Clinical trial NCT01962948
Conditions: Recurrent Fallopian Tube Cancer Recurrent Ovarian Epithelial Cancer Recurrent Primary Peritoneal Cavity Cancer
Sponsor: Fox Chase Cancer Center
Start date: 2013-10-09; Completion date: 2018-07-06
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase I/II trial studies the side effects and best dose of ganetespib when given together with paclitaxel and to see how well they work in treating patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Ganetespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving paclitaxel and ganetespib may be an effective treatment for ovarian, fallopian tube, or primary peritoneal cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the recommended Phase II dose of ganetespib with weekly paclitaxel. (Phase I) II. Probability of surviving progression-free for at least 6 months after initiating therapy. (Phase II) III. Clinical response rate (partial and complete responses as defined by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria). (Phase II)

SECONDARY OBJECTIVES:

I. Determine the nature and degree of toxicity of ganetespib and weekly paclitaxel in this cohort of patients as measured by the frequency and severity of adverse reactions. (Phase I) II. Determine the nature and degree of toxicity of ganetespib and weekly paclitaxel in this cohort of patients as measured by the frequency and severity of adverse reactions encountered. (Phase II) III. Duration of progression-free survival. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of ganetespib followed by a phase II study.

Patients receive paclitaxel intravenously (IV) over 1 hour and ganetespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Arms: arm 1: Patients receive paclitaxel IV over 1 hour and ganetespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ganetespib escalation will follow a modified 3+3 design and escalate from 100mg/m2 to 125mg/m2 to 150mg/m2. arm 2: Patients receive paclitaxel IV over 1 hour and ganetespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ganetespib escalation will follow a modified 3+3 design and escalate from 100mg/m2 to 125mg/m2 to 150mg/m2. arm 3: Patients receive paclitaxel IV over 1 hour and ganetespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ganetespib escalation will follow a modified 3+3 design and escalate from 100mg/m2 to 125mg/m2 to 150mg/m2. arm 4: Paclitaxel IV given over 1 hour at 80 mg/m2 days 1, 8 and 15 of a 28-day cycle. PLUS ganetespib IV at MTD/MED from Phase I on days 1, 8 and 15 of a 28-day cycle.
Interventions: intervention 1: paclitaxel intervention 2: ganetespib intervention 3: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies

Protocol documents:
Prot_SAP_001.pdf: 
Copyright© 2013 Fox Chase Cancer Center® Clinical Trials Operations. All rights reserved.
Protocol version date: 07/11/2018
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A Phase I/II trial of weekly paclitaxel in combination with ganetespib in patients with 
recurrent or persistent, platinum-resistant ovarian, fallopian tube or primary 
peritoneal cancer
Supported by Fox Chase Cancer Center
Principal Investigator:
Gina M Mantia-
Smaldone, M.D. 
Fox Chase Cancer Center 
333 Cottman Avenue
Philadelphia, PA 19111
Phone:  215-728-3175
Fax: 215-214-1590
Email: Gina.Mantia-Smaldone@fccc.edu
Co-Investigators:
Mark A. Morgan, MD
Jordan Center for Gynecologic Cancer
Abramson Cancer Center
Perelman Center for Advanced Medicine, 
West Pavilion, 3rd Floor
3400 Civic Center Boulevard
Philadelphia, PA19104
1-800-789-PENN (7366)
Statistician:
Samuel Litwin, PhD.
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia PA 19111
Phone 215-728-2724Email: Samuel.litwin@fccc.edu
Elizabeth Handorf
333 Cottman Avenue
Philadelphia PA 19111
Email: Elizabeth.Handorf@fccc.edu
Phone: 215-728-4773
Translational Investigator:
Denise Connolly, PhD.
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia PA 19111
Phone 215-728-1004
Email: denise.connolly@fccc.edu


Copyright© 2013 Fox Chase Cancer Center® Clinical Trials Operations. All rights reserved.
Protocol version date: 07/11/2018
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Version Date:   November 27, 2013 Amendment 1
October 20, 2014
Amendment 2
                         July 11, 2018           Amendment 3
IND# 120407


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Protocol version date: 07/11/2018
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PAr
Schema
Population: Up to 74 patients (up to 18 Phase I patients and up to 56 Phase II 
patients) with recurrent, platinum-resistant epithelial ovarian, primary peritoneal and 
fallopian tube carcinoma.
Phase I Treatment: Paclitaxel IV given over 1 hour at 80 mg/m2 days 1, 8 and 15 of a 
28-day cycle. PLUS ganetespib IV at a starting dose of 100 mg/m2 on days 1, 8 and 15 
of a 28-day cycle. Ganetespib escalation will follow a modified 3+3 design and 
escalate from 100mg/m2 to 125mg/m2 to 150mg/m2.
MTD/MED of 
ganetespib
MTD/MED of 
ganetespib
Phase II Treatment: Paclitaxel IV given over 1 hour at 80 mg/m2 days 1, 8 and 15 of 
a 28-day cycle. PLUS ganetespib IV at MTD/MED from Phase I on days 1, 8 and 15 
of a 28-day cycle.
Tumor Evaluation
Patients will be evaluated via CT –Chest,
Abdomen and Pelvis every 8 weeks until 
disease progression. Response will be based 
on RECIST 1.1 criteria as outlined in Section 
11.0.
Follow Up: Patients will be followed until  
death.
ii


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Table of Contents
1.0 Introduction
4
2.0 Objectives 
14
3.0 Study Plan 
14
4.0 Patient Selection, Inclusion & Exclusion 
15
5.0 Treatment Plan 
19
6.0 Dose Modifications 
22
7.0 Study Agent Information 
25
8.0 Correlative /Special Studies 
28
9.0 Study Calendar
31
10.0 Adverse Events 
32
11.0 Measures of Effect 
36
12.0 Statistical Considerations 
43
13.0 Data and Safety Monitoring Plan
47
14.0 Administrative Information
48
15.0 References
50
Appendices
53


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1.0 Introduction
1.1 Study Disease
Cancer of epithelial ovarian, fallopian tube or primary peritoneal origin (hereafter referred to
as EOC) continues to be a leading cause of death from cancer in women.  It is the eighth 
most common cancer in women in the U.S., and the fourth leading cause of death from 
cancer with 22,280 cases per year diagnosed and 15,500 deaths predicted for 2012.1    In the 
majority of women, disease is diagnosed at an advanced stage and will respond well to 
initial treatment, but up to 80% of patients with a diagnosis of Stage III or IV EOC will 
experience a recurrence of their disease, which causes significant morbidity and ultimately 
death.  The goal of treatment of recurrent disease is palliative, as there is no realistic chance 
of curing patients whose disease has recurred.  In light of this observation, quality of life, 
prolongation of survival, and control of symptoms related to the cancer are the primary 
goals of treatment of recurrent disease.  Median survival after diagnosis of recurrence is two 
years, but survival can range from months to years. The majority of patients with disease 
recurrence will receive a series of different regimens over the course of their disease, and in 
light of the limited benefit of the currently available treatments, there is a need for new 
therapies that are effective in treating recurrent EOC, particularly in patients who have 
developed early resistance to standard chemotherapy.
The treatment-free interval is predictive of both the expected response to treatment as well as 
the overall prognosis for the patient. The Gynecologic Oncology Group (GOG) has defined 
platinum resistant disease as recurrence seen less than 6 months from completion of front- 
line platinum-based therapy, and platinum sensitive disease as recurrence that occurs 6 or 
more months from completion of front-line platinum-based therapy, based on several 
retrospective studies.2-5   A third category of platinum-refractory disease refers to disease 
which progresses during front-line platinum-based therapy. Even within the group of 
patients with platinum sensitive disease, the duration of the front-line treatment-free interval 
is predictive of the likelihood of benefit from second-line platinum-based therapy.2-5   In 
patients with platinum sensitive recurrent disease there is a survival benefit from 
combination therapy.6   For those patients with platinum-sensitive disease who are eligible 
based on performance status and organ function, the current standard of care would include a 
combination of a platinum agent with either a taxane, gemcitabine or liposomal doxirubicin. 
The most commonly used chemotherapeutic agents for treatment of platinum-resistant 
recurrent EOC include paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), 
topotecan, oral etoposide and gemcitabine.
1.2 Agents under 
Investigation 
GANETESPIB
Ganetespib) is a novel, injectable, synthetic small molecule being developed by Synta 
Pharmaceuticals Corporation.  Ganetespib inhibits Hsp90 chaperone activity by binding to its 
N-terminal adenosine triphosphate (ATP) pocket.  Hsp90 inhibition causes its client proteins 
to adopt aberrant conformations, which are then targeted for ubiquitination and degradation 


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by the proteasome. Hsp90 is a molecular chaperone that regulates the post-translational 
folding and stability of its protein substrates (client proteins), which have crucial roles in 
cellular growth control, differentiation and survival.7   In cancer, many Hsp90 client proteins 
are essential for signal transduction pathways known to play critical roles in cancer initiation 
and progression including HER2, BRAF, EGFR, AKT, MET, EML4-ALK, and steroid 
receptors.  Inhibiting the ATPase activity of Hsp90 with small-molecule compounds such as 
ganetespib leads to client protein degradation and inhibition of tumor growth by inducing 
cell-cycle arrest and apoptosis.8,9   In vitro, ganetespib is a potent inducer of cell death in 
many cancer cell lines, and in vivo, it inhibits the growth of human tumor cell lines in mouse 
xenograft models.
Ganetespib has been given to over 600 patients in clinical trials 
[http://www.syntapharma.com/PrdHsp90.aspx]. It is well tolerated, with the most common 
side effects including fatigue, diarrhea/constipation, nausea/vomiting, anorexia and 
abdominal pain. Single agent clinical activity has been seen in patients with advanced breast 
cancer, NSCLC, GIST, CRC and melanoma.  Following completion of a Phase I trial 
demonstrating safety, ganetespib (150 mg/m2 q 15 days) is now undergoing Phase II 
evaluation in patients with NSCLC in combination with docetaxel (75 mg/m2). Based on our 
strong pre-clinical data in epithelial ovarian cancer (EOC) models and these early clinical 
successes, this Phase I/II trial will evaluate the efficacy of ganetespib in combination with 
paclitaxel in EOC patients.  Briefly, we have demonstrated dose-dependent sensitivity of a 
panel of EOC cell lines to ganetesipib, with significant inhibition of cell viability, induction 
of apoptosis and reduction of the levels and activation of several Hsp90 client proteins (e.g., 
JAK2, STAT3, STAT5, CDK1, PKA, PKE and SRC) evident at low nanomolar doses of 
drug. In addition, single agent activity of ganetespib was demonstrated in two independent 
orthotopic models of EOC xenografts(unpublished data Connolly et al.). Moreover, in vivo 
tumor growth inhibition was enhanced when ganetespib was combined with weekly 
paclitaxel. In vivo fluorescent molecular imaging analysis of tumor bearing mice showed 
significant inhibition of tumor-associated matrix metalloproteinase activity, and analysis of 
tumor protein lysates demonstrated inhibition of several Hsp90 clients (as noted above) in 
mice treated with ganetespib.
1.2.1 Preclinical experience
Anti-tumor Activity
Ganetespib is a highly potent Hsp90 inhibitor that selectively accumulates in tumors and
induces long-lasting client protein degradation and subsequent tumor growth inhibition in a 
lung cancer xenograft model.  Ganetespib displays potent activity across a broad spectrum of 
cancer cell lines, with an average IC50 value (the drug concentration that inhibits cell growth 
by 50%) 20-fold lower than 17-allylamino-17-demethoxygeldanamycin (17-AAG), another 
Hsp90 inhibitor currently in clinical trials for cancer.8   Similar potency was observed in a 
panel of NSCLC cell lines with diverse genetic alterations common to the disease.  This 
compelling activity of ganetespib is due to the degradation of Hsp90 client proteins and 
subsequent inactivation of their signaling effectors. Reverse phase protein arrays performed 
on lysates from four KRAS mutant NSCLC cells lines treated with ganetespib for 24 hours 
showed diminished expression of numerous receptor kinases (including EGFR, MET, 
HER2), signaling intermediates (CRAF, Src, STAT3, MAPK, GSK3), and kinases involved 
in protein synthesis and growth (AKT/mTOR), resulting in the activation of apoptotic 
mediators and cell cycle arrest.10


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Tumor neoangiogenesis is a hallmark of cancer development and progression, from an in situ 
lesion to invasive and metastatic disease, hence targeting angiogenic pathways is an 
important strategy for treating cancer. Hypoxia inducible factor 1 alpha (HIF-1α) plays an 
important role in angiogenesis by controlling the expression of multiple angiogenic factors 
including VEGF, SDF1 and PGF.11   Inhibition of HIF-1α activity dramatically inhibits tumor 
vascularization in animal models, and the transcription factor is a known client protein of 
Hsp90.12   A single bolus exposure of ganetespib greatly reduced the expression of HIF-1α in 
NSCLC tumor xenografts, as far as 150 µm from the nearest blood vessel, suggesting that 
ganetespib can penetrate deep into the hypoxic regions of tumor tissue.13   As a result, 
ganetespib had a marked effect on the tumor vasculature, reducing CD31 (endothelial cell 
marker) expression by 39%, coordinate with a reduction in cell proliferation and rise of both 
apoptosis and hypoxia.
Pharmacokinetics
The PK profiles of ganetespib were evaluated in mice, rats, and monkeys following IV
administration.  Ganetespib displayed dose proportional PK in all species over the dose 
ranges tested.  Ganetespib was highly cleared in mice and rats, and moderately cleared in 
monkeys.  No marked sex differences were observed in the PK of ganetespib in either rats or 
monkeys.  Ganetespib does not appear to accumulate after multiple dosing.
Distribution
Ganetespib was highly distributed into various tissues in rats and mice.
Tissue Distribution
After a 1-hour IV infusion of [14C]-ganetespib in Sprague-Dawley (albino) rats,
[14C]-ganetespib-derived radioactivity was widely distributed to all tissues by the first 
collection time point (approximately 1 hour following the start of infusion), with the 
exception of the CNS [Synta report, 6901-286, 2007]. Radioactivity was preferentially 
distributed into glandular tissues and organs of elimination. Radioactivity concentrations 
were highest in GI tract contents, indicating biliary excretion of [14C]-ganetespib-derived 
radioactivity.  The tissues showing the highest maximum concentrations of radioactivity, 
excluding the GI tract, were lymph nodes (iliac), liver, and adrenal gland in males and lymph 
nodes (iliac), adrenal gland, and pancreas in females. Radioactivity was eliminated from 
most tissues by 24 hours post dose but was still measurable in lymph nodes (iliac) by
168 hours post dose in both male and female rats.
[14C]-ganetespib also showed systemic distribution to a wide variety of tissues, with the 
exception of the CNS, after a 1-hour IV infusion in male Long-Evans (pigmented) rats [Synta 
report, 150N-1202 (DDPS12-055), 2012]. Similarly to Sprague-Dawley rats, radioactivity 
was preferentially distributed into glandular tissues and organs of elimination and 
radioactivity concentrations were highest in GI tract contents, indicating biliary excretion of 
[14C]-ganetespib-derived radioactivity.  The tissues showing the highest maximum 
concentrations of radioactivity, excluding the contents of the GI tract, were cecum, small 
intestine, and adrenal gland cortex. Radioactivity was eliminated from most tissues by
671 hours post dose but low concentrations were observed in adrenal gland cortex, thyroid, 
adrenal gland medulla, spleen, kidney cortex, bone marrow, and liver at 671 hours post-dose 
(last time point). Relatively low concentrations of radioactivity in uvea and skin (pigmented) 
suggest that binding of ganetespib to melanin is minimal.


