Clinical trial NCT02012192
Conditions: Epithelial Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Cancer
Keywords: High-grade serous high-grade endometrioid undifferentiated
Sponsor: Medical University Innsbruck
Start date: 2014-07-04; Completion date: 2017-12-04
Enrollment: 133 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy causing 41900 deaths annually in Europe. The predominance of aggressive Type II tumours, which are characterised by a high frequency of p53 mutations, and primary or acquired resistance to platinum-based chemotherapy profoundly contribute to the high mortality rate. With current standard therapy the median overall survival of metastatic platinum-resistant (Pt-R) ovarian cancer patients is only 14 month. There is a pressing need for more effective, innovative treatment strategies to particularly improve survival in this subgroup of EOC patients. This is a drug strategy targeting a central driver of tumour aggressiveness and metastatic ability, namely mutant p53, via an innovative new Hsp90 (heat shock protein 90) inhibition mechanism. The most advanced, second-generation Hsp90 inhibitor will be used, Ganetespib. The first part (Phase I) of the GANNET53 trial will test the safety of Ganetespib in a new combination with standard chemotherapy (Paclitaxel weekly) in Pt-R EOC patients. The second part (randomised Phase II) will examine the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone in EOC patients with Pt-R tumours.

Detailed description:

Arms: arm 1: Drug: ganetespib, dose will depend on phase I results, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle); Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression. arm 2: Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression
Interventions: intervention 1: Ganetespib intervention 2: Paclitaxel
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
GANNET53  
 
 
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A two-part, multicentre, international phase I and II trial assessing 
the safety and efficacy of the Hsp90 inhibitor ganetespib in 
combination with paclitaxel weekly in women with high-grade 
serous, high-grade endometrioid, or undifferentiated, platinum-
resistant epithelial ovarian, fallopian tube or primary peritoneal 
cancer 
 
 
GANNET53: Ganetespib in metastatic, p53-mutant, platinum-resistant 
ovarian cancer 
 
A seventh framework programme (FP7) project of the European Union 
(Grant agreement no 602602) 
 
 
Version 1.4 / Date 2 January 2014 
Version 1.5 / Date 16 April 2014 Amendment 1 
Version 1.6 / Date 10 June 2014 Amendment 2 
Version 1.7 / Date 06 February 2015 Amendment 3 
Version 1.8 / Date 11 January 2016 Amendment 4 
Version 1.9 / Date 18 February 2016 Amendment 5 
 
EUDRACT Number: 2013-003868-31 
 
 
 
 


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Confidentiality statement 
The information contained in this protocol, especially unpublished data, is confidential. It is 
therefore provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an Independent Ethics Committee or 
Institutional Review Board. It is understood that this information will not be disclosed to 
others without written authorization from the coordinating investigator Nicole Concin and the 
Austrian AGO trial centre, except to the extent necessary to obtain informed consent from 
those persons to whom the study drug may be administered. 
 


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1. 
CONTACTS & SIGNATURES  
Sponsor  
Medical University of Innsbruck 
Austrian AGO trial centre, Department of Gynaecology and Obstetrics  
Anichstraße 35, 6020 Innsbruck, Austria 
Phone: +43-512-504-24132, Fax: +43-512-504-22458,  
E-mail: ago.studienzentrale@i-med.ac.at 
 
 
_____________________________________ 
 
 
___________________ 
Signature (Univ.-Prof. Dr. Christian Marth)  
 
 
Date 
 
 
_____________________________________ 
 
 
___________________ 
Signature (Mag. Dr. Regina Berger)  
 
 
 
Date 
 
Coordinating investigator  
Univ.-Prof. Dr. Nicole Concin 
Department of Gynaecology and Obstetrics, Medical University of Innsbruck, Austria  
Phone: +43-512-504-23051, Fax: +43-512-504-23055 
E-mail: nicole.concin@i-med.ac.at 
 
 
____________________________________ 
 
 
___________________ 
Signature (Univ.-Prof. Dr. Nicole Concin) 
 
 
 
Date 
 
Statistician 
 
Univ.-Prof. Mag. Dr. Hanno Ulmer 
Department of Medical Statistics, Informatics and Health Economics, Medical University of 
Innsbruck, Austria 
Phone: +43-512-9003-70900, Fax: +43-512-9003-73922 
E-mail: hanno.ulmer@i-med.ac.at 
 
 
____________________________________ 
 
 
___________________  
Signature (Univ.-Prof. Mag. Dr. Hanno Ulmer) 
 
 
Date 
 
Monitor 
 
OE Clinical Trial Centre / Koordinierungszentrum für Klinische Studien 
Medical University of Innsbruck, Austria 
Phone: +43-512-9003-70086, Fax: +43-512-9003-73086 
E-mail: ctc@i-med.ac.at 
 
 
____________________________________ 
 
 
___________________   
Signature (Mag.(FH) Sabine Embacher-Aichhorn)  
 
Date 


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1.1 
Declaration of the sponsor and the coordinating investigator 
 
The present study protocol was subject to critical review. Its content is consistent with the 
current risk/benefit evaluation of the IMP as well as with the moral, ethical and scientific 
principles of good clinical practice, the latest version of the Declaration of Helsinki, the local 
laws and the regulations and the applicable regulatory requirements. 
 
Sponsor 
Univ.-Prof. Dr. Christian Marth 
 
 
 
Place, Date, Signature 
Coordinating investigator 
Univ.-Prof. Dr. Nicole Concin 
 
 
 
Place, Date, Signature 
 
 
The signatories above confirm that they have read this study protocol and agree that it 
contains all information required for study performance. They also agree to conduct the study 
as set out in this protocol. It has been understood that all documentation previously not 
published will be kept in strictest confidence. 
 
 
 
 


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Protocol authorisation – Investigator 
Study title 
 
GANNET53 
A two-part, multicentre, international phase I and II trial assessing the safety and efficacy of 
the Hsp90 inhibitor ganetespib in combination with paclitaxel weekly in women with high-
grade serous, high-grade endometrioid, or undifferentiated,  platinum-resistant epithelial 
ovarian, fallopian tube or peritoneal cancer. 
 
Version: 1. 9 
EudraCT Number: 2013-003868-31 
 
Principal investigator (Name in capital letters) _____________________________________ 
 
I declare that the study mentioned above will be conducted according to AMG/ICH-GCP 
Guidelines (ICH-E6; CPMP/135/95) and the most recent version of the Declaration of 
Helsinki.  
To ensure quality of data, study integrity, and compliance with the protocol and the various 
applicable regulations and guidelines, the sponsor may conduct site visits to institutions 
participating in this study.  
 
I consent to co-operate fully with any quality assurance visit undertaken by third parties, 
including representatives from the sponsor or national and/or foreign regulatory, as well as to 
allow direct access to documentation pertaining to the clinical trial (including CRFs, source 
documents, hospital patient charts and other study files) to these authorised individuals. 
I agree to inform the sponsor immediately in case a regulatory authority inspection is 
scheduled. 
 
 
 
_______________________________________        ______________________________ 
SIGNATURE Principal investigator  
 
 
 
place, date 
 
 
ONLY FOR GERMANY: 
 
 
________________________________________          _____________________________ 
SIGNATURE Substitute of investigator  
 
 
 
place, date 
 
NAME in capital letters: __________________________________________ 
 
 
________________________________________          _____________________________ 
SIGNATURE physician 
 
  
 
 
 
place, date 
 
NAME in capital letters: ___________________________________________         


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2. 
TABLE OF CONTENTS  
1. CONTACTS & SIGNATURES ............................................................................. 3 
1.1 
Declaration of the sponsor and the coordinating investigator ........................ 4 
2. TABLE OF CONTENTS ...................................................................................... 6 
3. PROTOCOL SYNOPSIS ..................................................................................... 9 
Part I: dose escalation/de-escalation phase I study .......................................................13 
Part II: randomised, open-label, two-arm, phase II study ...............................................13 
4. SCHEMATIC DIAGRAM OF THE STUDY DESIGN .......................................... 14 
5. ABBREVATIONS AND DEFINITIONS .............................................................. 15 
6. BACKGROUND INFORMATION....................................................................... 18 
6.1 
Disease ....................................................................................................... 18 
6.2 
Scientific background .................................................................................. 19 
6.3 
The investigational medicinal product ganetespib ....................................... 21 
6.3.1 
Preclinical experience .....................................................................................21 
6.3.2 
Clinical experience ..........................................................................................22 
6.3.3 
Ganetespib synergises with paclitaxel in vitro and in vivo ................................24 
6.3.3.1 
Clinical evidence for combination of taxane + ganetespib ........................24 
6.3.4 
Other clinical data of interest ...........................................................................27 
7. STUDY DESIGN ................................................................................................ 27 
7.1 
Description of study ..................................................................................... 27 
7.2 
Part I: phase I dose escalation/de-escalation study..................................... 27 
7.2.1 
3 + 3 design ....................................................................................................28 
7.2.2 
Dose-limiting toxicity (DLT) at the ganetespib dose level of 75 mg/m2 .............30 
7.3 
Part II randomised, open-label, two-arm phase II study .............................. 30 
7.4 
Subject population ....................................................................................... 31 
7.4.1 
Subject eligibility ..............................................................................................32 
7.4.1.1 
Inclusion criteria .......................................................................................32 
7.4.1.2 
Exclusion criteria ......................................................................................33 
7.5 
Study duration ............................................................................................. 34 
7.6 
End of study ................................................................................................ 35 
7.6.1 
Premature termination of the study ..................................................................35 
7.6.1.1 
Study site discontinuation .........................................................................36 
7.6.2 
Withdrawal and replacement of subjects .........................................................36 
7.6.2.1 
Discontinuation from IMP or non-IMP .......................................................37 
7.6.2.2 
Replacement of patients during part I of the trial ......................................37 
7.6.2.3 
Replacement of patients during part II of the trial .....................................37 
7.7 
Study objectives .......................................................................................... 37 
7.7.1 
Part I: dose escalation/de-escalation phase I study .........................................37 
7.7.2 
Part II: randomised, open-label, two-arm, phase II study .................................38 
7.8 
Randomisation and stratification.................................................................. 38 
7.9 
Statistical analysis ....................................................................................... 39 
7.9.1 
Analysis populations........................................................................................39 
7.9.2 
Part I statistical analysis ..................................................................................39 
7.9.3 
Part II statistical analysis (including sample size calculation) ...........................39 


