parent, for Minor Patient 
STUDY NUMBER: 14-C-0150  
CONTINUATION: page 14 of 14 pages  
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby consent to take part in this study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby give permission for my 
child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/ 
Legal Representative                                    Date 
 
 
 
Print Name 
Signature of Parent(s)/ 
Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the 
study. 
 
 
 
  
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM MAY 18, 2015 THROUGH MAY 17, 2016.   
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name