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In another study, female severe combined immunodeficiency (SCID) mice were implanted 
with NCI H1975 cells. Subsequently, mice that developed tumors were administered an IV 
bolus injection of 125 mg/kg ganetespib.  Results show that ganetespib was rapidly 
distributed to liver and lung; Cmax in the liver and lung occurred at the first collection time 
point (approximately 5 minutes post dose) while Cmax in the tumor occurred at 
approximately 30 minutes postdose [Synta report, DMPK09-185, 2009]. The concentrations 
of ganetespib in plasma, liver, and lung readily declined in a multi-exponential manner to 
below the quantitation limit (2.5 nM) within 24 to 48 hours post dose. The mean t1/2 value in 
plasma, liver, and lung was 3.0, 5.6, and 5.4 hours, respectively.  In contrast, the 
concentrations of ganetespib in tumor remained relatively constant throughout the study 
period (144 hours post dose), with the mean t1/2 value of 58.3 hours. The highest exposure 
of ganetespib was observed in tumor (295 h µg/mL), followed by plasma (145 h⋅µg/mL) and 
liver (128
h⋅µg/mL). The exposure to lung (69.1 h⋅µg/mL) was the lowest among the tissues tested in
this study.
Blood-to-Plasma Distribution Ratio
Mean blood: plasma radioactivity concentration ratios in rats were 0.586-1.11 [Synta report,
6901-286, 2007].  The ratio became close to 1 at later collection time points. Mean 
blood:plasma radioactivity concentration ratios in monkeys were 0.546-0.892.
Plasma Protein Binding
Ganetespib was highly bound to plasma proteins in mice (99.6%-99.7%), rats
(97.5%-98.5%), dogs (98.3%-98.6%), monkeys (99.3%-99.4%), and humans (98.6%-98.7%)
[Synta report, DMPK07-0036, 2007].
Drug Interactions
In preclinical studies evaluating distribution, biotransformation, and elimination, ganetespib
exposure (peak plasma concentration and total systemic exposure) increased in an 
approximately dose proportional manner.  Ganetespib was highly protein-bound and highly 
distributed throughout tissues, with the exception of the central nervous system (CNS). Fecal 
elimination via bile was the major route of excretion. Ganetespib was extensively 
metabolized in the liver to mainly glucuronide conjugates.
In vitro, ganetespib is an inhibitor of cytochrome P450 2C19 (CYP2C19) and 
cytochrome P450 3A4 (CYP3A4) (midazolam specific), but is not an inducer of 
cytochrome P450 (CYP) or uridine diphosphate (UDP)-glucuronosyltransferase (UGT)
enzymes.  Ganetespib is a substrate of P-glycoprotein (P-gp) but is not a substrate of breast 
cancer resistance protein (BCRP)-mediated transporter.  Ganetespib has no inhibitory 
activity against organic anion transporter 1 (OAT1), organic cation transporter 2 (OCT2), 
organic anion transporting polypeptide 1B3 (OATP1B3), bile salt export pump (BSEP), and 
BCRP- mediated transport of the probe substrates, and has weak inhibitory activity against 
organic anion transporter 3 (OAT3), organic cation transporter 1 (OCT1), organic anion 
transporting polypeptide 1B1 (OATP1B1), and P-gp-mediated transport of the probe 
substrates under the experimental conditions.
Preclinical Toxicology


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Preclinical GLP-compliant toxicology studies conducted with ganetespib include single-dose
(acute) toxicity in rats, rising-dose toxicity studies in cynomolgus monkeys, a 5-day
repeat-dose toxicity study in rats, a three-times-weekly repeat-dose toxicity study in rats, 
and twice weekly and once weekly repeat dose toxicity studies in rats and cynomolgus 
monkeys. Three-month dosing studies have been conducted in rats and cynomolgus 
monkeys. Additionally, genotoxicity and developmental toxicity studies, an ocular toxicity 
evaluation, a catheter compatibility study, and a local tolerance study were conducted.  
Studies were conducted in accordance with GLP regulations.  Evaluation for ganetespib-
related effects was based on mortality and morbidity, clinical signs, body weight, food 
consumption, hematology, serum chemistry, coagulation, urinalysis, ophthalmology, 
electrocardiographic examinations, and anatomic and microscopic pathology.
Rats survived a single 30 mg/kg dose of ganetespib, but doses of 85 or 250 mg/kg elicited 
moribundity and mortality.  Rats given 10 or 30 mg/kg twice weekly for 4 weeks survived 
and were in good clinical condition.  In contrast, rats given 100 mg/kg (reduced to 85 mg/kg 
beginning with the third dose) had pronounced clinical signs of systemic toxicity such as 
emaciation and decreased activity.  Several of these animals died or were euthanized early. 
For 100/85 mg/kg rats assigned to a 14-day recovery evaluation, most changes returned to 
normal or improved.  Male rats given 10, 30, 75, or 100 mg/kg once weekly for 4 weeks had 
no abnormal clinical findings; dose-related gross and microscopic changes occurred at 30, 
75, and 100 mg/kg.
The maximum tolerated single-administration dose in cynomolgus monkeys was 11 mg/kg. 
When administered on 2 consecutive days, up to 3 mg/kg/day was well tolerated. 
Cynomolgus monkeys tolerated a 1 mg/kg dose of ganetespib, administered twice weekly for 
4 weeks.  A monkey given 3 mg/kg was euthanized moribund; the dose was reduced to
1 mg/kg and remaining monkeys given the reduced dose were clinically normal. Monkeys 
given 6 mg/kg (reduced to 4 mg/kg) or 11 mg/kg (reduced to 9 mg/kg) exhibited clinical 
signs consistent with GI tract changes observed pathologically.  Two monkeys given
11/9 mg/kg were euthanized moribund. The incidence of histopathologic findings (in 
stomach and/or large intestine, adrenal gland, pancreas, and thymus) was lower in 
11/9 mg/kg and 6/4 mg/kg monkeys assigned to a 2- to 4.5-week recovery evaluation.
In 3-month studies, ganetespib was administered on Days 1 and 15 of four 21-day cycles. 
Rats receiving that regimen tolerated 20 mg/kg/dose of ganetespib, 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 in that regimen tolerated doses up to 7 mg/kg/dose, 
the NOAEL.  Transient diarrhea occurred at 2, 4, and 7 mg/kg/dose, with reversible 
microscopic pathologic changes occurring at 7 mg/kg/dose.
Ganetespib was considered to be well tolerated by cynomolgus monkeys when administered 
by 1-hour infusion twice weekly for 4 weeks via an implanted silicone venous catheter. 
When pregnant female rats were given ganetespib daily by infusion during organogenesis, 
doses up to 1 mg/kg/day did not elicit effects on maternal or fetal parameters. Maternal 
toxicity (clinical signs, decreased weight gain and food consumption) and developmental 
toxicity (postimplantation loss) occurred at doses of 3 mg/kg/day and higher.
As with the negative-control compound, 17-AAG (which has not been associated with ocular 
toxicity in clinical patients), ganetespib was rapidly eliminated from retinal tissue and did not 
cause photoreceptor cell apoptosis. Unlike 17-DMAG and AUY922, ganetespib was not 
associated with ocular toxicity in the rat model, suggesting that profiles of retina/plasma 


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exposure and retinal elimination rate play crucial roles in the onset of ocular toxicity. The 
ratio of the concentration of drug in retina and plasma, as well as the speed with which drug 
in the retina is cleared from that tissue, differ among the drugs tested, and is predictive of 
ocular toxicity.
In Vivo Activity of Ganetespib in Combination with Paclitaxel
Hsp90 inhibitors such as 17-AAG have been reported to enhance the activity of the 
microtubule stabilizer paclitaxel.14   Similarly, the combination of ganetespib plus paclitaxel 
was highly active in the NCI H1975 NSCLC xenograft model, which expresses an activated 
and erlotinib resistant form of the epidermal growth factor receptor. Single-agent treatments 
of either 50 mg/kg ganetespib or 7.5 mg/kg paclitaxel dosed once per week were moderately
efficacious, with %T/C values of 38 and 55, respectively. However, treatment with both 
drugs dosed at the same time was dramatically more efficacious, (%T/C = 7, p<0.05). This 
effect was not due to a pharmacokinetic (PK) interaction between ganetespib and paclitaxel, 
since no change in either agent’s plasma exposure level was observed when they were 
combined.  Similar combinatorial activity was observed when ganetespib was combined with 
docetaxel in this model and 5 other NSCLC xenograft models.15
1.2.2 Clinical experience
Ganetespib is being studied in 10 Synta-sponsored clinical trials. Studies include: four 
Phase 1 studies, one Phase 1/2 study, four Phase 2 studies, and one Phase 2b study. 
Ganetespib is also being studied in 15 ISTs, the majority of which are proof-of-concept 
studies across a variety of tumor types. The ISTs include:  two Phase 1/2 studies, three 
Phase 1 studies, and ten Phase 2 studies.
As of 20 September 2012, 630 patients have received at least 1 dose of IV ganetespib in one 
of these 25 studies.  A total of 472 patients have been treated in 1 of the 10 Synta-sponsored 
studies, with the majority treated in single-agent studies (322 patients in Study 9090-01 
through Study 9090-06 and 2 patients in Study 9090-09). The remaining patients (148/472) 
have been treated in Synta-sponsored combination therapy studies.  In addition to these 472 
patients, 158 patients have been enrolled in the ISTs.
Two Synta-sponsored Phase 1 studies evaluated the safety, tolerability, and preliminary 
activity of ganetespib in patients with solid tumors: Study 9090-01 (n=70) and Study 9090- 
02 (n=53).  The recommended Phase 2 doses for single-agent ganetespib in this population 
are 200 mg/m² once weekly and 150 mg/m² twice weekly (72-hour interval between doses). 
Two Synta-sponsored studies have evaluated the safety, tolerability, and preliminary 
antitumor activity of ganetespib in patients with hematologic malignancies: Study 9090-03 
(n=31) and Study 9090-04 (n=29).  In these studies, single-agent doses ranged from 120,  
150, and 200 mg/m2 (n=29) once weekly, and from 14 to 110 mg/m2 (n=31) twice weekly. 
Unlike the solid tumor studies, no rest week was incorporated into the dosing schedule. 
Patients received ganetespib once or twice weekly for 4 consecutive weeks of a 4 week 
cycle. The doses selected for further study in this population were 200 mg/m2 once weekly 
and 90 mg/m2 twice weekly.
The Phase 2 program was designed to evaluate the antitumor activity of ganetespib in a 
variety of solid tumors.  This includes 2 single-agent, proof-of-concept studies sponsored by 
Synta:  Study 9090-05 (n=27) in GIST and Study 9090-06 (n=112) in NSCLC.  In addition, 
Study 9090-06 was amended to offer combination therapy to a subset of NSCLC patients 
after treatment with single-agent ganetespib.
The Phase 2 program was expanded to evaluate ganetespib in combination with docetaxel in 
patients with solid tumors. In Study 9090-07 (n=27), the recommended combination dose is 