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7.10 
Risk-benefit considerations ...................................................................... 42 
8. STUDY PROCEDURES ..................................................................................... 43 
8.1 
Before treatment start/screening (days -28 to -1) ........................................ 44 
8.2 
Treatment period ......................................................................................... 45 
8.3 
Part I & II end of treatment/Safety follow-up ................................................ 49 
8.4 
Part I and II long-term follow-up................................................................... 49 
8.4.1 
Long-term FU in patients who discontinues treatment prior to progression ......50 
9. STUDY ASSESSMENTS ................................................................................... 50 
9.1 
Tumour response assessment .................................................................... 50 
9.1.1 
Radiologic tumour assessments ......................................................................51 
9.1.2 
GCIG criteria ...................................................................................................51 
9.2 
Patient-reported outcome (PRO) ................................................................. 52 
9.2.1 
PRO instruments .............................................................................................52 
9.2.2 
PRO assessment schedule .............................................................................52 
9.2.3 
PRO assessment procedure ...........................................................................52 
9.3 
Concomitant medications/therapies ............................................................. 53 
9.4 
Physical examination ................................................................................... 53 
9.5 
Electrocardiography and LVEF .................................................................... 53 
9.6 
Laboratory assessments ............................................................................. 55 
9.7 
Biomarker analysis in part II ........................................................................ 55 
9.7.1 
Determination of p53 status and other biomarkers in collected biomaterials in 
phase II 55 
9.8 
Pharmacokinetic (PK) analysis in Phase II, at selected centres .................. 56 
10. 
STUDY MEDICATION .................................................................................... 58 
10.1 
Dosage and administration ....................................................................... 58 
10.1.1 
Dose reduction levels for ganetespib ...............................................................59 
10.1.2 
Dose reduction levels for paclitaxel .................................................................60 
10.1.3 
Dose modifications ..........................................................................................61 
10.1.3.1 
Dose modification for hypertransaminasaemia (AST/ALT) .......................61 
10.1.3.2 
Dose modification for neutropenia ............................................................61 
10.1.3.3 
Dose modification for hyperbilirubinaemia ................................................62 
10.1.3.4 
Dose modification for thrombocytopenia ..................................................62 
10.1.3.5 
Dose modification for peripheral neuropathy ............................................63 
10.1.3.6 
Dose modification for ganetespib-related gastrointestinal toxicity .............63 
10.1.3.7 
Dose modification for ganetespib-related QTc prolongation .....................63 
10.1.4 
Management guidelines of the most significant AE diarrhoea ..........................64 
10.1.5 
Study drug interruption or discontinuation .......................................................64 
10.1.6 
Dose-limiting toxicity (DLT) in phase I .............................................................65 
10.2 
Summary of known and potential risks of the study drug ganetespib ....... 69 
10.2.1 
Medications used with caution .........................................................................70 
10.2.1.1 
Inhibitors of P-glycoprotein efflux Transporters.........................................70 
10.2.1.2 
Medications associated with QTc interval prolongation ............................70 
10.2.1.3 
Substrates of CYP3A4 or CYP2C19 .........................................................70 
10.3 
Summary of known and potential risks of paclitaxel ................................. 71 
10.3.1 
Study drug delivery & drug storage conditions .................................................72 
10.3.2 
Study drug packaging and labelling .................................................................73 


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10.4 
Concomitant medications ......................................................................... 73 
11. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ..................... 75 
11.1 
Adverse events ........................................................................................ 75 
11.2 
Serious adverse events (SAEs) ............................................................... 75 
11.2.1 
Hospitalisation – Prolongation of existing hospitalisation .................................76 
11.2.2 
Suspected unexpected serious adverse reactions (SUSARs) .........................76 
11.2.3 
Pregnancy .......................................................................................................76 
11.3 
Severity of adverse events/Grading ......................................................... 77 
11.4 
Relationship to study drug ........................................................................ 77 
11.5 
Procedures for recording of adverse events ............................................. 78 
11.5.1 
Diagnosis versus signs and symptoms ............................................................78 
11.5.2 
Persistent or recurrent adverse events ............................................................78 
11.5.3 
Abnormal laboratory values or vital signs ........................................................78 
11.5.4 
Progression of underlying malignancy .............................................................79 
11.6 
Reporting procedures ............................................................................... 79 
11.6.1 
Reporting procedures for SAEs and SUSARs .................................................80 
11.6.2 
Adverse event reporting period .......................................................................81 
11.7 
Handling of safety parameters ................................................................. 81 
11.7.1 
Treatment and follow-up of adverse events .....................................................81 
11.7.2 
Follow-up of abnormal laboratory test value ....................................................81 
12. 
DOCUMENTATION AND DATA MANAGEMENT ......................................... 82 
12.1 
Retention of documents/Investigator site file ............................................ 82 
12.1.1 
Case report form (CRF) ...................................................................................82 
12.2 
Data and safety monitoring committee (DSMC) ....................................... 82 
12.3 
Quality control and quality assurance....................................................... 83 
12.3.1 
Periodic monitoring .........................................................................................83 
12.3.2 
Audit and inspections ......................................................................................83 
12.4 
Reporting and publications ....................................................................... 83 
12.4.1 
Reports ...........................................................................................................83 
12.4.2 
Publication of study results ..............................................................................84 
13. 
ETHICAL AND LEGAL ASPECTS ................................................................ 84 
13.1 
Informed consent of subjects ................................................................... 84 
13.2 
Acknowledgement/Approval of the study ................................................. 84 
13.2.1 
Changes in the conduct of the study ...............................................................85 
13.3 
Insurance ................................................................................................. 85 
13.4 
Ethics and Good Clinical Practice (GCP) ................................................. 85 
14. 
REFERENCES ............................................................................................... 86 
15. 
APPENDICES ................................................................................................ 89 
 
 
 
 


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3. 
PROTOCOL SYNOPSIS 
Title 
A two-part, multicentre, international phase I and II trial assessing the 
safety and efficacy of the Hsp90 inhibitor ganetespib in combination with 
paclitaxel weekly in women with high-grade serous, high-grade 
endometrioid, or undifferentiated, platinum-resistant epithelial ovarian, 
fallopian tube or primary peritoneal cancer 
Short title 
GANNET53 
EudraCT number 
2013-003868-31 
Protocol 
version/date 
V 1.9 
18 February 2016 
Indication 
Women with platinum-resistant, high-grade serous, high-grade 
endometrioid, or undifferentiated epithelial ovarian, fallopian tube or 
primary peritoneal cancer 
Phase/Design 
Part I: 
Prospective, multicentre, international, phase I, dose escalation / de-
escalation study. 
Part II: 
Prospective, multicentre, international, randomised, open-label, two-
arm, phase II study. 
Investigational 
product 
Ganetespib 
Part I: initial dose: 100 mg/m2, target dose: 150 mg/m2 
Part II: 150 mg/m2 
Non-
investigational 
product 
Paclitaxel weekly 
Planned study 
duration 
Part I: 
First patient in: June 2014 
 
Part II: 
First patient in: April 2015 
 
Estimated study duration: 66 months 
Number of 
patients 
Part I:   10 patients 
Part II:  222 patients 
Sites / Countries  12 sites in 4 countries (Austria, Belgium, France, Germany) 
 


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Inclusion criteria 
 
Patients must meet the following criteria to be eligible for study entry: 
 
 
Ability to understand and willingness to sign and date a written 
informed consent document 
 
Female patients ≥18 years of age 
 
High-grade serous, high-grade endometrioid, or undifferentiated 
epithelial ovarian, fallopian tube or primary peritoneal cancer. 
o Patients 
in 
part 
II: 
High-grade 
serous, 
high-grade 
endometrioid, or undifferentiated epithelial ovarian, fallopian 
tube or primary peritoneal cancer confirmed by central 
histopathology through archival FFPE  
 
Platinum-resistant disease: 
o primary platinum-resistant disease: progression > 1 month 
and ≤ 6 months after completion of primary platinum-based 
therapy 
o secondary platinum-resistant disease (including secondary 
platinum-refractory disease): progression ≤ 6 months after 
(or during) reiterative platinum-based therapy 
 
Patients must have disease that is measurable according to RECIST 
1.1 or assessable according to the GCIG CA-125 criteria, and 
require chemotherapy treatment ECOG performance status of 0-1  
 
Life expectancy of at least 3 months as assessed by the investigator 
 
Adequate function of the bone marrow: 
o Platelets ≥ 100 x 109/L  
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 
Haemoglobin ≥ 8.5 g/dl. Patients may receive blood transfusion(s) to 
maintain haemoglobin values > 8.5 g/dl.  
 