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150 mg/m2 ganetespib on Days 1 and 15 and 75 mg/m2 docetaxel on Day 1 in a 21-day 
cycle in patients with solid tumors.
Following identification of the recommended combination dose for Phase 2 in Study 
9090- 07, a Phase 2b/3 Study 9090-08 was initiated in order to evaluate the safety and 
activity of ganetespib in combination with docetaxel vs. docetaxel alone in NSCLC.
The Phase 3 portion of the original Phase 2B/3 9090-08 study will be conducted as a 
standalone Phase 3 study, 9090-14.  Studies 9090-09 and 9090-11 are additional single-agent 
Phase 2 studies that will examine different patient populations.
Preliminary signals of clinical activity of ganetespib as a single agent have been observed in 
ongoing clinical studies at different dose levels and schedules in patients with solid 
malignancies.  In patients with hematological malignancies, some evidence of clinical 
activity has been observed in these heavily pre-treated patients. Preliminary safety findings 
in patients treated with ganetespib ± docetaxel show a pattern of adverse events (AEs) and 
incidence of special events that is similar to that of patients treated with single-agent 
ganetespib.  Diarrhea is the most significant AE associated with the use of ganetespib. 
Diarrhea management guidelines are provided in Appendix III.
Pharmacokinetics in Humans
The PK of ganetespib, administered at various doses on a weekly or twice-weekly schedule,
are under investigation in three Phase 1 trials. Preliminary data and calculated parameters 
are available from these trials in patients with solid and hematologic tumors and are 
summarized below.
Ganetespib PK shows distribution and elimination phases with concentrations declining by 
approximately 10-fold within the first hour and nearly 100-fold within 10 hours following 
infusion termination.  Mean terminal half-lives have ranged from approximately 5 to 15 
hours.  Ganetespib plasma concentrations following the first and subsequent doses are 
comparable following either once or twice-weekly dosing, indicating the lack of drug 
accumulation.  Ganetespib plasma concentrations are also comparable in the solid and 
hematologic tumor patients.  Cmax and AUC increase in approximate proportion to dose 
irrespective of dosing day with virtually identical dose-exposure ratios for doses given on 
different days, indicating linear PK (r2 = 0.7080 and 0. 7596 for Cmax and AUC versus dose, 
respectively).  Ganetespib Cmax correlates well with AUC (r2 = 0.9338).  CL and Vd are 
approximately constant across doses.
Two ganetespib glucuronide metabolites were quantified in Study 9090-07: STA-12-0671 
and STA-12-0672.  Terminal half lives were unaffected by ganetespib dosage.  At a 
ganetespib dose of 150 mg/m2, the mean STA-12-0671 terminal half life was 11.9 hours 
(n=16) and at a dose of 200 mg/m2 the terminal half life was 11.0 hours (n=4). For STA-12- 
0672, at a ganetespib dose of 150 mg/m2, the mean terminal half life was 9.9 hours (n=16) 
and at a dose of 200 mg/m2 the terminal half life was 9.4 hours (n=4). For both metabolites, 
Tmax was typically at the end of the ganetespib infusion and PK parameters were consistent 
across sampling days (Days 1, 8, and 15).
Safety in Humans
Monotherapy Studies
The MTD for once-weekly dosing in solid tumors was established at 216 mg/m2 ganetespib 
based on DLTs of asthenia and diarrhea at the highest tested dose level, 259 mg/m2
.  The 
recommended once-weekly dose is 200 mg/m2. The recommended dose for twice-weekly 


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dosing (72-hour interval between doses) in patients with solid tumors is 150 mg/m2 and is 
based on current safety, tolerability, and preliminary activity data.
The doses selected for further study in patients with hematologic malignancies were 200 
mg/m2 once weekly and 90 mg/m2 twice weekly.
Approximately 98% of the patients in the largest pooled data set (single-agent studies, 
n=322) experienced at least 1 AE; 90% experienced at least 1 treatment-related event. The 
most frequently reported AEs were related to GI toxicity, and included diarrhea (77%), 
nausea (42%), decreased appetite (28%), vomiting (24%), constipation (21%), and 
abdominal pain (21%).  Non-GI related events that occurred frequently have included fatigue 
(53%), headache (19%), and anemia (22%). Two-thirds (66%) of these patients experienced 
an event that was a Grade ≥3; 29% experienced a Grade ≥3 treatment-related event.  Thirty-
nine percent experienced at least 1 serious adverse event (SAE); 8% of patients had at least 1 
treatment-related SAE.
Combination Study
In the Phase 2b study in patients treated with ganetespib in combination with docetaxel,
Study 9090-08, preliminary findings show a similar safety profile.  In the combination arm 
(ganetespib + docetaxel), 92% of patients experienced at least 1 AE, 66% at least 1 
treatment-related event.  The most frequently reported AEs were related to GI toxicity and 
included diarrhea (41%), nausea (17%), decreased appetite (16%), vomiting (10%), 
constipation (6%), Non-GI related events that occurred frequently include neutropenia 
(31%), fatigue (27%), and anemia (22%).
Half (53%) of the 9090-08 patients treated with ganetespib and docetaxel had treatment- 
emergent AEs that were Grade 3 or Grade 4. Thirty-two percent had at least 1 SAE and 
11%, at least 1 treatment-related SAE. The most common Grade 3 or 4 event in patients 
receiving the combination treatment was neutropenia (14% and 11%, respectively).  In 
patients treated with docetaxel only, 12% of patients experienced a Grade 3 event of 
neutropenia and 8% experienced a Grade 4 event.  The most common SAE was febrile 
neutropenia, experienced by 7% of those receiving the combination treatment compared to 
5% of patients treated with docetaxel only.
Events of Special Interest
Events that may be a class effect of Hsp90 inhibition include diarrhea, ocular toxicities, and
elevations in liver enzymes.  Diarrhea is the most significant AE associated with the use of 
ganetespib.  In Study 9090-08, 41% of patients treated with both ganetespib and docetaxel 
experienced at least 1 AE of diarrhea compared to 11% of patients treated with docetaxel 
alone.  In single-agent studies, approximately 77% of ganetespib patients experienced this 
event. The postulated mechanism of action is inhibition of EGFR in cells that line the GI 
tract, leading to a transient secretory diarrhea, limited to 24 to 48 hours following ganetespib 
infusion.  This AE is manageable with loperamide or Lomotil® (atropine diphenoxylate). 
Prophylactic use of loperamide can reduce the occurrence of diarrhea from >80% to 
approximately 40%.
Ocular toxicity, manifested as visual disturbances, has been reported for several Hsp90 
inhibitors.  Of the 443 patients treated with ganetespib (single-agent and combination 
treatment studies) as of 20 September 2012, 10 (2%) patients experienced an event of visual 
disturbance that was assessed as related.  In Study 9090-08, a visual disturbance of blurred 
vision was experienced by 2% of patients treated with ganetespib in combination with 
docetaxel.  There were no such treatment-emergent events in the group treated with 


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docetaxel alone.  In studies using single-agent ganetespib, visual disturbances included:  
blurred vision (4%), visual impairment (2%), and dry eye, reduced visual acuity, 
chromatopsia, night blindness, scotoma, and vitreous floaters (all <1%). The mechanism of 
visual disturbances is linked to induction of apoptosis in cells in the outer nuclear layer of the 
retina, which occurs following treatment with 17-DMAG or AUY922.16   In contrast, 
ganetespib did not elicit induction of apoptosis in preclinical studies using rodent models, 
consistent with the very low number of reported visual disturbance cases in the clinic.
Hepatocellular injuries are usually detected by enzyme elevations in serum aminotransferases 
(ATs), total bilirubin, and alkaline phosphatase.  In the combination treatment arm of Study 
9090-08, AEs of elevated aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) were reported in 3% and 2%, of patients, respectively.  An AE of elevated alkaline 
phosphatase was reported in 3% of patients and an AE of elevated bilirubin was reported in
<1% of patients.  Grade 3 elevations of AST and ALT were reported in <1% and 2% of 
patients, respectively.  In the pooled data from 322 patients who received single-agent 
ganetespib, AEs of elevated AST and ALT were reported in 14% of patients. An AE of 
elevated alkaline phosphatase was reported in 16% of these patients and an AE of elevated 
bilirubin was reported in 6%. Grade ≥3 elevations of AST and alkaline phosphatase were 
reported in 4% of patients and Grade ≥3 elevations of ALT and bilirubin in 3% of patients. 
None of the patients reported concomitant elevations of ATs ≥3X the upper limit of normal 
(ULN) and bilirubin ≥2X ULN. Liver toxicity in the 1st-generation geldanamycin-derivative 
Hsp90 inhibitors is an off-target effect.  According to a study by Cysyk et al, the presence of 
benzoquinone moiety in the molecule is the suspected cause of liver toxicity.17   Ganetespib 
does not contain the benzoquinone moiety and, therefore, liver toxicity is not expected. This 
correlates with the safety information collected to date.
Electrocardiogram Intervals Analysis Findings
Synta Pharmaceuticals conducted a thorough QT study, Protocol 9090-13, “A Randomized, 
Partially Double-blind, Placebo- and Positive-Controlled, 3-Arm, Crossover Study to Assess 
the Effect of Ganetespib (STA-9090) on Electrocardiogram Parameters in Healthy Volunteers, 
a Thorough ECG/QT Study”.  In Protocol 9090-13, healthy volunteers were administered a 
single dose of 200 mg/m2 ganetespib which is the therapeutic dose for monotherapy studies and 
33% higher than the ganetespib dose in combination studies.  Analyses of the ECG data 
revealed a placebo-corrected modest change in QTcF from baseline of 20.9 msec at 24 hours 
post-dose. No increase in QTcF was observed at the time of ganetespib Cmax (at the end of 
ganetespib infusion).  This observation of a prolonged QTc interval is consistent with an 
indirect effect of ganetespib on cardiomyocyte repolarization, since the QTc prolongation 
occurred at a time when plasma concentrations of ganetespib are less than 0.5% of the Cmax 
concentrations.
At this point, in the clinical development program there have been 362 patients treated with  
ganetespib as a single agent and 218 treated with ganetespib plus docetaxel (total 580 patients).  
Seven patients (1.2%) had prolonged QT interval reported as an adverse event, and none had 
torsades de pointes or other ventricular arrhytmias on any ECG recording.  Eight deaths 
(8/580, 1.4%) potentially resulting from cardiovascular SAEs have been reported and were 
described by investigators as cardiac arrest (n=3), sudden cardiac death (n=2), sudden death 
(n=1), cardiopulmonary failure (n=1) and cardiovascular insufficiency (n=1).  The incidence of 
deaths on treatment with ganetespib due to cardiovascular SAEs does not seem excessive for 
this advanced cancer patient population.  


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In addition, the randomized Phase 2b/3 study 9090-08, the frequency of cardiovascular SAEs 
resulting in death is comparable in patients treated with ganetespib plus docetaxel relative to 
the docetaxel-only control arm.  In the ganetespib plus docetaxel arm there were 4 
cardiovascular deaths reported among 191 patients (2.1%) vs. 5 cardiovascular related deaths 
reported among 192 patients (2.6%) in the docetaxel control arm.
Based on the data from Protocol 9090-13, the review of cardiac safety data from the 580 
patient safety database, the apparent survival benefit seen in the interim analysis of the Phase 
2b/3 9090-08 study in favor of the ganetespib plus docetaxel combination arm relative to the 
docetaxel control arm, and proposed modifications to ECG monitoring in our clinical 
protocols, we assess the benefit/risk for clinical trials of ganetespib as positive. 
PACLITAXEL
1.2.3 Clinical experience
Paclitaxel is an FDA approved chemotherapeutic agent that is one of the standard treatments 
available for patients with EOC.  Paclitaxel was initially tested in patients with recurrent 
EOC every 3 weeks and response rates of 21-37% were seen, including response rates of 21- 
33% in patients with platinum resistant disease who had not previously received 
paclitaxel.18,19
In light of preclinical data suggesting improved efficacy from more frequent dosing of 
paclitaxel, a Phase I trial evaluating the weekly administration of paclitaxel in patients with 
platinum/paclitaxel resistant recurrent ovarian cancer was completed, and demonstrated 
responses.20   Another Phase II trial confirmed the activity of weekly paclitaxel in patients 
whose disease had recurred or progressed on paclitaxel given at the higher dose every three 
weeks.21   Additional clinical trials utilizing weekly paclitaxel have been performed, with 
response rates ranging from 21-54%.22-26   Thus, paclitaxel has efficacy when given every 3 
weeks as well as on a weekly schedule for patients with both platinum sensitive and 
platinum resistant disease, and when given on a weekly schedule, this agent has activity in 
patients with resistance to paclitaxel given every 3 weeks.20,21,26
In the trial conducted by the Gynecologic Oncology Group(GOG), 48 patients treated with 
weekly paclitaxel at a dose of 80 mg/m2 were evaluable for safety. Hematologic toxicities 
were tolerable, with Grade 3 neutropenia seen in 2 patients (4%), and Grade 2 
thrombocytopenia seen in 1 patient (2%).  The most common toxicity was neuropathy, Grade 
3 in 2 patients (4%) and Grade 2 in 10 patients (21%).27
1.3 Study Rationale
Rationale for Assessment of Treatment with Ganetespib with Weekly Paclitaxel
Heat shock protein 90 (Hsp90) is a highly conserved, ATP-dependent chaperone protein that 
regulates the post-translational folding of its protein substrates, Hsp90 client proteins, many 
of which are involved in signal transduction pathways important in the development and 
progression of cancer.28  Its role in the regulation of multiple proteins important in malignant 
transformation and disease progression makes it an attractive target for cancer therapy.  It is 
well tolerated, with the most common side effects consisting of GI toxicities.  Weekly 
paclitaxel has been shown to be an effective treatment in patients with recurrent ovarian 
cancer and is also well tolerated, with the most common side effects consisting of 


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neuropathy.  Preclinical data suggest synergy when paclitaxel is combined with Hsp90 
inhibitors. (See Section 1.2).  Based on our strong pre-clinical data in epithelial ovarian 
cancer models, we will proceed to a Phase I/II trial of this combination in patients with 
recurrent disease.
1.4 Correlative Testing
Laboratory correlative studies will be performed at FCCC and include: 1) analysis of patient
pre- and post-drug treatment blood specimens (serum and peripheral blood mononuclear 
cells) for changes in the levels of expression of HSP70 and established HSP90 client 
proteins; 2) analysis of patient formalin fixed paraffin embedded (FFPE) tumor specimens 
for the expression and activation of established HSP90 client proteins; and 3) analysis of 
patient pre-treatment serum samples for the presence of secreted HSP90α. The goal of these
correlative analyses is to determine patterns of HSP90, HSP70 and HSP90 client protein
expression that may predict patient response to treatment and provide a rational basis for 
patient selection for this agent going forward.
2.0 Objectives
2.1 Primary 
Objective Phase I
1) Determine the recommended Phase II dose of ganetespib with 
weekly paclitaxel.
Phase II
1) Probability of surviving progression-free for at least 6 months after
initiating therapy.
2) Clinical response rate (partial and complete responses as defined 
by RECIST 1.1 criteria).
2.2 Secondary 
Objectives Phase I
1) Determine the nature and degree of toxicity of ganetespib and weekly
paclitaxel in this cohort of patients as measured by the frequency and severity 
of adverse reactions.
Phase II
1) Determine the nature and degree of toxicity of ganetespib and weekly
paclitaxel in this cohort of patients as measured by the frequency and severity 
of adverse reactions encountered.
2) Duration of progression-free survival and overall survival.
3.0 Study Plan
3.1 Description of Study Design, Population and Duration of Study Therapy
This is an open-label study evaluating the combination of ganetespib with weekly paclitaxel.
The study will commence with a Phase I dose escalation to evaluate up to 3 dose levels of 
ganetespib with weekly paclitaxel in adult women with epithelial ovarian, primary peritoneal 
and fallopian tube carcinoma. The lead-in phase I portion of this study will determine the 
recommended Phase II dose of the combination of weekly paclitaxel and weekly gaetespib 
for the second phase of the study. During the lead-in Phase I portion of the study, paclitaxel 


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will be dosed at 80 mg/m2 weekly for 3 weeks with of a 4 week cycle, and ganetespib will 
be given initially at 100 mg/m2 for 3 weeks of a 4 week cycle and escalated to 125 mg/m2 
and 150 mg/m2 weekly as tolerated in subsequent cohorts. The maximum dose of 
ganetespib to be evaluated will be 150 mg/m2 weekly in combination with paclitaxel. The 
Phase I portion of the study will evaluate tolerance and safety of the combination of 
paclitaxel in combination with ganetespib to determine the recommended Phase II dose, and 
the Phase II portion of the study will evaluate efficacy of the combination in terms of 
response rates and the probability of 6-month progression-free survival and overall survival.
4.0 Patient Selection Inclusion & Exclusion
4.1 Inclusion Criteria
4.1.1 Patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers 
who have received up to two prior treatment regimens.
4.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension in accordance with RECIST criteria
v. 1.1 as described in detail in section 11.0. 
4.1.3 Patients must have had one prior platinum-based chemotherapeutic regimen for 
management of primary disease containing carboplatin, cisplatin, or another 
organoplatinum compound. This initial treatment may have included intraperitoneal 
therapy, high-dose therapy, consolidation, or extended therapy administered after 
completion of initial chemotherapy.  Patients who have received one prior regimen must 
be considered platinum resistant or refractory according to standard GOG criteria, i.e., 
have had a treatment-free interval following platinum of less than 6 months, have 
persistent disease at the completion of primary platinum-based therapy or have 
progressed during platinum-based therapy. Patients with greater than 6 month disease 
free interval after completion of primary therapy must have received a second platinum 
based regimen, and have persistent or progressive disease, or disease that recurs within 
12 months of completion of second line platinum-based therapy. Patients who are 
unable to receive platinum-based therapy for recurrent disease would also be eligible.
4.1.4 Age > 18 years.
4.1.5 ECOG performance status 0 -2.
4.1.6 Patients must have normal organ and marrow function as defined below:

Hemoglobin
> 9 g/dL

Leukocytes
> 3,000/mcL

Absolute neutrophil count
> 1,500/mcL

Platelets
> 100,000/mcL

Total Bilirubin
≤ normal institutional limits

AST/ALT (SGOT/SGPT)
< 2 times institutional normal limits

Creatinine
≤ normal institutional limits
OR

Creatinine Clearance 
> 60 Ml/min/1.73 m2 for patients


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with creatinine levels above institutional 
normal
4.1.7 Ability and willingness to comply with scheduled visits, treatment plan, laboratory 
assessments and other study procedures.
4.1.8 Ability to understand and willingness to sign a written informed consent and 
HIPAA consent document.
4.2 Exclusion Criteria
4.2.1 Patients who have had surgery, chemotherapy or radiotherapy within 4 weeks prior to 
entering the study or those who have toxicity that has not recovered to ≤ Grade 1 
from adverse events due to agents administered more than 4 weeks earlier (with the 
exception of alopecia). Patients may not be receiving any other investigational 
agents.
4.2.2 Histologic diagnosis of a benign or borderline tumor (‘tumor of low malignant 
potential’) or of a malignant tumor of non-epithelial origin (such as a germ cell 
tumor, sex-cord stromal tumor) of the ovary, fallopian tube or peritoneum.
4.2.3 Patients with known brain metastases.
4.2.4 History of allergic reactions to Cremophor EL, paclitaxel or its components.
4.2.5 Prior history of ≥ Grade 2 neurotoxicity or any other toxicity requiring 
discontinuation of taxane therapy that has not resolved to ≤Grade 1, with the 
exception of alopecia.
4.2.6 Diagnosis of another malignancy, with the exception of non-melanoma skin cancers 
within two years before the first dose, or previously treated for another 
malignancy with evidence of residual disease, with the exception of a 
synchronous endometrial cancer and non-melanoma skin cancers.  Carcinoma in 
situ will not be considered as malignancy.
4.2.7
Patients with clinically unstable cardiac disease, including unstable atrial 
fibrillation, symptomatic bradycardia, unstable congestive heart failure, active 
myocardial ischemia, or indwelling temporary pacemaker. 
4.2.8  Patients with ventricular tachycardia or supraventricular tachycardia that requires 
treatment with a Class Ia antiarrhythmic drug or Class III antiarrhythmic drug. 
4.2.9 Use of medications that have been linked to the occurrence of torsades de pointes 
4.2.10 Complete left bundle branch block (LBBB) 


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4.2.11
History of long QT syndrome or a family member with this condition 
4.2.12
Serum potassium, magnesium and calcium levels outside the laboratory’s 
reference range. 
4.2.13
Patients receiving QT prolonging medications (such as ondansetron). 
4.2.14 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, known serious cardiac illness or psychiatric illness/social situations that 
would limit compliance with study requirements. Known serious cardiac illness or 
medical conditions include, but are not limited to:
i.
History of documented congestive heart failure (CHF), New York Heart 
Association (NYHA) class II/III/IV (see Appendix II), with a history of 
dyspnea, orthopnea, or edema that requires current treatment with 
angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor 
blockers, beta blockers, or diuretics.
NOTE: Use of these medications for the treatment of hypertension is 
allowed
ii.
Screening QTc (QT interval corrected for heart rate) >470 msec or history 
of QT (cardiac interval from start of Q wave to end of T wave) 
prolongation while taking other medications
iii.
High-risk uncontrolled arrhythmias (ventricular arrhythmias, high-grade 
AV-block, supra-ventricular arrhythmias that are not adequately rate- 
controlled)
iv.
Arrhythmias that require current treatment with the following anti- 
arrhythmic drugs:  flecainide, moricizine, or propafenone
v.
Current coronary artery disease with a history of myocardial infarction, 
angioplasty, or coronary bypass surgery within the preceding 6 months, or 
angina pectoris that has been symptomatic within the preceding 6 months
4.2.15 Known HIV-positive patients on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with 
ganetespib.  In addition, these patients are at increased risk of lethal infections 
when treated with marrow-suppressive therapy.
4.2.16
Pregnant or breast feeding. Refer to section 4.4 for further detail.
4.3 Inclusion of Women and Minorities
Women, regardless of race, ethnic group or sexual orientation are eligible for this study.
4.4 Pregnancy
The effects of ganetespib and paclitaxel on the developing human fetus at the recommended
therapeutic dose are unknown.  For this reason and because anticancer agents as well as other 
therapeutic agents used in this trial are known to be teratogenic, women of child-bearing 
potential (WOCBP) and male sexual partners must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration 
of treatment, and for at least 3 months after the completion of treatment. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she must inform 
her treating physician immediately.


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Prior to study enrollment, WOBCP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.
All WOCBP must have a negative pregnancy test within 7 days of registration.  If the 
pregnancy test is positive, the patient must not receive protocol treatment and must not be 
enrolled in the study.
WOCBP is defined as follows: Any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive 
months, or women on hormone replacement therapy (HRT) with documented plasma 
follicle- stimulating hormone (FSH) level > 35 mIU/ml).  Even women who are using oral, 
implanted, or injectable contraceptive hormones or mechanical products (diaphragm, 
condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is 
sterile (e.g. vasectomy), should be considered to be WOCBP. Patients of childbearing 
potential should agree to use dual forms of contraception.
4.5 Research Participant Registration
Eligible patients will be entered on study centrally by the Fox Chase Cancer Center QA
Coordinator or their designee. Following registration, research participants must begin 
protocol treatment within 7 days of registration.  Issues that would cause treatment delays 
must be discussed with the Principal Investigator.  If a research participant does not receive 
protocol therapy following registration, the research participant will be replaced. The QA 
Coordinator must be notified as soon as possible if the research participant will not receive 
protocol therapy.
Research participants may be registered from 9:00 am to 5:00 pm excluding holidays by 
calling the QA Coordinator at 215-728-4770. The site’s investigator or designee will then 
fax the completed registration form, entire, completed consent form,HIPAA authorization 
formand eligibility checklist to 215-214-1511.  The QA Coordinator or designee will notify 
the site by fax when registration is confirmed and the sequence number has been assigned. 
Research participants must be registered and have received a sequence number assigned by 
the QA Coordinator prior to the initiation of treatment. The following forms must be 
completed at the time of registration:
•
Signed and dated informed consent form
•
Signed and dated HIPAA authorization form
•
Registration form
•
Signed eligibility checklist
Exceptions to the current registration policies will not be permitted including but not 
limited to:
•
Late registrations (after initiation of treatment)
•
Exceptions to eligibility requirements
•
Participation by an institution/member not identified as eligible
•
Non-Compliance with regulatory paperwork


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5.0 Treatment Plan
Treatment will be administered on an outpatient basis. Treatment will be administered as
described below.  Dose delays and modifications should only be done following protocol 
guidelines described in section 6.0.  If treatment delays are > 14 days study therapy will 
be discontinued.
5.1 Treatment Administration
Regimen description
Agent
Premedications,
precautions
Dose
Route
Schedule
Cycle
Length
Paclitaxel
Premedicate with 
dexamethasone, 
diphenhydramine, 
ranitidine and -
prochlorperazine
80 mg/m2
IV over 1 hr
+/- 15 minutes
Days 1,
8, and 15
Ganetespib
Loperamide
Starting at 
100 mg/m2 to 
a maximum 
dose of 150
mg/m2
IV over  1 hr
+/- 15 minutes
Days 1,
8, and 15
4
weeks
5 (28 days)
5.1.1 Paclitaxel During the Phase I and II portions of this study, paclitaxel 
will be administered IV over 1 hour +/- 15 minutes at 80 mg/m2 on days 1, 8 
and 15 of a 28-day cycle.  Paclitaxel is infused over 1 hour, however the 
infusion time may be modified if needed after review and agreement by the 
study PI. Patients will be premedicated as per institutional standards, with  
diphenydramine, dexamethasone, ranitidine and  prochlorperazine. 
Modifications to the premedications are allowed upon review and agreement 
by the study PI, and will be documented.
The product label will be followed for additional details regarding paclitaxel 
administration.
5.1.2 Ganetespib During the Phase I portion of the study, ganetespib will be 
administered IV over 1 hour +/- 15 minutes at a starting dose of 100 mg/m2 on 
days 1, 8 and 15 of a 28-day cycle, in conjunction with, but not simultaneously, 
with paclitaxel, as described above, given on the same schedule. Patients will be 
premedicated with loperamide before each dose of ganetespib.  The dose of 
ganetespib will be increased to 125 mg/m2 and then 150 mg/m2 in two 
subsequent cohorts if DLT is not observed. Doses of ganetespib will not exceed 
150 mg/m2 and this will be the maximum dose evaluated and the recommended 
Phase II dose if DLT is not identified at any of the three dose levels evaluated. 


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The recommended Phase II dose will be administered at the same schedule during 
the Phase II portion of the study.
Cohort
Paclitaxel weekly
Ganetespib weekly
Cohort 1
80 mg/m2
100 mg/m2
Cohort 2
80 mg/m2
125 mg/m2
Cohort 3
80 mg/m2
150 mg/m2
5.2 Concomitant Medications, Supportive Care, Excluded Therapies and Restrictions
Patients should receive full supportive care therapies concomitantly during the study 
including transfusions of blood and blood products, antibiotics when appropriate.
Any disease progression requiring other forms of specific anti-tumor therapy will be cause 
for early discontinuation of study treatment.
Prohibited during the study:
•
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy (except as stated above), immunotherapy, and 
hormonal anticancer therapy, is not permitted while participating in this study.
•
Use of concurrent investigational agents is not permitted.
5.3 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
•
Unacceptable adverse events
•
Treatment held > 14 days for toxicity
•
Patient required > 3 dose reductions of either paclitaxel or ganetespib
•
Patient becomes pregnant
•
Patient decides to withdraw from the study or
•
General or specific changes in the patient’s condition that render the
patient unacceptable for further treatment in the judgment of the 
investigator.
Treatment may be postponed to the next treatment day due to weather emergencies, missed 
appointments, holiday or other unplanned events not related to toxicity.
5.4 Duration of Follow up
Patients will be followed after removal from treatment until death. Patients removed from 
study for unacceptable adverse events that are related to the study treatment will be followed 


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until resolution or stabilization of the adverse event.
5.5 Criteria for Discontinuation
Patients will be removed from study when any of the criteria listed in Section 5.3
applies.  The reason for study removal and the date the patient was removed must be 
documented in the medical record and case report form.
6.0 Dose Modifications
6.1 General Principles
Dose modifications should be made based only on the guidelines described in Section 6.0. 
There are no dose re-escalations. Patients requiring > 3 dose reductions of paclitaxel or > 3 
dose reductions of ganetespib must discontinue protocol treatment. Missed doses are not to be 
made up.   Patients requiring treatment to be held > 14 days for recovery from toxicity must 
discontinue protocol treatment. Dose reduction should occur for Grade 4 non-hematologic 
toxicities including gastrointestinal toxicities and should be targeted to the drug most likely to 
cause the toxicity or both drugs if both are potential culprits. Dose reduction should occur for 
grade 4 neutropenia and febrile grade 3 or 4 neutropenia. 
Dose reduction should not occur for grade 4 thrombocytopenia or grade 4 anemia if they are 
believed to be solely attributable to paclitaxel.
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective June 14, 
2010, which are available at HTTP://ctep.cancer.gov/reporting/ctc.html.
Dose limiting toxicities will include the following events that are attributable to study 
treatment:
1. Grade 4 neutropenia or thrombocytopenia lasting more than 7 consecutive days
2. Grade 4 neutropenia associated with coincident fever (temp > 100.5°F)
3. Grade 3 or 4 thrombocytopenia with clinically significant bleeding, or a platelet count 
at any time of < 10,000/mm3
4. Grade 3 or greater nonhematologic toxicity, with the exception of:
a.
Nausea or vomiting occurring in the absence of optimal supportive therapy
b. Diarrhea occurring in the absence of optimal supportive therapy
c.
Grade 3 or greater fatigue lasting less than a week
d. Grade 3 or greater nonhematologic toxicity that can be controlled to ≤ Grade 2
with appropriate treatment
5. Grade 2 or greater nonhematological toxicity that is related to study treatment and 
requires a dose reduction in the opinion of the study PI
6. Delay of a subsequent of therapy by more than 7 days.
Only DLTs occurring during Cycle 1 of therapy will influence decisions regarding dose 
escalation and/or enrollment of additional patients to a dose level. Grade 4 anemia is not 
considered a DLT due to its known attribution to paclitaxel.
6.2 Dose Level Adjustment
6.2.1 Paclitaxel Paclitaxel may be reduced in 10 mg/m2 increments from the
starting dose of 80 mg/m2.  If the specific toxicity is related to myelosuppression, 
the treating physician may opt to drop the day 15 dose of paclitaxel and use 