Adequate organ functions: 
o Creatinine < 2 mg/dl (<177 µmol/L) 
o Total bilirubin ≤ 1.5 x upper limit of normal 
o SGOT/SGPT (AST/ALT) ≤ 3 x upper limit of normal 
o Urinanalysis or urine dipstick for proteinuria less than 2+. 
Patients with ≥ 2+ on dipstick should undergo 24-hour urine 
collection and must demonstrate < 1 g of protein/24 hours; 
except the proteinuria is clearly related to a catheter in the 
urinary system. 
 
Adequate coagulation parameters: aPTT ≤ 1.5 x ULN (patients on 
heparin treatment must have an aPTT between 1.5 – 2.5 x ULN), or 
INR ≤ 1.5. (In patients receiving anticoagulants (such as warfarin) 
INR must be between 2.0 and 3.0 in two consecutive measurements 
1-4 days apart). 
 
Negative urine/serum pregnancy test in women of childbearing 
potential (WOCBP, see section 5). WOCBP who are sexually active, 
agree to use highly-effective means of contraception during the 
study and for at least 6 months post-study treatment. Allowed are 
accepted and effective non-hormonal methods of contraception and 
sexual abstinence or vasectomised partners (> 3 months 


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previously). Vasectomy has to be confirmed by two negative semen 
analyses. 
 
Only in part II of the trial:  
 
Availability 
of 
archival 
ovarian 
cancer 
tissue 
for 
central 
histopathological review and p53 mutational analysis 
 
Exclusion criteria 
 
Patients who meet any of the following criteria will be excluded from 
study entry: 
 
CANCER-RELATED: 
 
Ovarian tumours with low malignant potential (i.e. borderline 
tumours) 
 
Carcinosarcoma of the ovary 
 
Primary platinum-refractory disease (progression during primary 
platinum-based chemotherapy) 
 
PRIOR, CURRENT OR PLANNED TREATMENT: 
 
Previous treatment with > 2 chemotherapy regimens in the platinum-
resistant setting (excluding targeted and endocrine therapies). 
 
Previous weekly paclitaxel in relapse treatment 
 
More than 4 previous lines of chemotherapy.  
 
Any prior radiotherapy to the pelvis or abdomen 
 
Surgery (including open biopsy and traumatic injury) within 4 weeks 
prior to first dose of ganetespib, or anticipation of the need for major 
surgery during study treatment 
 
Minor surgical procedures, within 24 hours prior to the first study 
treatment 
 
Current or recent (within 10 days prior to the first study drug dose) 
chronic daily treatment with aspirin (>325 mg/day). 
 
Chronic daily treatment with corticosteroids (dose >10 mg/day 
methylprednisolone equivalent), excluding inhaled steroids. 
 
PRIOR OR CONCOMITANT CONDITIONS OR PROCEDURES: 
 
Patients with a history of prior malignancies, except:  
o disease-free time-frame of ≥ 3 years prior to randomisation. 
 
Patients with prior in-situ carcinomas, except: 
o  complete removal of the tumour is given 
 
Known history of severe (grade 3 or 4) allergic or hypersensitivity 
reactions to excipients (e.g. polyethylene glycol [PEG] 300 and 
Polysorbate 80)  
 
History of intolerance or hypersensitivity to paclitaxel and/or adverse 
events related to paclitaxel that resulted in paclitaxel being 
permanently discontinued 
 
Peripheral neuropathy of grade > 2 per NCI CTCAE, version 4.03, 
within 4 weeks prior to randomisation 
 


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 
Clinically significant gastro-intestinal (GI) tract abnormalities that 
may increase the risk for GI bleeding and/or perforation including but 
not limited to: active peptic ulcer disease, known intraluminal 
metastatic lesion/s with risk of bleeding, inflammatory bowel disease 
(e.g. ulcerative colitis, Crohn’s disease), history of bowel obstruction 
within 1 year prior to first study treatment (excluding postoperative, 
i.e. within 4 weeks post surgery), other GI condition with increased 
risk of perforation such as a recurrence deeply infiltrating into the 
muscularis or mucosa of the rectosigmoid or the mucosa of the 
bladder, or history of abdominal fistula, gastrointestinal perforation or 
intra-abdominal abscess  
 
Non-healing wound or non-healing bone fracture 
 
Patients with symptomatic brain metastases 
 
Left ventricular ejection fraction defined by ECHO below the 
institutional lower limit of normal 
 
Cerebrovascular accident (CVA) / stroke or transient ischemic attack 
(TIA) or sub-arachnoid haemorrhage within ≤6 months prior to first 
study treatment. 
 
Significant cardiac disease: New York Heart Association (NYHA) 
Class 3 or 4; myocardial infarction within the past 6 months; 
unstable angina; coronary angioplasty or coronary artery bypass 
graft (CABG) within the past 6 months; or uncontrolled atrial or 
ventricular cardiac arrhythmias. 
 
History of prolonged QT syndrome, or family member with prolonged 
QT syndrome 
 
QTc interval > 470 msec when 3 consecutive ECG values are 
averaged 
 
Ventricular tachycardia or a supraventricular tachycardia that 
requires treatment with a Class Ia antiarrhythmic drug (e.g. 
quinidine, procainamide, disopyramide) or Class III antiarrhythmic 
drug 
(e.g. 
sotalol, 
amiodarone, 
dofetilide). 
Use 
of 
other 
antiarrhythmic drugs is permitted 
 
Second- or third-degree atrioventricular (AV) block, except: 
o treated with a permanent pacemaker 
 
Complete left bundle branch block (LBBB) 
 
History of evidence of haemorrhagic disorders, patients with active 
bleeding or pathologic conditions that carry high risk of bleeding, 
such as known bleeding disorders, coagulopathy or tumour involving 
major vessels. 
Any other condition that, in the opinion of the investigator, may 
compromise the safety, compliance of the patient, or would preclude 
the patient from successful completion of the study. 
 
Participation in another clinical study with experimental therapy 
within 28 days before start of treatment.  
 
Women who are pregnant or are lactating 


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Endpoints 
 
Part I: dose escalation/de-escalation phase I study 
The primary aim of the phase I study is to determine the safety of 
ganetespib in combination with weekly paclitaxel and also to determine 
the ganetespib combination dose to be used in the randomised phase II 
study. 
 
Primary endpoint: 
• 
Safety: Adverse events (AEs) (measure according to NCI 
CTCAE, 
version 
4.03), 
laboratory 
parameters, 
Eastern 
Cooperative Oncology Group (ECOG) performance status (PS), 
vital signs 
 
Secondary endpoint: 
• 
Objective response rate (ORR) 
• 
Progression-free survival (PFS) 
Part II: randomised, open-label, two-arm, phase II study 
The primary aim of the phase II study is to determine efficacy of 
ganetespib in combination with weekly paclitaxel compared to weekly 
paclitaxel alone. 
 
Primary endpoint: 
• 
Progression-free survival (PFS) and PFS rates at 6 months 
 
Secondary endpoints:  
• 
Overall survival (OS), 
• 
Objective response rate (ORR): best ORR, confirmed ORR 
• 
Post-progression PFS (PFS II) 
• 
Patient-reported outcome: EORTC C30, EORTC OV28, and 
additional items 
• 
Safety: AEs (according to NCI CTCAE, version 4.03), laboratory 
parameters, ECOG PS, vital signs 
• 
Pharmacokinetics (only in 30 patients in selected sites) 
o evaluate the possible effects of paclitaxel on ganetespib 
pharmacokinetics 
o evaluate the possible effects of ganetespib on paclitaxel 
pharmacokinetics 
o quantify 
ganetespib 
and 
ganetespib 
metabolite 
exposures in the presence of paclitaxel  
 
Exploratory endpoints 
• 
Molecular efficacy analysis 
• 
Biomarker analysis e.g. p53 status on DNA, RNA and protein 
level 


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4. 
SCHEMATIC DIAGRAM OF THE STUDY DESIGN 
Part I 
 
 
Part II 
 
 
 