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GCSF or a similar agent during subsequent cycles of therapy.  Ganetespib may be 
continued on day 15.
6.2.2 Ganetespib Ganetespib may be reduced in increments of 25 m/m2 weekly 
from the starting dose. Patients enrolling in Cohort 1 of the Phase I portion of 
the study will be allowed no more than 2 dose reductions of ganetespib.
The decision regarding which study drug requires reduction will depend upon the 
specific toxicity.  For example, paclitaxel has been shown to cause neuropathy, 
but neuropathy has not been associated with ganetespib. Diarrhea is known to be 
related to ganetespib and other Hsp90 inhibitors and is not commonly associated 
with paclitaxel. Therefore, paclitaxel will be reduced for dose-limiting 
neuropathy, while ganetespib will be reduced for dose limiting diarrhea, 
unresponsive to recommended prophylactic treatment for diarrhea.
Guidelines for Dose Modification or Dosing Delays due to Drug-Related Toxicities
Parameter
Paclitaxel 
administration
Ganetespib 
administration
Non-Hematologic Toxicity:
Any Grade 3 or higher except :
A.
Nausea or vomiting occurring in the 
absence of optimal supportive therapy
B.
Diarrhea occurring in the absence of 
optimal supportive therapy
C.
Grade 3 or greater fatigue lasting less 
than a week
D.
Grade 3 or greater nonhematologic 
toxicity that can be controlled to ≤ Grade 
2 with appropriate treatment
Delay until recovery
Reduce Dose
Delay until recovery
Reduce Dose
Unresolved Grade 4 toxicity exceeding 2 weeks 
beyond the planned administration date
Discontinue treatment
Discontinue treatment
QTc Prolongation
-
Grade 3 (≥ 501 ms on at least 2
separate ECGs)
-
Grade 4 or repeated Grade 3
Delay until recovery
Reduce dose
 Discontinue
Hematologic Toxicity Neutropenia:-
Grade 3: ANC < 1.0 × 109/L but ≥0.5 x 109/L
Delay until recovery
Maintain dose level
Grade 4: ANC < 0.5 × 109/L
Delay until recovery
Delay until recovery to at 
least Grade 3
Grade 3 or 4 neutropenia associated with fever 
>100.50F
Delay until recovery
Reduce Dose
Delay until recovery
Reduce Dose


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Hematologic Toxicity Thrombocytopenia
Grade 4 Thrombocytopenia lasting more than 7 
consecutive days
Grade 3 or 4 thrombocytopenia with 
clinically significant bleeding, or a platelet 
count at any time of < 10,000/mm3
Delay until recovery
Reduce Dose
Delay until recovery
Reduce Dose
Delay until recovery
Reduce Dose
Delay until recovery
Reduce Dose
In order for a patient to receive treatment, on day 1, 8 or 15 or at the start of a new 
cycle of therapy, the following criteria must be met:
ANC ≥ 1,000/mm3 (≥ 1,000 mm3 for the start of a cycle)
Platelet count ≥ 75,000/mm (≥ 100,000/mm for the start of a cycle)
All other toxicity consider related to therapy must have resolved to Grade 
1 or as considered acceptable by the treating physician or to baseline 
(with the exception of alopecia).
In the event that a patient is not able to proceed to the next cycle of 
therapy based on the above criteria, and the toxicity is attributable to 
paclitaxel, a patient who is deemed to be achieving clinical benefit may 
be allowed to continue treatment with ganetespib, given on a weekly 
schedule for 3 weeks out of a 4 week cycle, after discussion with the 
study PI.
6.3 Specific Toxicities and Modifications (See also Appendix III)
Management of Gastrointestinal Adverse Events in Ganetespib-treated Patients
Many patients receiving ganetespib will experience diarrhea, and some patients may
experience Grade 3 or 4 diarrhea.  The following proactive and ongoing management 
principles are necessary to avoid more serious complications of diarrhea.  However, 
guidelines such as these should never replace sound clinical judgment.
Experience suggests that diarrhea is an expected drug class effect for Hsp90 inhibitors and it 
typically starts 2 to 3 hours following administration of ganetespib in most patients.
However, when appropriately managed with anti-diarrheal treatment, it is generally 
mild to moderate and its duration limited to 24 hours.
Diarrhea must be proactively managed for all patients treated with ganetespib to 
avoid complications or worsening of the patient’s condition.  Without appropriate 
prophylactic treatment, the diarrhea can be prolonged, severe, and lead to severe 
dehydration and other complications.  Loperamide 2 mg must be given 
prophylactically, starting approximately 1 to 2 hours before ganetespib administration, 
to be repeated every 4 hours for the first 12 hours.
In the event of diarrhea, patients should take loperamide at an initial 4 mg dose, followed by 
2 mg doses every 4 hours.  In the presence of uncomplicated Grade 1 or 2 diarrhea, 
loperamide should be continued until the patient is free from diarrhea for 12 hours.  The 
total daily dose may not exceed 16 mg (8 capsules).
For Grade 3 or 4 diarrhea or complicated Grade 1 or 2 diarrhea (severe cramping, severe 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, 
frank bleeding, dehydration), IV fluids should be used as appropriate, as well as 
prophylactic antibiotics.


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Management of Neutropenia
First occurrence of Grade 2, Grade 3, or Grade 4 neutropenia (ANC ≤ 1500/mm³) on Day 1
(any cycle)
o
Delay dosing of both ganetespib and paclitaxel until neutrophil recovery 
to at least Grade 1.
o
Grade 2 and Grade 3 neutropenia (ANC 500 -1500/mm³) on Day 
8 and 15 (any cycle)
o Administer ganetespib without delay or dose modification.
o Delay dosing of paclitaxel until neutrophil recovery to at 
least Grade 1.
Management of Severe or Complicated Neutropenia
G-CSF prophylactic use is recommended during subsequent treatment cycles in case of
neutropenia lasting more than 7 days, febrile neutropenia, or documented infection with 
neutropenia. In this case, the treating physician may opt to treat with paclitaxel and 
ganetespib on days 1 and 8 only during each cycle.
Ganetespib Premedication and Management of Hypersensitivity Reactions
Generally, ganetespib does not require premedication for hypersensitivity reactions.
However, ganetespib contains a surfactant (polysorbate 80) that has been associated with 
hypersensitivity reactions in other medications administered by infusion.  Symptoms 
have included pruritus, flushing, shortness of breath, chest tightness, dizziness, 
headache, increased systolic blood pressure, and heart rate.
If an infusion reaction is suspected, the following is provided as guidance only; treatment 
will be based on clinical presentation.  Institution-specific premedication and/or 
treatment procedures and regimens may also be appropriate in lieu of these guidelines:
Mild or Moderate Symptoms: 
Stop ganetespib administration.
Give IV dexamethasone 10 mg and diphenhydramine HCl 25 to 50 mg.
After recovery from symptoms, resume ganetespib infusion or re-schedule patient for re- 
treatment as soon as possible.
Use premedication for subsequent infusion drug administrations.
Severe Symptoms (such as hypotension requiring pressor therapy or IV fluids, angioedema, 
respiratory distress requiring bronchodilator therapy, or generalized urticaria):
Stop ganetespib administration.
Give IV dexamethasone 10 mg and diphenhydramine HCl 25 to 50 mg, as above. 
Add adrenaline (1:1000) or bronchodilators, as indicated.
If severe symptoms recur with optimal premedication, treatment with ganetespib must be 
discontinued.
Example of infusion premedication regimen:
Dexamethasone 12 mg PO and diphenhydramine HCl 25-50 mg PO approximately 12 to 
24 hours prior to the next dose of study drug
Repeat dexamethasone 12 mg PO and diphenhydramine HCl 25 to 50 mg PO approximately 
4 to 6 hours prior to the re-challenge
7.0 Study Agent Information
7.1 Study Drug Paclitaxel


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7.1.1 Paclitaxel is an FDA- approved cytotoxic therapy. Please refer to the FDA-
approved package insert for product information, preparation instructions and a list 
of adverse events.
7.1.2 Commerically available paclitaxel will be used throughout this study.
7.1.3 Solution preparation:  Paclitaxel must be diluted prior to administration. 
Dilution will be as per institutional standards and within the package insert.
7.1.4 Storage requirements: Vials should be stored at controlled room temperature in 
the original package to protect from light and will be used up until the expiration 
date on the vial.  Refrigeration does not adversely affect stability.
7.1.5 Stability:  Intact vials are stable when stored as per Section 7.2.3 until the 
expiration date. Diluted solutions are stable for up to 27 hours at room temperature 
under normal room lighting.
7.1.6 Route of administration: Paclitaxel will be administered via intravenous 
infusion over 1 hour (+/- 15 minutes) as per institutional standards.
7.2 Study Drug Ganetespib
7.2.1 Product description
The current ganetespib investigational product is a concentrate for solution for infusion 
provided in a single-use vial containing 300 mg of ganetespib, as described in the 
Pharmacy Manual.  The concentration of ganetespib is 25 mg/mL in a polyethylene 
glycol 300 (PEG 300), polysorbate 80 (Tween-80) and dehydrated alcohol non-aqueous 
solvent system. The drug product is a clear, colorless-to-pale-yellow solution, 
essentially free of visible particles.
Ganetespib Drug Product, 25 mg/mL, 300 mg/vial (identified with a dark blue color 
cap and applicable product label):  Each vial contains 12 mL of deliverable volume
(12.84 mL total including an overage per USP requirements) equivalent to 300 mg of 
ganetespib at a concentration of 25 mg/mL in a PEG 300, polysorbate 80, and dehydrated 
alcohol non-aqueous solvent system.  The drug product, as noted, is a clear, colorless-to- 
pale-yellow solution.
The amount of ganetespib administered will depend upon the patient’s body surface area. 
The drug product is diluted before infusion.
Container/Closure
The ganetespib drug product is provided in a 30 mL type I amber glass vial fitted with a 20 
millimeter stopper and sealed with an aluminum crimp and flip-off cap.
7.2.2 Availability
Ganetespib will be supplied by Synta Pharmaceuticals Corp.
7.2.3
Solution preparation
Ganetespib must be diluted prior to administration. The appropriate drug administration 


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instructions per the preparation guidelines must be carefully followed prior to use.  
Refer to the Pharmacy Manual for detailed ganetespib preparation guidelines.
7.2.4
Storage requirements
Store the infusion solution at room temperature until use, avoiding direct exposure to light. 
Upon completing the infusion solution preparation, the 1-hour administration of the infusion 
solution must be completed within 4 hours. The time needed to prepare the dosing solution 
does not count against the 4-hour limit. There is no need to protect the IV bag from ambient 
light during the infusion.
Caution: Do not refrigerate the infusion solution.
Caution: The 1-hour administration must be completed within 4 hours of finishing the 
infusion solution preparation.
7.2.5
Route of administration
Set up the infusion pump to deliver the 500mL ganetespib infusion solution over 60 minutes.
Note: Use of Vascular Access Devices:
Based on preclinical data, use of vascular access devices (VADs) (such as ports and 
peripherally-inserted central catheters [PICCS]) containing silicone catheters are
permitted.
Use of VADs with catheters made of any 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.
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.
7.3 Drug Ordering, Storage and Handling
Ganetespib will be supplied by SyntaPharmaceuticals, Corp.
Following submission and approval of the required regulatory documents, participation in the 
study initiation meeting and receipt of the site activation letter from the CTO Regulatory 
Coordinator, the initial order may be placed. Drug order forms and ordering procedure will be 
presented at the site initiation meeting.
7.4 Destruction of Drug
At the time of study closure, the unused, used and expired study drug will be destroyed at
the site per Institutional SOPs unless otherwise specified.
7.5 Records to be kept at Site; Dispensing and Accountability
It is the responsibility of the Investigator to ensure that a current record of investigational
product (ganetespib) disposition is maintained at each study site where investigational 
product is inventoried and disposed. Records or logs (supplied by CTO) must comply 
with applicable regulations and guidelines, and should include:
7.5.1
Number of vials received and placed in storage area.


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7.5.2
Number of vials currently in storage area.
7.5.3
Label ID number or batch number.
7.5.4
Dates and initials of person(s) responsible for each investigational product
7.5.5
inventory entry/movement.
7.5.6
Number of vials dispensed to and returned for each patient, including unique 
patient identifiers.
7.5.7
Number of vials transferred to another area for dispensing or storage after ensuring 
adequate storage and accountability procedures are in place.
7.5.8
Non-study disposition (e.g., lost, wasted, broken).
8.0 Correlative /Special Studies
8.1 Study Correlative #1
Analysis of patient pre- and post-ganetespib blood specimens (serum and peripheral 
blood mononuclear cells) for changes in the levels of expression of HSP70 and 
established HSP90 client proteins.
Rationale: The standard correlative studies performed in conjunction with HSP90 
inhibitors include analysis of pre- and post-drug treatment blood specimens for 
biomarker analysis in PBMCs 29. Specifically, levels of relevant biomarkers, including 
HSP90, HSP70 and established HSP90 client proteins (e.g., HER-2,
STAT3/pSTAT3, RAF-1, CDK1/pCDK1, etc.) are evaluated by immunoblot analysis of 
protein lysates isolated from PBMCs from pre- and post-treatment blood specimens. 
Treatment with HSP90 inhibitors commonly results in increased levels of HSF1 which 
result in induction of HSP70 (reviewed in 30). More recent studies suggest that HSP70 is 
secreted and that detection and quantification of HSP70 levels in serum is a potentially 
valuable correlative measure to indicate response to ganetespib 31,32.
Outcome measure: Alterations (significant increase or decrease) in protein biomarker 
level in post-treatment specimens (PBMCs and/or serum) compared to pre-treatment 
specimen.
Assessment, method, timing: Biomarker levels in PBMCs will be assessed by the 
standard method of immunoblot analysis followed by densitometry of the blots 
comparing biomarker levels to standard loading controls and/or purified protein 
standards 29.  In addition to immunoblot analyses, levels of HSP90, HSP70 and HSP90 
client proteins (e.g., AKT/pAKT,pSTAT3, etc.) in PBMC’s will be assayed by ELISA 
using commercially available kits (Enzo Life Sciences, MesoScale Discovery). Levels of 
secreted HSP70 and HSP90 and secreted HSP90 clients (soluble HER-2 and IGFBP-2) 
present in pre- and post-drug treatment serum specimens will be assayed by ELISA 
using commercially available kits (Enzo Life Sciences, MesoScale Discovery).
Data recording, method, timing: Analyses will be performed after patient accrual to the 
clinical trial and specimen collection is complete.
8.1.1 Collection of specimen- Blood specimens (two 10 ml tubes of blood) will be 
collected prior to  treatment with ganetespib and paclitaxel on day # 1 of Cycle # 1 
and on Day # 15 of Cycle # 1 and Day # 1 of Cycle # 2.and Day #15 of Cycle #2
8.1.2 Handling of specimen- After collection, blood specimens will be transferred to the 


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FCCC protocol support laboratory where they will be logged in and processed for 
collection and storage of PBMCs and serum.
8.1.3 Shipping of specimen- None
8.1.4 Site(s) performing correlative study- FCCC
8.2 Study Correlative #2
Analysis of patient formalin fixed paraffin embedded (FFPE) tumor specimens for the 
expression and activation of established HSP90 client proteins
Rationale: In addition to the analysis of HSP90-related biomarkers in PBMCs and serum, 
we will also analyze levels of expression and/or activation of HSP90 client proteins in 
patient primary tumor specimens by immunohistochemistry (IHC). The goal of this 
analysis is to survey patient tumor specimens for activation of HSP90 clients to 
determine if overall levels of client activation or activation of specific clients are 
associated with response to drug therapy. In the event that there are patients that 
experience PR or CR, we may further analyze the tumor specimen by high throughput 
genomic techniques (microarray, array comparative genomic hybridization, and/or 
DNA/RNA sequencing analyses) in order to discover the mechanistic basis of response 
to therapy.
Outcome measure: High levels of expression and/or activation of HSP90 client protein 
level in primary tumor tissue compared to archives specimens of normal ovary and 
fallopian tube tissue.
Assessment, method, timing: HSP90 client protein biomarker levels in tumor tissue will 
be assessed by IHC using standard methods. Analysis of the stained sections will be 
performed using the Aperio image analysis instrument and accompanying software 
analysis package. Staining levels will be compared in patient samples using archived 
specimens (available through the FCCC-UPenn Ovarian Cancer SPORE Pathology Core 
Facility). HSP90, HSP70 and HSP90 client proteins (e.g., JAK2, pSTAT3, pSTAT5, 
CDK1/pCDK1, S6K/pS6K, c-MYC, EGFR, HER-2, pAUR, AKT/pAKT,
and others) will be detected using commercially available antibodies that are suitable for 
IHC. Levels of client expression and/or activation will be compared to normal ovarian 
and fallopian tube tissue. In addition, levels of expression/activation of clients will be 
analyzed in the context of response to therapy. If necessary, high throughput genomic 
analyses (microarray, array comparative genomic hybridization, and/or DNA/RNA 
sequencing) will be performed using standard methodologies available through the FCCC 
Genomics Facility or the Cancer Genome Institute.
Data recording, method, timing: Analyses will be performed after patient accrual to the 
clinical trial and specimen collection is complete.
8.2.1 Collection of specimen- Banked tumor tissue (FFPE tumor tissue specimens) 
will be obtained from a previous resection or biopsy that was done as part of the 
patient’s standard care from the Pathology Department at FCCC, or in the case of 
patients who have undergone prior surgery at an outside institution, from the 
Pathology Department of the respective institution.
8.2.2 Handling of specimen- FFPE specimens will be transferred to the FCCC 
protocol support laboratory where they will be logged in and stored until all 
specimens for the trial are accrued and ready for testing.


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8.2.3 Shipping of specimen- None
8.2.4 Site(s) performing correlative study- FCCC
8.3 Study Correlative #3:
Analysis of patient pre-treatment serum samples for the presence of secreted HSP90α 
Rationale: Recent studies have shown increased levels of HSP90α in the serum of patients 
with prostate (PC), colorectal (CRC) and hepatocellular (HCC) carcinomas compared to 
normal controls 33-35. To investigate whether patients with EOC similarly exhibit elevated 
levels of secreted HSP90α in serum, we will use banked serum specimens collected from 
EOC patients and age matched donors to compare levels of HSP90α detected by ELISA. 
The aforementioned studies in PC and HCC identified significant differences in HSP90α 
levels using relatively small numbers of serum specimens from cancer patients and 
controls (N ≤ 20 specimens each of cancer compared with controls). We predict that 
analysis of similar sized cohorts of EOC patient serum and normal controls (n = 20-25) 
will determine whether HSP90α levels are significantly elevated in EOC patients. De-
identified serum specimens for this analysis have been obtained from the FCCC-UPenn 
Ovarian Cancer SPORE Pathology Core Facility for this analysis.
Outcome measure: Determine if EOC patients exhibit elevated levels of serum HSP90α 
and if increased levels of serum HSP90α correlate with response to drug therapy.
Assessment, method, timing: Assessment of HSP90α levels will be performed by ELISA 
using a commercially available (Enzo Life Sciences) or custom-built assay (MesoScale 
Discovery chemiluminescent ELISA assay platform).
Data recording, method, timing: Analyses will be performed after patient accrual to the 
clinical trial and specimen collection is complete.
8.2.1 Collection of specimen- Pre-treatment serum specimens (collected for Study 
Correlative #1) will be used for the ELISA assay.
8.2.2 Handling of specimen- As in Study Correlative #1
8.2.3 Shipping of specimen- None
8.2.4 Site(s) performing correlative study- FCCC


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9.0 Study Calendar
Pre- 
Study
b
C1 
D1 
b
C1 
D2
C1 
D8
C1 
D15
C1 
D22
C2 
D1
C2 
D8
C2 
D15
C2 
D22
C3 
D1
C3 
D8
C3 
D15
C3 
D22
Day 1 of all 
subsequent 
cycles
Off Studyg
Informed consent & HIPAA
a
X
Medical history
X
Physical exam(b)
X
X
X
X
X
X
Concurrent meds(b)
X
X---------------------------------------------------------------------------------------------X
Vital signs (T, P, R, BP)(b)
X
X
X
X
X
X
Height
X
Weight(b)
X
X
X
X
X
X
Performance status(b)
X
X
X
X
X
X
CBC w/diff, plts(b)
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry(b,c)
X
X
X
X
X
X
X
X
X
ECG (b,h)
X
X
X
X(h)
Adverse event evaluation
X---------------------------------------------------------------------------------------------X
X
Tumor measurements
(CT- Chest, Abd. & Pelvis)
X
Tumor measurements are repeated every 8  weeks. Documentation 
(radiologic) must be provided for patients removed from study for 
progressive disease.
Xg
β-HCG
Xd
Correlate Blood/Serum 
Draw
Xe
X
X
X
Collection of FFPE tumor 
tissue
Xf
Ganetespib
X
X
X
X
X
X
X
X
X
Paclitaxel
X
X
X
X
X
X
X
X
X


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a:  Informed consent must be signed within 30 days of registration. If signature is outside that window the patient must sign a new consent
b:  Pre-study H&P and all labs must be < 14 days  prior to registration. Tumor measurements and radiologic evaluations must be < 30 days prior to    
     registration.  Pre-study assessments may be used for C1D1 assessments if completed < 7 days from day one of treatment.
c:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein,     
SGOT [AST], SGPT [ALT], sodium. Will be performed weekly during cycle 1, and then Day 1 for cycles 2 and beyond.
d:  Serum pregnancy test (women of childbearing potential) must be completed < 7 days before registration. 
e:  Two 10 ml tubes of blood to be drawn pretreatment  on  C1,D1; C1, D15; C2,D1 and C2,D15.
f:  In the event of any biopsies or collection of ascites required for appropriate medical care of the patient throughout the course of the study,
    samples not needed for medical care will be collected and used for further analysis as per correlative aim #2.
g.   Off-study evaluation. If PD documented during scheduled on-study assessment, tumor measurements and radiologic staging do not need to be        
repeated. Follow up for PD, resolution of treatment related toxicities should be conducted every 3 months for 2 years, every 6 months for 
      2 years,  annually until death.
h.   ECG must be performed prior to treatment on day 1 of every odd cycle. 


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10.0 Adverse Events
10.1 Definitions
10.1.1 Adverse Event (AE) is any unfavorable and unintended sign (including
an abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medicinal (investigational) product, treatment or procedure 
regardless of whether it is considered related to the medical treatment or 
procedure (NCI CTEP Guidelines March 28, 2011)
10.1.2 Serious Adverse Event (SAE) is an AE that is fatal or life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization (for
> 24 hours), persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or is a congenital anomaly/ birth defect, 
or results in any important medical event that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the above outcomes.  A “life- 
threatening” adverse event places the patient at immediate risk of death in the 
judgment of the investigator or sponsor.
10.1.3 Severity Rating
The investigator will evaluate the severity of each adverse event. NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific 
toxicity tables provided in the protocol define severity.  If not included in 
CTCAE v.4.0, severity is expressed in numerical grade using the following 
definitions:
1.
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
2.
Grade 2: Moderate-minimal, local or noninvasive intervention 
indicated; limiting age appropriate instrumental ADL.
3.
Grade 3: Severe-severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self care ADL.
4.
Grade 4: Life-threatening consequences; urgent intervention indicated.
5.
Grade 5: Death related to AE
10.1.4 Attribution/Relationship to study drug
1.
Definite – clearly related
2.
Probable – likely related
3.
Possible – may be related
4.
Unlikely – doubtfully related
5.
Unrelated – clearly not related


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10.1.5 Expectedness
An Expected Adverse Event is one where the specificity or severity is 
consistent with the current information available from the resources.
An Unexpected Adverse Event is one where the nature, severity, or 
frequency of the event which occurs during participation in the research is 
not consistent with either:
1.
The known or foreseeable risk of adverse events associated with the 
investigational product(s) or procedures involved in the research that 
are described in (a) the protocol-related documents, such as the IRB- 
approved research protocol, any applicable investigator brochure, and 
the current IRB-approved informed consent document, and (b) other 
relevant sources of information, such as product labeling and 
package inserts: or
2.
The expected natural progression of any underlying disease, 
disorder, or condition of the subject (s) experiencing the adverse 
event and the subjects(s) predisposing risk factor profile for the 
adverse event. (OHRP Guidance on reviewing unanticipated 
problems 2007)
10.2 Recording and Reporting Responsibilities
10.2.1 Investigative site recording responsibilities:
1.
Upon identification of an AE or SAE, the site investigator will 
utilize the above definitions to properly classify the event. 
Each category listed above must be recorded for each event.
2.
All AEs and SAEs will be recorded in the “AE case report forms” 
(CRF) and in progress reports with details about the grade and 
attribution of each episode, action taken with respect to the study 
drug, and the patient’s outcome will be recorded in the CRF. All 
events will be recorded on case report forms for the duration of 
the study until they resolve.
3.
All SAEs will be recorded on the FDA MedWatch form 3500a.
After submitting the initial report it may be necessary to submit 
follow up reports to the CTO, Sponsor and the FDA should the 
event require further investigation.
4.
SAE reporting will begin after the research participant has 
received their first dose of drug unless the SAE was due to a study 
specific test or procedure.
10.2.2 Investigative site reporting responsibilities:
1.
The investigator/ site is responsible for reporting all SAEs to the QA 
Specialist / Study Monitor within 24 hours of becoming aware of 
the event.  A written report must follow within 48 hours.
2.
Each investigator is responsible for reporting all AEs/SAEs to 


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their local IRB following guidelines set by that IRB. The FCCC 
CTO reserves the right to request an event be reported to the IRB 
at their discretion.  Copies of events reviewed by the IRB must be 
sent via fax to the CTO Regulatory Coordinator at (215) 728-2914
3.
If the investigator or IRB feels the event warrants a revision to 
the informed consent that was not already initiated by the CTO, 
draft revisions will be made in track changes and submitted to the 
CTO for consideration. Any consent revisions must receive CTO 
approval prior to submission to the IRB.
4.
Any investigator who is in doubt of whether a particular AE needs 
to be reported is directed to call the QA Specialist / Study Monitor 
for confirmation with the Principal Investigator
5.
If the results of an investigator or CTO investigation show an 
adverse event not initially determined to be reportable is so 
reportable, the investigator will report the event following the 
above guidelines based on the date the determination is made.
6.
Copies of all related correspondence and reporting documents 
must be submitted to the CTO Regulatory Coordinator and will be 
maintained in a regulatory file.
The participating site should report events to: 
QA Specialist / Study Monitor
Fox Chase Cancer Center Clinical Trials 
Operations 333 Cottman Avenue
Philadelphia, PA 19111
Telephone: 215-214-3704
Fax: 215-214-1511
Email: beth.adaire@fccc.edu
10.2.3 ERP Reporting Responsibilities:
1.
Adverse events which meet all of the following criteria must be 
reported to all participating institutions for IRB submission within 
2 weeks of notification of the event.
i.
Unexpected (in terms of nature, severity, or frequency) given 
(a) the investigational product that is described in the protocol- 
related documents, such as the Investigational Brochure, IRB-
approved research protocol and informed consent document; and
(b) the characteristics of the subject population being studied;
ii. Possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the one or 
more of the procedures involved in the research); and
iii. Serious (refer to above definition) or otherwise one that 
suggests that the research places subjects or others at a greater 
risk of physical or psychological harm than was previously 
known or recognized.
2.
If the adverse event requires modification of the study protocol and 