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5. 
ABBREVATIONS AND DEFINITIONS 
17AAG 
17-allylamino-17-demethoxygeldanamycin 
AE 
adverse events 
AGO 
Arbeitsgemeinschaft Gynäkologische Onkologie 
Akt 
protein kinase B 
ALT (SGPT) 
alanine-aminotransferase 
ALK 
anaplastic lymphoma kinase 
AMG 
Arzneimittelgesetz (Austrian Drug Law, German Drug Law) 
ANC 
absolute neutrophil count 
AP 
alkaline phosphatase 
AST (SGOT) 
aspartate-aminotransferase 
ATPase 
adenosine triphosphatase 
AUC 
area under the curve  
bcr-abl 
fusion gene 
BRAF 
v-raf murine sarcoma viral oncogene homolog B 
BSA 
body surface area 
B-Raf 
proto-oncogene 
CA 
Competent Authority 
CA-125 
carbohydrate antigen 125 
CABG 
coronary artery bypass graft  
CDK4 
cyclin-dependent kinase 4 
Cmax 
maximum drug concentration  
c-MET 
proto-oncogene 
CRF 
case report form 
CRO 
clinical research organisation 
c-Src 
proto-oncogene tyrosine-protein kinase Src 
CT 
computed tomography 
CTC 
circulating tumour cells  
CTCAE 
common terminology criteria for adverse events 
CTNNB1 
catenin (cadherin-associated protein), beta 1 
CYP 
cytochrome protein 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DSMC 
data and safety monitoring committee 
EC 
Ethics Committee 
ECG 
electrocardiography 
ECOG PS 
Eastern Co-Operative Oncology Group performance status 
EGFR 
epidermal growth factor receptor 
EOC 
epithelial ovarian cancer 
EORTC 
European Organisation for Research and Treatment of Cancer  
EOS 
end of study 
EOT 
end of treatment 
EpCAM 
epithelial cell adhesion molecule 
ERBB2 
v-erb-b2 avian erythroblastic leukaemia viral oncogene homolog 2 


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FP6 
6th framework programme 
FPI 
first patient in 
GCIG 
Gynaecologic Cancer Intergroup 
GCP 
Good Clinical Practice  
GI 
gastrointestinal  
GOF 
gain-of-function 
GOG 
Gynaecologic Oncology Group 
HER2 
human epidermal growth factor receptor 2 
HGS 
high-grade serous  
HR 
hazard ratio 
Hsp90 
heat shock protein 90 
Hsp90i 
Hsp90 inhibitor 
ICH 
International Conference of Harmonisation  
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IMP 
investigational medical product 
IRB 
institutional review board 
IST 
investigator-sponsored clinical trial  
ITT 
intention-to-treat 
iv 
intravenous  
KIT 
signalling protein 
KRAS 
v-ki-ras2 kirsten rat sarcoma viral oncogene homolog 
LCK 
lymphocyte-specific protein tyrosine kinase 
LDH 
lactate dehydrogenase 
LLT 
lower level terms 
M 
month 
MDM2 
mouse double minute 2 homolog 
MedDRA 
Medical Dictionary for Regulatory Activities  
MRI 
magnetic resonance imaging 
MUC1 
mucin 1 
mutp53 
mutant p53 
NCI 
National Cancer Institute 
NSCLC 
non small cell lung cancer 
NYHA 
New York Heart Association  
ORR 
objective response rate 
OS 
overall survival 
p53 
tumour protein 
PCR 
polymerase chain reaction  
PET 
positron emission tomography 
PFS 
progression-free survival 
PICCS 
peripherally-inserted central catheters 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha 
PK 
pharmacokinetics 
PLA 
proximity ligation assay  
PLD 
pegylated liposomal doxorubicin 
PROC 
platinum-resistant ovarian cancer 


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PRO 
patient-reported outcome 
PTEN 
phosphatase and tensin homolog 
Pt-R 
platinum-resistant 
QT 
interval between Q wave and T wave in the hearts electrical cycle 
R172H 
hot-spot mutation in human tumours 
RBC 
red blood cells 
RECIST 
response evaluation criteria in solid tumours 
SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid  
SOP 
standard operating procedures 
SGOT 
serum glutamate-oxaloacetate-transaminase 
SGPT 
serum glutamate-pyruvate-transaminase 
SUSAR 
suspected unexpected serious adverse reaction 
TCGA 
Cancer Genome Atlas Research Network  
TdP 
Torsades de Pointes 
UGT 
uridine diphosphate-glucuronosyltransferase 
ULN 
upper limit of normal 
VAD 
vascular access devices  
VEGFR 
vascular endothelial growth factor receptors 
WBC 
white blood cells 
WHO  
World Health Organization  
WOCBP 
women of childbearing potential 
wtp53 
wild type p53 
 
 
Definitions 
 
Women of childbearing potential (WOCBP): is defined as premenopausal women or less 
than 12 months of amenorrhoea post-menopause, and women who have not undergone 
surgical sterilisation or hysterectomy or bilateral salpingo-oophorectomy.  
 
 
 


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6. 
BACKGROUND INFORMATION 
6.1 
Disease 
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy. Recent data 
from the EUROCARE database showed an age-standardised 5-year overall survival rate of 
EOC patients of only 36.1% (95% CI 35.4–36.8; (1)). Across Europe 66,700 women are 
diagnosed with ovarian cancer and 41,900 die of the disease every year. This high mortality 
rate is due to the predominance of late-stage diagnoses, a high relapse rate after primary 
therapy and poor response of metastatic platinum-resistant tumours to current regimens. 
70% of EOC patients present with metastasised disease at the time of primary diagnosis 
(peritoneal carcinosis). The current standard of primary therapy is cytoreductive surgery and 
adjuvant platinum-based chemotherapy. The addition of bevacizumab has recently been 
shown to improved progression-free survival in women with ovarian cancer (2;3). Initial 
response rates to primary therapy are high, but inevitably the vast majority of patients will 
relapse within a short period of time and ultimately die of the disease. 
 
A major treatment obstacle is the 25-30% of patients who are resistant to first-line 
platinum-based chemotherapy. By definition, they experience progressive or persistent 
disease during initial platinum-based therapy (primary platinum-refractory), or relapse of 
disease after less than 6 months after completion of first-line platinum-based therapy 
(primary platinum-resistant). Eventually most patients will become resistant to platinum after 
repetitive therapy with platinum-based regimens (secondary platinum-resistant disease). 
 
Treatment options are limited for platinum-resistant (Pt-R) patients. There is general 
consensus that surgery is only indicated in selected cases, where palliation of symptoms has 
priority (4). No “standardised” chemotherapy is currently available and systemic treatment is 
highly dependent on the physician’s choice. A number of cytotoxic agents including non-
pegylated or pegylated liposomal doxorubicin (PLD), topotecan, gemcitabine and alkylating 
agents such as treosulphan or cyclophosphamide have shown a relatively modest anti-
tumour activity as single agent. This is reflected by low response rates < 20% for each agent 
and only short lasting remissions (5;6). However, paclitaxel given as single agent on a 
weekly basis at a dose of 80-90 mg/m2/week, proved to be one of the most effective 
regimens in this situation, with response rates in the range of 20-60% (7) (Richard et al, 
Nature Reviews Clinical Oncology 7:575-82, 2010). This efficacy is even seen in cases that 
exhibit resistance to paclitaxel administered every 3 weeks. It is noteworthy that the weekly 
schedule is by far less toxic. However, the progression-free interval may be short. 
The large subgroup of ovarian cancer patients with PROC disease face particularly dismal 
survival rates with a median progression-free survival of 4 months and a median overall 
survival of only 14 months that did not improve in over 10 years (8). In sum, there is a 
pressing need for truly innovative and more effective treatment strategies to improve the 
survival in ovarian cancer patients with metastatic Pt-R disease. 
 
Data from clinicopathological and molecular studies performed to date led to a model in 
which EOC can be divided into two broad categories, designated type I and type II tumours 
(9;10). In this model, type I and type II refer to critical molecular tumorigenic pathways and 
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Type II tumours are highly aggressive. They evolve rapidly, have a high metastatic activity 
and therefore have almost always already spread beyond the ovaries at primary diagnosis. 
Thus, this tumour type is the most problematic from a clinical point of view. Moreover, type II 
tumours account for the overwhelming majority (>70%) of epithelial ovarian cancer (EOC). 
Histologically, type II tumours are mainly high-grade serous (HGS) carcinomas, and the 
remainder are high-grade endometrioid, undifferentiated carcinomas or a subset of clear cell 
carcinomas. HGS carcinoma accounts for ~ 85 % of all ovarian cancer deaths. 
Importantly, type II tumours are characterised by the near ubiquitous presence of p53 
mutations - their preeminent molecular hallmark, which in contrast are very rare in type I 
tumours. This strongly suggests that mutp53 is a central oncogenic driver in the 
pathogenesis of these tumours. Ahmed et al (11) sequenced exons 2-11 and intron-exon 
boundaries in DNA from 145 patients with HGS tumours and identified p53 mutations in 
96.7% of cases. Also, the Cancer Genome Atlas Research Network (TCGA) completed 
whole-exome sequencing on an unprecedented 316 cases of HGS tumours and established 
that p53 mutations are present in > 96 % (12). 
In sharp contrast, type I tumours almost always lack p53 mutations, but often harbour 
somatic mutations of protein kinase genes including PIK3CA and ERRB2, and other 
signalling molecules including KRAS, BRAF, CTNNB1 and PTEN (13). Type I tumours are 
slow-growing, often confined to the ovary at diagnosis, and develop in a stepwise fashion 
from well-recognised precursors, in most cases borderline tumours. Type I tumours include 
low-grade serous carcinomas, low-grade endometrioid carcinomas, mucinous carcinoma and 
a subset of clear cell carcinomas. 
Based on the fact that type II tumours are the most lethal and the most prevalent EOC type 
and that mutp53 is the central oncogenic driver in these tumours, we will apply our novel 
therapeutic approach in a stratified molecularly-defined patient population with high-grade 
serous, high-grade endometrioid and undifferentiated EOC. This offers the highest potential 
for achieving the most profound survival benefit. 
 