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informed consent, these changes will be provided to all participating 
institutions in the form of an amendment from the CTO for each 
site’s IRB of record along with the report of the adverse event.
3.
Copies of all related correspondence and reporting documents will 
be maintained in a centralized regulatory file for this study at CTO.
4.
SAEs that are related, unexpected, fatal, or life-threatening are 
reportable through the Food and Drug Administration (FDA) 
MedWatch program by telephone or fax no later than 7 calendar days 
after initial receipt of the information.  Further information on the 
timing of submissions are as directed by FDA guidelines 
(http://www.fda.gov/medwatch/index.html).  Serious, unexpected 
events that suggest significant clinical risk will be submitted to within 
15 calendar days after initial receipt of this information.
5.  Synta Pharmaceuticals as the manufacturer of ganetespib is responsible 
for all SAEs in patients using its products. All SAE MedWatch forms, 
regardless of expectedness or relationship to the study drug must be 
submitted to TELERX within 24 hours of the investigator’s (or 
designee’s) becoming aware of the event. MedWatch forms should be 
faxed to: 
TELERX at 1-888-975-2207
All transmission confirmations must be maintained with the 
submission documents.
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-800-FDA-0178
http://www.fda.gov/medwatch/report.htm
Mandatory Drug Reporting: 
Central Document Room
Center for Drug Evaluation and Research 
Food and Drug Administration
12229 Wilkins Avenue
Rockville, MD 20852
Office of Post-Marketing Drug Risk Assessment (HFD 730) 
Center for Drug Evaluation and Research
Food and Drug Administration 
5600 Fishers Lane
Rockville, MD 20857
(301) 827-3169 for any further questions regarding where to 
send drug mandatory reporting forms
10.4 Pregnancy


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All WOCBP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual period) at 
any time during study participation.
In the event of a confirmed pregnancy in a patient participating in the study, 
the Investigator must immediately notify the Fox Chase Cancer Center QA 
Specialist / Study Monitor who will notify the study PI.
All pregnancies occurring during the study must be reported to Synta within 
24 hours of investigator/site awareness of the pregnancy. Pregnancies 
should be followed for outcome, including early termination of any kind as 
well a delivery details in the event of complications and to report fetal 
outcome.  In the event of fetal demise, Synta may request additional 
information.
11.0 Measures of Effect
Response Evaluation Criteria in Solid Tumors (RECIST)
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used 
for objective tumor response assessment.  Assessments will be performed after every 
8 weeks of treatments. Once protocol treatment has been completed research 
participants will be assessed every three months or sooner as indicated and judged by 
treating physicians.
11.1 Definitions
Evaluable for adverse events:  All research participants will be evaluable for
adverse events from the time of their first treatment with paclitaxel and 
ganetespib.
Evaluable for objective response:  Only those research participants 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 research participants will have their response classified 
according to the definitions stated below.  (Note:  Research participants who 
exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.)
Evaluable Non-Target Disease Response: Research participants who have 
lesions present at baseline that are evaluable but do not meet the definitions of


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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.
11.2 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 for solid tumors) as >20 mm by chest x-ray, as >10 mm with CT 
scan or MRI, or >10 mm with calipers by clinical exam.
Note:  Tumor lesions that are situated in a previously irradiated area might or 
would not be considered measurable unless there is documented disease 
progression prior to commencement of the study treatment.
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 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, 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,


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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.
11.3 Methods 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 must 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.
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.
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).
MRI has excellent contrast, spatial, and temporal resolution; however, there 
are many image acquisition variables involved in MRI, which greatly impact 
image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, 
the technical specifications of the scanning sequences used should be


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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.
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.  If CA-125 is initially 
elevated, it must decrease to normal for patient to be considered to have a CR. 
Patients with resolution of visible disease by imaging whose CA-125 remains 
elevated will be considered to have a PR. CA-125 elevation or increase alone 
will not be considered sufficient evidence of disease progression in the 
absence of worsening clinical symptoms or visible progression on imaging 
analysis.


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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.
11.4 Response Criteria
Evaluation of Target Lesions


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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 progression).
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
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.
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances.
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.


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Protocol version date: 10/20/2014
o
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.
For Patients with Measurable Disease (i.e., Target Disease)
Target
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
11.5 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 


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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.
11.6 Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first.
11.7 Response Rate
Response rate is defined as the proportion of patients with a best response of 
CR or PR.
12.0 Statistical Considerations
12.1 Study Design/Endpoints
Dose escalation will follow a modified 3+3 design (Table 1). If doses in Cohort 
1 are tolerable, Dose Level 1 will proceed to Dose Level 2. If Dose Level 2 
doses are tolerable, dosing will proceed to Dose Level 3 and this cohort will be 
expanded to a total of 6 patients; if 1 or 0 patients experience a dose-limiting 
toxicity (DLT), this will be the chosen regimen for the Phase II trial. If ≥2 
patients experience a DLT, dose expansion will proceed at the next lower Dose 
Level, and an additional 3 patients would be evaluated at the lower dose level. If 
one patient of the first 3 experiences a DLT in any cohort, that cohort will be 
expanded to enroll, in sequence, an additional 3 patients. If 1 additional patient 
experiences a DLT, enrollment will proceed at the next lower Dose Level for 
expansion to 6 patients. We will enroll an additional 6 patients at the MTD or 
the maximum evaluated dose (MED), which is Dose Level 3, level to gather 
additional safety and toxicity information prior to proceeding with a Phase II 
trial. There will be no escalation beyond Dose Level 3, even in the absence of 
DLTs.  DLTs will include grade 4 neutropenia lasting longer than 7 days, 
neutropenic fever, grade 4 thrombocytopenia or any Grade 3 non-hematologic 
toxicity lasting greater than 7 days, not controlled with optimal medical 
management.
Table 1
Ganetespib
weekly dose:
Paclitaxel 80 mg/m2 weekly
100 mg/m2
Cohort 1
125 mg/m2
Cohort 2
150 mg/m2
Cohort 3


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Protocol version date: 10/20/2014
For the Phase II portion of the study we will test the composite null hypothesis 
that the chance of response to the combination therapy is at most 25% and the 
chance of PFS at 6 months is at most 30%. The alternative for which power is 
computed is that the chance of response is at least 40% OR the chance of PFS at 
6 months is at least 50%. We used the design of Sill and colleagues.36 This 
flexible double end-point design evaluates the first 29, 30 or 31 (n1) patients, 
(which, depending on control of patient accrual). If 7/29, or 7/30 or 7/31 
(cr1/n1) respond or if 10/29, or 11/30 or 12/31 (cs1/n1) are PF at 6 months then 
recruitment will be continued until 54, 55 or 56 (n2) patients are on available for 
study. Final decision rules (cr2 and cs2) to reject the null are given in the tables 
below.
On the assumption of independence of response and PFS at 6 months the study 
will have at least 80% power and at most 9.5% type I error. Average power 
under all 9 possible combinations of early and final sample numbers is 82% 
with 9.1% average type I error. The chance of early stopping under the null is at 
least 42% and at most 6.6% under any alternative.
Statistics under the most extreme forms of dependence are also tabulated below. 
In all cases the average performance of the design gives at least 80% power and 
at most 10% type I error.
pr(null) 0.250  pr(alt) 0.400  Response
ps(null) 0.300  ps(alt) 0.500  PFS
n1: 29 30 31
cr1:  7  7  7
cs1: 10 11 12
cr2
n1\n2:54 55 56
29
18 18 18
30
18 18 18
31
18 18 18
cs2
n1\n2:54 55 56
29
22 23 24
30
22 23 24
31
22 23 24
--------------------------------------------------------
independence case


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Protocol version date: 10/20/2014
min
ave
max
min
ave
max
pr
ps
power power  power
pes
pes
pes
0.250 0.300 0.0882 0.0911 0.0953 0.4222 0.4279 0.4324
0.250 0.500 0.8152 0.8481 0.8814 0.0379 0.0520 0.0664
0.400 0.300 0.8019 0.8271 0.8523 0.0295 0.0367 0.0439
0.400 0.500 0.9726 0.9744 0.9764 0.0039 0.0043 0.0046
--------------------------------------------------------
fullest dependence case: p11=min(pr,ps)
min
ave
max
min
ave
max
pr
ps
power power  power
pes
pes
pes
0.250 0.300 0.0665 0.0745 0.0841 0.4719 0.5091 0.5444
0.250 0.500 0.7814 0.8218 0.8638 0.0656 0.0934 0.1220
0.400 0.300 0.7928 0.8212 0.8496 0.0330 0.0445 0.0570
0.400 0.500 0.8891 0.8939 0.9003 0.0278 0.0310 0.0333
--------------------------------------------------------
fullest dependence case: p11=max(0,pr+ps-1)
min
ave
max
min
ave
max
pr
ps
power power  power
pes
pes
pes
0.250 0.300  0.0891 0.0923 0.0963   0.3811 0.3887 0.3931
0.250 0.500  0.8657 0.8903 0.9145   0.0102 0.0148 0.0198
0.400 0.300  0.8225 0.8423 0.8623   0.0177 0.0196 0.0212
0.400 0.500  0.9998 0.9999 0.9999   0.0000 0.0000 0.0000
---------------------------------------------------------
nb: Output from dblep19.doc
---------------------------------------------------------
Testing for excess toxicity:
We will consider 15% or lower as reasonable for the chance of DLT. 33.3%, or 
1/3 will be considered excessive. If the number of DLTs among the first 15 
patients ever reaches 6, the study will be
terminated for excess toxicity. Similarly if ever 9 of the first 29 patients 
experience DLTs the study will be stopped early for excess toxicity. Finally, if 
ever 14 patients experience DLTs the treatment will be considered too toxic.
The chance of finding the treatment too toxic when the true rate of DLT is 1/3 is 
92%. The chance of declaring it too toxic when the true rate of DLT is 15% is 
4.73%. The table below gives the chance of declaring the study too toxic under 
null or alternative and at each early and the final sample number. The 15 and 29 
rules may be applied before the efficacy early stopping point is reached. 
Similarly, if the study accrues 55 or 56 patients, the 54 rule is to be applied 


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whenever 54 patients are accrued. The stopping numbers are fixed even though 
the early and final sample numbers are not known. In all 9 combinations of early 
and final sample numbers the chance of declaring the study too toxic when it is 
at least 90%. The type I error is at most 6.12% over these same combinations.
p(declare tox | ptox = 0.150000000000000 ): 4.730297624299153E-002
p(early stop) at 15 patients: 1.681008604795003E-002 
p(early stop) at 29 patients: 1.521020715756849E-002 
p(final stop) at   54  patients:  1.528268303747300E-002
p(declare tox | ptox =  0.333333300000000 ):   0.918379342938625
p(early stop) at  15 patients: 0.381628054489728
p(early stop) at  29 patients: 0.310791894575327
p(final stop) at   54  patients:  0.225959393873570
---------------------------------------------------------------------
nb: output of tox3.f, see tox3b.out for complete listing. 
tox3.f and tox3b.f both on stats.
---------------------------------------------------------------------
12.2 Sample Size/Accrual Rate
The Phase I portion of the study will include no more than 18 patients, and the 
Phase II portion of the study will include no more than 56 patients.
12.3 Stratification Factors
N/A
12.4 Analysis of Correlative Endpoints
For the correlative studies, as described in Section 8.0, evaluations will be as 
follows:
For correlate 8.1: We will compare protein biomarker pre-treatment levels to 
their post-treatment levels. With 54 patients we will test the null hypothesis that 
the two levels do not differ. This corresponds to the hypothesis that the post- 
treatment levels exceed pre-treatment levels with probability 0.5. We expect 27 
such exceedences under the null. If this number is at least 35 or at most 19 we 
will reject the null and conclude that pre and post-treatment levels differ. The 
test will have 84% power and 4% two-sided type-I error.
For correlate 8.2: We will compare Hsp90 expression or activation levels in our 
patients to those in 54 archived specimens of normal ovary and fallopian tube 
tissue. We will classify all 108 specimens as high or low level IHC staining. We 
will submit this doubly dichotomized data to Fisher’s exact test which will have 
at least 80% power and at most 5% type I error to test the null hypothesis that 
patient and control staining levels are the same versus that patients tissues


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experience higher staining levels and patients are at least 24% more likely to be 
in the higher staining category.
For correlative study 8.3: We will compare patient pre-treatment serum samples 
of secreted Hsp90-alpha to serum from age-matched normal controls. With 25 
such differences we will test the null hypothesis of no difference, i.e. the chance 
that patient exceeds control is one-half, versus the hypothesis that the chance 
that  patient levels exceed the control levels is at least 75%. This test of the 
binomial proportion will have 85% power and 5.4% type-I error to detect such a 
difference.
12.5 Reporting and Exclusions
12.5.1 Evaluation of toxicity: All patients who have received any amount of 
study drug will be evaluable for toxicity.  All patients will be 
evaluated for safety.
12.5.2 Evaluation of response:  All patients included in the study must be 
assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories:  1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, 
insufficient data).
All of the patients who met the eligibility criteria (with the possible 
exception of those who received no study medication) should be 
included in the main analysis of the response rate.  Patients in 
response categories 4-9 should be considered to have a treatment 
failure (disease progression).  Thus, an incorrect treatment schedule 
or drug administration does not result in exclusion from the analysis 
of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.
13.0 Data and Safety Monitoring Plan
13.1 Monitoring Plan
The QA Specialist/Study Monitor will monitor the medical and study records
of each participant accrued throughout the course of the study.  In addition, 
the CTO will collect and report data to the study Principal Investigator who 
will review these data on a regular basis at a rate dependent on subject 
accrual.  All serious adverse events (SAEs) will be reviewed on a real time 