6.2 
Scientific background  
Stabilised mutant p53 protein (mutp53) is a novel, rational and potent druggable target in 
cancer treatment.  
 
Missense mutp53 proteins (which make up > 85% of all p53 mutations) not only lose their 
tumour suppressor function, but often acquire new oncogenic functions (gain-of-function, 
GOF) to actively drive higher proliferation, metastatic ability and chemoresistance. 
 
Compelling new evidence from mutp53 knock-in (KI) mice carrying human hotspot mutations 
provide definitive genetic proof for GOF in vivo (14-16): The knock-in mice show a broader 
tumour spectrum including adenocarcinomas, higher tumour bulk, grade and invasion, 
multiple tumour types per mouse, and newly gained metastatic ability compared to the 
traditionally used p53 null mice (knock-out) that mainly get T-lymphomas and never 
metastasise. 
 
Constitutive stabilisation is the hallmark of (full-length missense) mutp53 proteins in 
tumour cells and their aberrant accumulation is the prerequisite for exerting GOF. 
Most importantly, mutp53 cancers develop a strong dependency on high levels of 
mutp53 for survival (‘addiction’ to mutp53). This was recently proven with KI mice. 


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 
As a consequence, acute withdrawal of mutp53 triggers strong spontaneous 
cytotoxicity, blocking invasion and metastasis and restoring chemotherapy-induced 
cell death in human cancer xenografts in vivo (17-20). 
Due to their aberrant conformation mutp53 proteins depend on permanent folding support by 
the multi-component HspP90 chaperone machinery (which in turn is constitutively activated 
in tumour but not in normal cells), and it is this stable interaction between mutp53 and Hsp90 
that is largely responsible for mutp53 accumulation specifically in tumour cells (Figure 1). 
Pharmacological inhibition of the machine’s core ATPase Hsp90 (such as by the highly 
potent second generation Hsp90 inhibitor ganetespib) destroys the complex between Hsp90 
and mutp53, thereby liberating mutp53 and inducing its degradation by MDM2 and CHIP E3 
ubiquitin ligases. As a consequence, Hsp90 blockade shows preferential and strong 
cytotoxicity for mutp53 cancer cells in culture and in xenografts. In contrast, wtp53 or nullp53 
cells show only minimal responses. Moreover, Hsp90 blockade - by virtue of depleting 
mutp53 - dramatically sensitises mutp53 cancer cells to chemotherapeutics. Thus, Hsp90 
inhibition mediates effective destabilisation and degradation of mutp53 in human tumour 
cells, acutely withdrawing an oncoprotein these cells depend on for survival. This is strongly 
cytotoxic in mutp53 harbouring tumour cells. Given the advanced development of Hsp90 
inhibitors, this new paradigm holds immediate strong translational potential for significantly 
improving outcome in mutp53-driven cancers such as type II EOC. 
 
Figure 1: Scientific principle of the GANNET53 trial (18). 
Destabilisation of mutant 
p53 protein by inhibition of 
the 
Hsp90 
chaperone 
causes 
subsequent 
degradation by MDM2 or 
CHIP E3 ligases: Stable 
complex 
formation 
with 
Hsp90 
causes 
aberrant 
stabilisation of mutp53 in 
cancer cells. MDM2 and 
CHIP, which in principle are 
capable 
of 
degrading 
mutp53, 
are 
unable 
to 
degrade mutp53 as long as 
it 
is 
protected 
by 
the 
complex (‘caging’). Stabilised mutp53 exerts oncogenic gain-of-function (GOF). Acute 
depletion of mutp53 in tumour cells is strongly cytotoxic in all mutp53 solid cancer cell types 
tested (ovarian, breast, colon, and prostate). Small molecule inhibitors of the Hsp90 ATPase 
(such as the highly potent second generation Hsp90i ganetespib, or the weaker first 
generation 17AAG + SAHA [causes Hsp90 inhibition via HDAC6 inhibition, an obligate 
positive regulator of the Hsp90 ATPase]) acutely deplete mutp53, which is strongly cytotoxic 
in mutp53 harbouring tumour cells. 
 
Hsp90 chaperone alterations in cancer: essential adaptive response to the malignant lifestyle 
and a second alteration that accounts for stabilisation of mutant p53 protein upon malignant 
transformation. 
Molecular chaperones from the heat shock family (Hsp) - in particular the multi-component 
Hsp90 machine (which includes Hsp90 and Hsp70 ATPases, co-chaperones, CHIP) - are 
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mature proteins. Intimately linked to this support function is that Hsp90 interactions also 
regulate protein levels of their clients (21). By a poorly understood mechanism the 
chaperone-associated E3 ubiquitin ligase CHIP can under certain conditions bind to Hsp90 
and Hsp70 and promote degradation of a number of Hsp90-regulated clients, possibly if they 
cannot be rescued. Importantly, the normal Hsp90 function is subverted during oncogenesis 
to enable maintenance of malignant transformation (‘co-oncogenesis’). This is due to 
massive up-regulation of Hsp90 that almost ubiquitously accompanies malignant 
transformation, and to differences in structure/affinity: Hsp90 purified from tumours has a 
100-fold stronger binding affinity to its inhibitor 17AAG than Hsp90 purified from normal 
tissue, generating a cancer-specific therapeutic window (22). Cancer cells are in a constant 
state of proteotoxic stress, both from an adverse microenvironment (hypoxia, acidosis) and 
from within (conformationally aberrant or over-expressed oncoproteins such as ErbB2, bcr-
abl, Akt and ALK fusions; high reactive oxygen species, spontaneous DNA damage, 
aneuploidy) - and require massive chaperone support to prevent oncoprotein aggregation 
and degradation and to promote cell survival. Hsp90 plays a key role in conformational 
stabilization of many mutant oncoprotein signalling clients and is a powerful anti-apoptotic 
system. Hence, in addition to their oncogene addiction, cancer cells are addicted to massive 
Hsp90 chaperone support (23). 
 
6.3 
The investigational medicinal product ganetespib 
Ganetespib (Figure 2) exhibits its function by competitively inhibiting the ATPase activity of 
the Hsp90 core protein. The multicomponent Hsp90 (which includes Hsp90 and Hsp70 
ATPases, co-chaperones, CHIP) is a molecular chaperone machine from the heat shock 
family and includes many important signalling proteins that cancers depend on, such as 
chimeric Alk, Akt, bcr-abl, B-Raf, CDK4, KIT, c-MET, c-Src, EGFR, LCK, HER2 and VEGFR. 
Of central importance is the fact that mutp53 was recently found to be a Hsp90 client (24;25). 
In vitro, ganetespib leads to degradation of oncogenic client proteins and is a potent inducer 
of cell death in many cancer cell lines that depend on high levels of the respective client. 
In vivo, it inhibits the growth of human tumour cell lines in mouse xenograft models. 
 
 
Figure 2: Chemical structure of ganetespib, chemical name: 5-
[2,4-dihydroxy-5-(1-methylethyl)phenyl]-2,4 dihydro-4-(1-methyl-1H-
indol-5-yl)-3H-1,2,4-triazole-3-one. Ganetespib is a novel triazolone 
heterocyclic compound. Its molecular formula is C20H20N4O3. 
Ganetespib is a white-to-off-white solid with a molecular weight of 
364.40 g/mol. 
 
6.3.1 
Preclinical experience 
ABSORPTION, DISTRIBUTION, METABOLISM AND ELIMINATION:  
A series of nonclinical pharmacokinetic studies have been conducted in mice, rats, and 
monkeys. Ganetespib serum levels generally increased in a dose-proportional manner in all 
species after intravenous (iv) administration. No significant gender differences were 
observed. In mice, ganetespib’s terminal half-life was about 4 hours after intravenous 


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administration. In rats, ganetespib’s terminal half-life ranged from 2.8 to 12.6 hours. In 
monkeys, its terminal half-life was 6.3 to 12.3 hours. Ganetespib did not appear to 
accumulate after repeat dosing. There was minimal cytochrome P450 (CYP) involvement in 
the metabolism of ganetespib. The major metabolites were glucuronide conjugates. 
Radioactively labelled ganetespib in rats was widely distributed throughout the body except 
in the brain. Ganetespib-associated radioactivity was mainly excreted via faeces in rats, and 
via faeces and urine in monkeys. Ganetespib was extensively bound to plasma proteins in 
rats, monkeys and humans. Ganetespib appears to be an inhibitor of CYP2C19 and CYP3A4 
(midazolam-specific), but does not appear to be an inducer of CYP or uridine diphosphate-
glucuronosyltransferase (UGT) enzymes. 
 
TOXICOLOGY:  
Several studies have been conducted in animals to assess the safety of ganetespib. Acute 
toxicity studies revealed that rats survived a single 30 mg/kg dose of ganetespib. Ganetespib 
at doses of 85 or 250 mg/kg elicited more pronounced effects, including morbidity and 
mortality. Histopathological findings were present in the spleen, thymus, adrenal glands, 
gastrointestinal (GI) tract, and the epiphyseal regions of the bones. High-dosed rats allowed 
to recover for 14 days generally returned to normal, although some effects persisted. In rats 
dosed with 30 mg/kg all findings reversed by 14 days. The maximum tolerated single-
administration dose in cynomolgus monkeys was 11 mg/kg; clinical findings at that dose 
included emesis, watery faeces, and decreased activity. There was also a transient decrease 
in absolute lymphocyte counts. At 15 mg/kg, the clinical signs above were more pronounced 
and full recovery required 14 days. 
Ganetespib administered once weekly at 4, 7 or 10 mg/kg for four weeks was generally well 
tolerated by cynomolgus monkeys. One female monkey given 10 mg/kg was euthanized after 
three doses due to ganetespib-related toxicity. Monkeys that were analysed to scheduled 
necropsy had clinical signs that were mild and included soft or liquid faeces. Target organs 
identified in the treated groups were stomach, gallbladder, testes and the sternal bone 
marrow; histopathologic changes included degeneration, apoptosis/single cell necrosis and 
decreased spermatogenesis/spermiogenesis. After four weeks of dosing-free recovery, all 
changes in the stomach and sternal bone marrow had resolved completely, while in the 
gallbladder and testes the changes had resolved partially. The mean exposure (AUC 0-24 h) 
in monkeys after four weekly doses of ganetespib at 7 mg/kg was 4729 ng/mL. The highest 
non-severely toxic dose administered once weekly was determined to be 7 mg/kg. In 
addition, a rising-dose cardiovascular assessment in cynomolgus monkeys showed 
acceptable cardiac effects, in particular no QT prolongation (Rising dose cardiovascular 
study, Study No: ECA00170, Charles River).  
6.3.2 
Clinical experience 
Ganetespib has been studied in 10 completed Synta Pharmaceuticals-sponsored clinical 
trials (studies 9090-01, 9090-02, 9090-03, 9090-04, 9090-05, 9090-06, 9090-07, 9090-08, 
9090-09 and 9090-11) and 3 completed Synta-sponsored studies in normal healthy 
volunteers (9090-12, 9090-13, and 9090-15). Ganetespib is currently being studied in 1 
Synta-sponsored clinical trial (9090-14).Ganetespib has also been studied in 27 investigator-
sponsored clinical trials (ISTs), 15 of which are currently enrolling patients and 12 ISTs that 
are closed to enrolment. The majority of ISTs are proof-of-concept studies across a variety of 
tumour types as well as hematologic malignancies. The ISTs currently enrolling include: four 


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phase I studies, six phase I/II studies, three phase II studies, one phase II/III study, and one 
phase III study. Please refer to Investigator’s Brochure and http://clinicaltrials.gov for further 
information. 
As of 21 September 2015, 1524 individuals (patients and normal, healthy volunteers) have 
received at least 1 dose of ganetespib in one of these 41 studies. A total of 402 patients have 
been treated with single-agent ganetespib (studies 9090-01 through study 9090-06, study 
9090-09, and study 9090-11). A total of 412 patients have been enrolled in studies 9090-07 
and 9090-08, of which 222 have been treated with ganetespib in combination with docetaxel. 
Six hundred forty seven (647) patients have been enrolled in study 9090-14, of which 327 
patients received at least one dose of ganetespib. In Synta-sponsored studies of normal 
healthy volunteers, 102 subjects received ganetespib: 8 in the Human Mass Balance study 
(9090-12), 46 in the Thorough QT study (9090-13), and 48 in the DDI study (9090-15). The 
remaining patients (471) have been treated in investigator sponsored trials (ISTs). 
 
PHARMACOKINETICS IN HUMANS: 
The PK of ganetespib, administered at various doses on a weekly or twice weekly schedule, 
are under investigation in three phase I trials. Preliminary data and calculated parameters 
are available from these trials in patients with solid and hematologic tumours and normal 
healthy male subjects, and are summarised 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 
in most studies. In the human mass balance study, where PK sampling was most complete 
and longest (through 96 hours), the mean plasma terminal half-life was 17.9 h (n=8). 
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 tumour 
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 = 0.6680 and 0. 7234 for Cmax and AUC versus dose, respectively). At doses of 
150 mg/m² and 200 mg/m², AUC values of approximately 5600 ng•h/mL and 7600 ng•h/mL 
are generally expected, respectively. At these same doses, Cmax values of approximately 
3800 ng/mL and 5000 ng/mL, respectively, are generally expected. Ganetespib Cmax 
correlates well with AUC (r2 = 0.9309). CL and Vd are approximately constant across 
therapeutic doses. Ganetespib median CL is approximately 27 L/h/m2. 
Two ganetespib glucuronide metabolites (STA-12-0671 and STA-12-0672) were quantified in 
three studies; studies 9090-07 (ganetespib in combination with docetaxel), 9090-12 (human 
mass balance), and 9090-13 (thorough QT). Metabolite STA-12-0671 mean half-life values 
ranged from 11.9 to 27 hours. Metabolite STA-12-0672 mean half-life values ranged from 9.4 
to 17.9 hours. 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).  
In study 9090-12 following a single 1-hour IV infusion of 86 mg/m2 [14C]-ganetespib, median 
Tmax total radioactivity in plasma and whole blood occurred at the end of the IV infusion. Total 
plasma radioactivity half-life was 26.4 hours and 19.6 hours in whole blood. 
Ganetespib was extensively metabolised to STA-12-0671, and moderately metabolised to 
STA-12-0672. Based on the comparison of AUC0-∞, exposure to ganetespib accounted for 
approximately 14% of the total radioactivity in plasma, with exposure to metabolites STA-12-
0671 and STA-12-0672 accounting for approximately 50% and 6% of the total radioactivity, 


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respectively, resulting in the classification of STA-12-0671 as a “major” metabolite according 
to the Metabolites in Safety Testing (MIST) guidance. 
6.3.3 
Ganetespib synergises with paclitaxel in vitro and in vivo 
The combination of ganetespib with the microtubule stabiliser paclitaxel was shown to result 
in synergistic anti-proliferative effects in vitro in the H1975 non-small-cell lung cancer 
(NSCLC) cell line, which expresses an activated and erlotinib-resistant form of the epidermal 
growth factor receptor (EGFRL858R/T790M). This synergistic benefit translated to improved 
efficacy in H1975 xenografts in vivo, with nearly complete inhibition of tumour growth when 
ganetespib was combined with paclitaxel (Figure 3). 
 
Figure 3: In vivo activity of 
ganetespib in combination with 
paclitaxel 
in 
H1975NSCLC 
xenografts 
(26). 
SCID 
(severe 
combined immunodeficiency) mice 
bearing H1975 NSCLC tumours were 
iv dosed with ganetespib (50 mg/kg) 
and paclitaxel (7.5 mg/kg) alone or in 
combination on a 1x/week schedule 
for 3 weeks (arrowheads). Data 
represent the mean and standard 
error of the mean (SEM). Weekly 
administration of ganetespib (50 
mg/kg) and paclitaxel (7.5 mg/kg) 
reduced tumour growth by 45% and 
62%, 
respectively. 
Concurrent 
treatment with both drugs resulted in a significant enhancement of antitumor activity 
compared to either agent alone, blocking tumour growth by 93%.  
 
6.3.3.1 Clinical evidence for combination of taxane + ganetespib 
Two Synta-sponsored trials, one phase I and one ongoing phase IIb/III trial, have 
evaluated/are evaluating the combination of ganetespib + docetaxel. As of 21 September 
2015, 408 patients were treated with this combination. Important (preliminary) results are 
summarised below: 
Phase I (study 9090-07; n=27 patients), pharmacokinetic (PK) study of ganetespib in 
combination with docetaxel in patients with advanced solid malignancies; design: open-label, 
dose-escalation; status: enrolment completed.  
Results: Data from this study established that 150 mg/m2 ganetespib on days 1 and 15 and 
75 mg/m2 docetaxel on day 1 in a 21-day cycle is the recommended combination dose in 
patients with solid tumours. This dose was selected for further study in the phase IIb/III trial. 
The study also demonstrated that the combination of ganetespib + docetaxel was well 
tolerated. The safety profile was similar to that observed in single-agent studies. Under the 
dosing regimen of this study (docetaxel infusion was initiated 1 hour after the end of 
ganetespib infusion), docetaxel PK estimates were similar to those of docetaxel alone (27-
29), indicating absence of drug-drug-interaction (DDI) between ganetespib and docetaxel. 
 