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basis first by the study site PI and subsequently study PI.
13.2 Extramural Data Safety Monitoring Committee
Interim analysis of toxicity, outcome and ongoing scientific investigations
may be performed every 6 months by the Extramural Data Safety Monitoring 
Committee (EDSMC).  In this capacity the EDSMC will serve as an advisory 
committee to the PMEC. The EDSMC will review those aspects of this trial 
that are outlined in the responsibilities section of the Extramural Data and 
Safety Monitoring Plan (DSMP).  If the committee decides that changes 
should be made to this trial, it will make recommendations in writing to the 
Study PI, the Extramural Research Committee and Division Medical Director, 
which, in turn, have the authority to approve or disapprove these 
recommendations.  These changes will be discussed with the Study Principal 
Investigator before they are implemented. These changes may include early 
termination of accrual.  Other changes might include altering the accrual goals 
or changing the eligibility criteria for the trial.
14.0 Administrative
This study will be conducted in accordance will local, state and Federal regulations
and according to accepted good clinical practice guidelines.
14.1 Data Reporting
The FCCC QA Specialist / Study Monitor will request case report form
submission upon resolution of outstanding queries. Participating sites are 
responsible to respond to queries prior to the next scheduled monitoring visit. 
Participating sites are responsible for submitting case report forms to the QA 
Specialist / Study Monitor within two weeks of request.
The QA Coordinator is responsible for compiling and submitting data to the 
study PI and statistician on an ongoing basis for monitoring as described in 
the data safety monitoring plan and reporting to the Extramural Data and 
Safety Monitoring Committee.
All patient information will be stored on an electronic Microsoft Office Excel 
Spreadsheet on a drive accessible only to the study team members for the 
purpose of entering, reviewing and analyzing data.  Any paper records, such 
as case report files, produced will be stored in locked file cabinets with limited 
access.
The CTO Regulatory Coordinator is responsible for distributing and tracking 
review of all IND Action Letters, Safety Reports, study specific Serious 
Adverse Events
14.2 Retention of Records
Time points for the retention of records are described in detail in the contract
between the grantor and the CTO and passed on to the participating site. 
Please refer to the study specific terms for specific time points.  In all cases


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the QA Specialist / Study Monitor must be notified of any plans to move 
records to an offsite location prior to doing so.
14.3 Study Agents
Any study agent supplied through the CTO from the manufacturer or a third
party distributor may not be used for any purpose outside the scope of this 
protocol.  The agent may not be transferred to any party not participating in 
the clinical trial.
14.4 Informed Consent
The IRB approved informed consent documents must be signed by the patient,
or the patient’s legally authorized representative, before his or her 
participation in the study.  The case history for each patient shall document 
that informed consent was obtained prior to participation in the study.  A copy 
of the informed consent documents must be provided to the patient or the 
patient’s legally authorized representative.  If applicable, they will be 
provided in a certified translation of the local language.
Original signed consent forms must be filed in each patient’s study file or 
medical record with a copy in the study file.


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15.0 References
1.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 
2012;62:10-29.
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Markman M, Reichman B, Hakes T, et al. Responses to second-line cisplatin- 
based intraperitoneal therapy in ovarian cancer: influence of a prior response to 
intravenous cisplatin. J Clin Oncol 1991;9:1801-5.
3.
Gore ME FI, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of the 
ovary with cisplatin or carboplatin following initial treatment with these compounds. 
Gynecol Oncol 1990;36:207-11.
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Blackledge G LF, Redman C, Kelly K. Response of patients in phase II studies of 
chemotherapy in ovarian cancer: implications for patient treatment and the design of 
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Dizon DS, Dupont J, Anderson S, et al. Treatment of recurrent ovarian cancer: a 
retrospective analysis of women treated with single-agent carboplatin originally treated 
with carboplatin and paclitaxel: The Memorial Sloan-Kettering Cancer Center 
experience. Gynecol Oncol 2003;91:584-90.
6.
Orlando M, Costanzo MV, Chacon RD, Tajer CD. Randomized trials of 
combination chemotherapy (combo) versus monotherapy (mono) in relapsed ovarian 
carcinoma (ROC): A meta-analysis of published data. J Clin Oncol (Meeting Abstracts) 
2007;25:5524-.
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Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nature reviews 
Cancer 2005;5:761-72.
8.
Ying W, Du Z, Sun L, 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;11:475-84.
9.
Proia DA, Foley KP, Korbut T, et al. Multifaceted intervention by the Hsp90 
inhibitor ganetespib (STA-9090) in cancer cells with activated JAK/STAT signaling. 
PloS one 2011;6:e18552.
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Acquaviva J, Smith DL, Sang J, et al. Targeting KRAS-mutant non-small cell 
lung cancer with the Hsp90 inhibitor ganetespib. Mol Cancer Ther 2012;11:2633-43.
11.
Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and 
targets for cancer therapy. Trends Pharmacol Sci 2012;33:207-14.
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Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL. Acriflavine inhibits HIF- 
1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci U S A 
2009;106:17910-5.
13.
Shimamura T, Perera SA, Foley KP, 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;18:4973-85.
14.
Nguyen DM, Lorang D, Chen GA, Stewart JHt, Tabibi E, Schrump DS. 
Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino 
geldanamycin: in vitro and in vivo analysis. The Annals of thoracic surgery 2001;72:371- 
8; discussion 8-9.
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Proia DA, Sang J, He S, et al. Synergistic activity of the Hsp90 inhibitor 
ganetespib with taxanes in non-small cell lung cancer models. Invest New Drugs 
2012;30:2201-9.


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16.
Zhou D, Teofilovici F, Liu Y, et al. Associating retinal drug exposure and 
retention with the ocular toxicity profiles of Hsp90 inhibitors. ASCO Meeting Abstracts 
2012;30:3086.
17.
Cysyk RL, Parker RJ, Barchi JJ, Jr., Steeg PS, Hartman NR, Strong JM. Reaction 
of geldanamycin and C17-substituted analogues with glutathione: product identifications 
and pharmacological implications. Chem Res Toxicol 2006;19:376-81.
18.
McGuire WP RE, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, 
Donehower RC  Taxol: a unique antineoplastic agent with significant activity in 
advanced ovarian epithelial neoplasms Ann Intern Med 1989;111:273-9.
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Thigpen JT, Blessing JA, Ball H, Hummel SJ, Barrett RJ. Phase II trial of 
paclitaxel in patients with progressive ovarian carcinoma after platinum-based 
chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 1994;12:1748-53.
20.
Fennelly D, Aghajanian C, Shapiro F, et al. Phase I and pharmacologic study of 
paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 
1997;15:187-92.
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Markman M, Hall J, Spitz D, et al. Phase II Trial of Weekly Single-Agent 
Paclitaxel in Platinum/Paclitaxel-Refractory Ovarian Cancer. J Clin Oncol 2002;20:2365- 
9.
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Dunder I BB, Atabekoglu C, Bilgin T. Preliminary experience with salvage 
weekly paclitaxel in women with advanced recurrent ovarian carcinoma. Eur J Gynaecol 
Oncol 2005;26:79-82.
23.
Ghamande S LS, Marchetti D, Baker T, Odunsi K. Weekly paclitaxel in patients 
with recurrent or persistent advanced ovarian cancer. Int J Gynecol Cancer 2003;13:142- 
7.
24.
Kita T, Kikuchi Y, Takano M, et al. The effect of single weekly paclitaxel in 
heavily pretreated patients with recurrent or persistent advanced ovarian cancer. Gynecol 
Oncol 2004;92:813-8.
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Le T, Hopkins L, Baines KA, Rambout L, Al Hayki M, Kee Fung MF. 
Prospective evaluations of continuous weekly paclitaxel regimen in recurrent platinum- 
resistant epithelial ovarian cancer. Gynecol Oncol 2006;102:49-53.
26.
Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, Waggoner S. Phase II 
trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and 
primary peritoneal cancers: A Gynecologic Oncology Group study. Gynecol Oncol 
2006;101:436-40.
27.
Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, Waggoner S. Phase II 
trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and 
primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol 
2006;101:436-40.
28.
Young JC, Agashe VR, Siegers K, Hartl FU. Pathways of chaperone-mediated 
protein folding in the cytosol. Nature reviews Molecular cell biology 2004;5:781-91.
29.
Hubbard J, Erlichman C, Toft DO, et al. Phase I study of 17-allylamino-17 
demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid 
tumors. Invest New Drugs 2011;29:473-80.
30.
Powers MV, Jones K, Barillari C, Westwood I, van Montfort RL, Workman P. 
Targeting HSP70: the second potentially druggable heat shock protein and molecular 
chaperone? Cell Cycle 2010;9:1542-50.


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31.
Dakappagari N, Neely L, Tangri S, et al. An investigation into the potential use of 
serum Hsp70 as a novel tumour biomarker for Hsp90 inhibitors. Biomarkers 2010;15:31- 
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Zhang H, Chung D, Yang YC, et al. Identification of new biomarkers for clinical 
trials of Hsp90 inhibitors. Mol Cancer Ther 2006;5:1256-64.
33.
Burgess EF, Ham AJ, Tabb DL, et al. Prostate cancer serum biomarker discovery 
through proteomic analysis of alpha-2 macroglobulin protein complexes. Proteomics Clin 
Appl 2008;2:1223.
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Chen JS, Hsu YM, Chen CC, Chen LL, Lee CC, Huang TS. Secreted heat shock 
protein 90alpha induces colorectal cancer cell invasion through CD91/LRP-1 and NF- 
kappaB-mediated integrin alphaV expression. J Biol Chem 2010;285:25458-66.
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Sun Y, Zang Z, Xu X, et al. Differential proteomics identification of HSP90 as 
potential serum biomarker in hepatocellular carcinoma by two-dimensional 
electrophoresis and mass spectrometry. Int J Mol Sci 2010;11:1423-33.
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efficacy outcome measures to screen regimens for activity in two-stage Phase II clinical 
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Appendices:
Appendix I New York Heart Association Classification 
Functional  Class Description
0
No cardiac disease or limitations
I
Patients with cardiac disease but without limitations of physical activity.
Ordinary physical activity does not cause undue fatigue, dyspnea or palpitation.
II
Patients with cardiac disease that results in slight limitations of physical activity.
Ordinary physical activity results in fatigue, palpitation, dyspnea or angina.
III
Patients with cardiac disease that results in marked limitation of physical activity.
Although patients are comfortable at rest, less than ordinary activity will lead to 
symptoms.
IV
Patients with cardiac disease that results in an inability to carry on physical 
activity without discomfort. Symptoms of congestive heart failure are present 
even at rest. With any physical activity, increased discomfort is experienced.
Appendix II Management of Events of Special Interest
Management of Gastrointestinal Adverse Events
Many patients will experience diarrhea, and some patients may experience Grade 3 or 4 
diarrhea.  The following proactive and ongoing management principles are necessary to 
avoid more serious complications of diarrhea. However, guidelines such as these should 
never replace sound clinical judgment.
Experience suggests that diarrhea is an expected drug class effect for Hsp90 inhibitors 
and it typically starts 2 to 3 hours following administration of ganetespib in most patients. 
However, when appropriately managed with anti-diarrheal treatment, it is generally mild 
to moderate and its duration limited to 24 hours.
Diarrhea must be proactively managed for all patients treated with ganetespib to 
avoid complications or worsening of the patient’s condition. Without appropriate 
prophylactic treatment, the diarrhea can be prolonged, severe, and lead to severe 
dehydration and other complications.  Loperamide 2 mg must be given 
prophylactically, starting approximately 1 to 2 hours before ganetespib administration, 
to be repeated every 4 hours for the first 12 hours.
In the event of diarrhea, patients should take loperamide at an initial 4 mg dose, followed 
by 2 mg doses every 4 hours.  In the presence of uncomplicated Grade 1 or 2 diarrhea,


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loperamide should be continued until the patient is free from diarrhea for 12 hours.  The 
total daily dose may not exceed 16 mg (8 capsules).
For Grade 3 or 4 diarrhea or complicated Grade 1 or 2 diarrhea (severe cramping, severe 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, 
frank bleeding, dehydration), IV fluids should be used as appropriate, as well as 
prophylactic antibiotics.
Ganetespib Premedication and Management of Hypersensitivity 
Reactions
Generally, ganetespib does not require premedication for hypersensitivity reactions. 
However, ganetespib contains a surfactant (polysorbate 80) that has been associated with 
hypersensitivity reactions in other medications administered by infusion.  Symptoms 
have included pruritus, flushing, shortness of breath, chest tightness, dizziness, headache, 
increased systolic blood pressure, and heart rate.
If an infusion reaction is suspected, the following is provided as guidance only; treatment 
will be based on clinical presentation. Institution-specific premedication and/or treatment 
procedures and regimens may also be appropriate in lieu of these guidelines:
Mild or Moderate Symptoms:
•
Stop ganetespib administration.
•
Give IV dexamethasone 10 mg and diphenhydramine HCl 25 to 50 mg.
•
After recovery from symptoms, resume ganetespib infusion or re-schedule patient for 
re-treatment as soon as possible.
•
Use premedication for subsequent infusion drug administrations.
Severe Symptoms (such as hypotension requiring pressor therapy or IV fluids, 
angioedema, respiratory distress requiring bronchodilator therapy, or generalized 
urticaria):
•
Stop ganetespib administration.
•
Give IV dexamethasone 10 mg and diphenhydramine HCl 25 to 50 mg, as above.
•
Add adrenaline (1:1000) or bronchodilators, as indicated.
If severe symptoms recur with optimal premedication, treatment with ganetespib must be 
discontinued.
Example of infusion premedication regimen:
•
Dexamethasone 12 mg PO and diphenhydramine HCl 25-50 mg PO approximately 12 
to 24 hours prior to the next dose of study drug
Repeat dexamethasone 12 mg PO and diphenhydramine HCl 25 to 50 mg PO 
approximately 4 to 6 hours prior to the re-challenge