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Phase IIb/III (GALAXY-1; study 9090-08; n=385 patients, 195 received ganetespib), 
randomised study of ganetespib in combination with docetaxel versus docetaxel alone in 
stage IIIb or IV non-small cell lung cancer (NSCLC); study design: randomised, multicentre, 
parallel group study; status: enrolment completed.  
Results: The safety profile of patients treated with the combination of ganetespib and 
docetaxel was generally similar to that of docetaxel alone, consistent with previously reported 
results. The most common AEs, all grades, were neutropenia (46% vs. 43%), diarrhoea 
(46% vs. 15%) and fatigue (29% vs. 26%), for ganetespib and docetaxel (N=123) vs. 
docetaxel alone (N=126), respectively. Diarrhoea was effectively managed with supportive 
care; the incidence of grade 3 or 4 diarrhoea was 3% (ganetespib and docetaxel) vs. <1% 
(docetaxel). Fatigue was predominantly grade 1 and grade 2; grade 3 or 4 fatigue was 5% 
(ganetespib and docetaxel) vs. 4% (docetaxel).  
The most common grade 3 or 4 AEs were neutropenia (42% vs. 40%), febrile neutropenia 
(9% vs. 5%), and anaemia (8% vs. 1%). The proportions of patients deaths while on 
treatment were 17.3% (1% of them were treatment-related) vs. 12.2% (<1.1% were 
treatment-related), and SAEs leading to treatment discontinuation were 7.2% vs. 4.3% for 
ganetespib and docetaxel vs. docetaxel, respectively. Consistent with prior findings with 
ganetespib, reports of visual impairment in this study were infrequent: 1 (1%) in the 
ganetespib and docetaxel arm and 0 (0%) in the docetaxel arm. The case of visual 
impairment was transient and was grade 1. 
 
Summary of the latest safety data of the GALAXY-1 trial  
Table 1: Safety Summary: Intention-to-treat population  
Number of patients who experienced at least 
one of the following: 
Ganetespib + docetaxel 
n=123 
n (%) 
Docetaxel 
n=126 
n (%) 
Any AE  
190 (97.4) 
171 (91.9) 
Any AE grade ≥3  
141 (72.3) 
116 (62.4) 
SAE 
78 (40.0) 
54 (29.0) 
Treatment-related SAE  
33 (16.9) 
22 (11.8) 
Treatment discontinuation due to AE  
28 (14.4) 
14 (7.5) 
Treatment discontinued due to SAE 
14 (7.2) 
8 (4.3) 
SAE leading to hospitalisation  
61 (31.3) 
36 (19.4) 
Death on treatment 
34 (17.3) 
23 (12.2) 
Death, treatment-related  
2 (1.0) 
2 (1.1) 
Death due to cardiac events  
1 (<1) 
2 (1.1) 
 
 
 
 
 


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Table 2: Adverse events: intention-to-treat population 
 
Grade 1 
Grade 2 
Grade 3 & 4 
 
G + D 
n=195 
n (%) 
D 
n=186 
n (%) 
G + D 
n=195 
n (%) 
D 
n=186 
n (%) 
G + D 
n=195 
n (%) 
D 
n=186 
n (%) 
Key AEs > 10% 
n (%) 
Neutropenia 
3 (2) 
0 
5 (3) 
5 (3) 
81 (42) 
75 (40) 
Diarrhoea 
53 (27) 
22 (12) 
30 (15) 
5 (3) 
6 (3) 
1 (<1) 
Fatigue 
20 (10) 
23 (12) 
26 (13) 
18 (10) 
10 (5) 
7 (4) 
Nausea  
27 (14) 
23 (12) 
17 (9) 
8 (4) 
3 (2) 
2 (1) 
Anaemia 
4 (2) 
5 (3) 
26 (13) 
21 (11) 
16 (8) 
2 (1) 
Alopecia 
19 (10) 
17 (9) 
18 (9) 
13 (7) 
0 
0 
Decreased appetite 
21 (11) 
17 (9) 
13 (7) 
4 (2) 
4 (2) 
3 (2) 
Dyspnoea 
13 (7) 
9 (5) 
15 (8) 
9 (5) 
9 (5) 
5 (3) 
Asthenia 
13 (7) 
6 (3) 
14 (7) 
11 (6) 
9 (5) 
5 (3) 
Neurotoxicity 
18 (9) 
18 (10) 
9 (5) 
6 (3) 
4 (2) 
1 (<1) 
Cough 
14 (7) 
17 (9) 
8 (4) 
9 (5) 
2 (1) 
1 (<1) 
Pain 
19 (10) 
9 (5) 
8 (4) 
6 (3) 
5 (3) 
1 (<1) 
Tachycardia 
19 (10) 
19 (10) 
3 (2) 
2 (1) 
1 (<1) 
0 
Leukopenia 
0 
4 (2) 
4 (2) 
5 (3) 
16 (8) 
9 (5) 
Pyrexia 
11 (6) 
14 (8) 
7 (4) 
6 (3) 
0 
0 
Vomiting 
17 (9) 
11 (6) 
6 (3) 
3 (2) 
1 (<1) 
0 
Other AEs of Interest 
n (%) 
Febrile Neutropenia 
0 
0 
0 
0 
17 (9) 
10 (5) 
Mucositis 
10 (5) 
9 (5) 
5 (3) 
3 (2) 
4 (2) 
2 (1) 
Haemoptysis 
7 (4) 
4 (2) 
5 (3) 
2 (1) 
 1 (<1) 
0 
Pulmonary Embolism 
0 
0 
1 (<1) 
0 
4 (2) 
6 (3) 
Visual Impairment 
1 (<1) 
0 
0 
0 
0 
0 
G = ganetespib, D = docetaxel 
 
Preliminary results indicate an improvement in efficacy with the addition of ganetespib to 
docetaxel for second-line therapy of advanced adenocarcinoma of the lung [Wong et al, JCO 
29:2011 (Suppl; Abstract 7500 ASCO 2011)]. Most promising, a significant improvement in 
survival was observed across key predefined subgroups (e.g. in patients >6 months since 
their diagnosis of advanced disease: combination arm (n=90) versus Docetaxel alone (n=88), 
Overall Survival HR 0.75; p = 0.065; Ramalingam et al, WLC Meeting 2013, Vienna, Austria; 
Abstract # 003.01).  
 
 
 


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The combination of ganetespib with the taxane docetaxel has shown: 
1) to be well tolerated, 2) a lack of DDI in phase I trials, 3) a similar safety profile in 
phase IIb/III trials compared to single agent use, and has 4) promising synergistic 
effects in vitro and in xenografts, and 5) promising efficacy in patients with advanced 
adenocarcinoma of the lung. 
6.3.4 
Other clinical data of interest 
The results from a thorough QT study conducted in healthy volunteers (Study 9090-13) 
reported a modest increase in QT interval 24 hours post ganetespib dose. The mean 
QTcF reached 21.5 msec. QTcF was back to baseline 7 days after ganetespib dose. 
One (2%) subject exhibited QTcF > 450 msec and none greater than 480 msec after 
ganetespib administration. Two (4%) subjects exhibited QTcF > 30 msec and none greater 
than 60 msec after ganetespib administration. To date, clinical experience with ganetespib 
does not support an evidence of a clinical safety risk for QTc interval prolongation and 
Torsade de Pointes or other uncontrolled arrhythmias.  
7. 
STUDY DESIGN 
7.1 
Description of study 
This is a multicentre, international two part trial, with a safety run-in phase I study (part I), 
and a randomised, open-label, two-arm phase II study (part II). 
 
Depending on the results of part I, the ganetespib dose to be used in part II of the trial will be 
chosen. 
7.2 
Part I: phase I dose escalation/de-escalation study  
Note: as of Amendment 4, enrolment for the phase I dose escalation/de-escalation study has 
been completed. The description of planned assessments for these patients is retained in the 
protocol for completeness.  
 
Phase I will be open at selected trial sites in four European countries (i.e. Austria, Germany, 
France, and Belgium).  
 
Study type: interventional 
Study design: single group assignment; open label 
Estimated enrolment: 9-18 patients 
 
An estimated number of 9-18 high-grade serous, high-grade endometrioid or undifferentiated 
PROC patients will take part in the dose escalation/de-escalation study with a traditional 3+3 
design. There will be no intra-patient dose escalation. Each patient will receive 2 cycles of 
experimental therapy, followed by a safety follow-up 28 days (± 7 days) after the last 
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All patients may continue to receive ganetespib in combination with paclitaxel until 
progression if a benefit for the patient has been observed (same schema; for dose reductions 
and dose modifications after the first 2 cycles of experimental therapy please see sections 
10.1, 10.1.2, 10.1.3). After six cycles of ganetespib combination therapy, the physician is 
allowed to discontinue paclitaxel (e.g. in case of peripheral neuropathy) and to continue 
maintenance therapy with ganetespib (i.e. ganetespib once a week for 3 out of 4 weeks; at 
the dose level previously used in the combination or re-escalated to the ganetespib dose 
level 0). Patients who did not appear to have had a benefit of the combination therapy after 
the two mandatory cycles, including also patients who have stopped experimental therapy 
due to the occurrence of dose-limiting toxicity in their dose group, will be treated according to 
physician’s choice. Safety will continuously be evaluated until 28 days (±7 days) after the last 
IMP administration (safety follow-up visit) or EOT or until initiation of the new anti-cancer 
treatment, whichever occurs first. 
 
A total of 6 patients will be treated at the dose level to be used in part II (phase II) of 
the trial.  
 
Figure 4: phase I trial design 
 
Arm  
Assigned intervention 
Experimental 
Paclitaxel 80 mg/m2 and ganetespib will be given once weekly (on 3 weeks 
out of a 4-week cycle) for 2 cycles (days 1, 8, 15 of each 4-week cycle). 
Agents will be administered as a separate 1-hour infusion. 
 
The sequence of administration will be ganetespib followed by paclitaxel. 
7.2.1 
3 + 3 design 
The first three patients will be treated with a starting dose of 100 mg/m2 ganetespib and a 
standard dose of paclitaxel weekly (80 mg/m2, fixed dose). If this dose does not cause a 
dose-limiting toxicity (DLT) [as defined per protocol (see section 10.1.6 for grading of DLT) 
and measured according to NCI CTCAE, version 4.03, Appendix C] in the first cohort during 
cycle 1 (weeks 1-4, i.e. D1-D28), ganetespib will be escalated to 150 mg/m2, as a second 
cohort takes part in the study. 
 
In general, should one of the first three patients at a given dose level experience DLT, 
three more patients will be treated at the same dose level.  
 


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Dose escalation from 100 mg/m2 to 150 mg/m2 ganetespib will be performed if only one of six 
patients among a cohort of six experience DLT (i.e. < 33% of patients with a DLT).  
 
If the dose of 150 mg/m2 does not cause dose-limiting adverse effects during cycle 1 of the 
first cohort, a second cohort at this ganetespib dose level will be included in the study. In 
case of DLT at 150 mg/m2 in < 2 patients in a cohort of six, this ganetespib dose will be used 
in the phase II trial (Figure 5a: expected course). 
 
In case of DLT at 150 mg/m2 in ≥ 2 patients in a cohort of three to six (i.e. ≥ 33% of patients 
with DLT) a dose reduction of ganetespib to 125 mg/m2 is permitted (Figure 5b: unexpected 
course).  
 
In case of DLT at 125 mg/m2 in ≥ 2 patients in a cohort of three to six, another cohort at the 
ganetespib starting dose level of 100 mg/m2 will be included (Figure 5c: unexpected course). 
 
In the highly improbable case of DLT in ≥ 2 patients among a cohort of three to six at the 
ganetespib starting dose level of 100 mg/m2 a dose reduction of ganetespib to 75 mg/m2 is 
permitted (Figure 5d: unexpected course).  
 
After all phase I patients have completed two cycles of treatment the Data Safety and 
Monitoring Committee (DSMC) will meet and decide if the established dose is safe to be 
used in the GANNET53 phase II study. 
The DSMC will be informed by the sponsor of any dose-limiting adverse events (as defined 
in section 10.1.6) immediately after knowledge of it. A teleconference of the DSMC will be 
held before the dose escalation step from 100 mg/m2 to 150 mg/m2. 
 
 
 
Figure 5: Potential courses of the phase I study. a) expected course, b), c), and d) 
unexpected courses 


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7.2.2 
Dose-limiting toxicity (DLT) at the ganetespib dose level of 75 mg/m2 
Of note, the risk for DLT at the ganetespib dose level of 75 mg/m2 is considered 
insignificantly low and seems highly improbable, taking the comprehensive previous findings 
of clinical ganetespib testing into account (see 6.3.3.1).  
However, if ganetespib at a dose level of 75 mg/m2 should cause DLT in  33% of patients (≥ 
2 patients among a cohort of three to six) we will conclude that the combination of 
ganetespib with weekly paclitaxel is not feasible. The randomised phase II trial will then 
examine single agent ganetespib at a dose of 200 mg/m² weekly (i.e. the recommended 
weekly ganetespib single agent dose in solid tumours) versus paclitaxel weekly (Figure 6 
highly improbable course). 
Figure 6: Highly improbable course 
 
7.3 
Part II randomised, open-label, two-arm phase II study 
The randomised, open-label, two-arm phase II study will be conducted in 12 trial sites in four 
European countries (Austria, Germany, France and Belgium), the ganetespib dose to be 
used in phase II has been determined to be 150 mg/m² in the phase I study. The expected 
number of enrolled patients is 222. 
 
Study type: interventional 
Study design: randomised 1:2 ratio, parallel assignment, open-label 
Estimated enrolment: 222 patients (74 + 148 patients) 
 
Eligible patients will undergo central histopathological review of archival ovarian cancer 
tissue at primary diagnosis to ensure high-grade serous, high-grade endometrioid or 
undifferentiated histology. Two hundred and twenty-two patients with verified histology will be 
randomised in a 1:2 ratio (74 + 148) to receive either paclitaxel once a week for 3 out of 4 
weeks alone or the combination of ganetespib and paclitaxel once a week for 3 out of 4 
weeks. The ganetespib dose used was determined in phase I of this trial to be 150 mg/m². 
For paclitaxel weekly the standard dose of 80 mg/m2 will be used (Figure 7). 
 
Patient will receive the respective therapy until disease progression or End of Treatment due 
to any other cause. After at least six cycles of ganetespib combination therapy, the physician 
is allowed to discontinue paclitaxel (e.g. in case of peripheral neuropathy) and to continue 
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the dose level previously used in the combination or re-escalated to the ganetespib dose 
level 0). 
 
All patients included will be analysed for p53 mutational status from archival ovarian cancer 
tissues. 
 
 
Figure 7: Phase II trial design 
 
Arm  
Assigned intervention 
Experimental 
arm 
Drug: ganetespib, 150 mg/m², given iv once weekly for 3 out of 4 weeks (days 
1, 8, 15 of each 4-weeks/28-days cycle);  
Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 
8, 15 of each 4-weeks/28-days cycle), until progression. 
The sequence of administration will be ganetespib followed by paclitaxel. 
Active 
comparator 
Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 
8, 15 of each 4-weeks/28-days cycle), until progression or EoT due to any 
other cause. 
 
A schedule of assessments is provided in Appendix A. 
 
7.4 
Subject population 
For both parts of the trial the target study population consists of female patients with high-
grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube 
or primary peritoneal cancer with previous platinum-resistant disease. By definition, patients 
will have experienced progressive disease > 1 month and ≤ 6 months after initial platinum-
based therapy (primary platinum-resistant) or ≤ 6 months after (including during) reiterative 
therapy with platinum-based regimens in recurrent disease (secondary platinum-resistant 
disease; including secondary platinum-refractory disease).  
 
 
 


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7.4.1 
Subject eligibility 
Before any study-specific procedure, the appropriate written informed consent must be 
obtained. 
7.4.1.1 Inclusion criteria  
 
Patients must meet the following criteria to be eligible for study entry: 
 
 
Ability to understand and willingness to sign and date a written informed consent 
document 
 
Female patients ≥18 years of age 
 
High-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, 
fallopian tube or primary peritoneal cancer. 
o Patients in part II: High-grade serous, high-grade endometrioid, or undifferentiated 
epithelial ovarian, fallopian tube or primary peritoneal cancer confirmed by central 
histopathology through archival FFPE. 
 
Platinum-resistant disease: 
o primary platinum-resistant disease: progression > 1 month and ≤ 6 months after 
completion of primary platinum-based therapy 
o secondary platinum-resistant disease (including secondary platinum-refractory 
disease): progression ≤ 6 months after (or during) reiterative platinum-based 
therapy 
 
Patients must have disease that is measurable according to RECIST 1.1 or assessable 
according to the GCIG CA-125 criteria, and require chemotherapy treatment  
 
ECOG performance status of 0-1  
 
Life expectancy of at least 3 months as assessed by the investigator 
 
Adequate function of the bone marrow: 
o Platelets ≥ 100 x 109/L  
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 
Haemoglobin ≥ 8.5 g/dl. Patients may receive blood transfusion(s) to maintain 
haemoglobin values > 8.5 g/dl.  
 
Adequate organ functions: 
o Creatinine < 2 mg/dl (< 177 µmol/L) 
o Total bilirubin ≤ 1.5 x upper limit of normal 
o SGOT/SGPT (AST/ALT) ≤ 3 x upper limit of normal 
o Urinanalysis or urine dipstick for proteinuria less than 2+. Patients with ≥ 2+ on 
dipstick should undergo 24-hour urine collection and must demonstrate < 1 g of 
protein/24 hours, except the proteinuria is clearly related to a catheter in the 
urinary system.  
 
Adequate coagulation parameters: aPTT ≤ 1.5 x ULN (patients on heparin treatment 
must have an aPTT between 1.5 – 2.5 x ULN), or INR ≤ 1.5. (In patients receiving 
anticoagulants (such as warfarin) INR must be between 2.0 and 3.0 in two consecutive 
measurements 1 – 4 days apart). 
 
Negative urine/serum pregnancy test in women of childbearing potential (WOCBP, see 
section 5). WOCBP who are sexually active, agree to use highly-effective means of 
contraception during the study and for at least 6 months post-study treatment. Allowed 
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abstinence or vasectomised partners (> 3 months previously). Vasectomy has to be 
confirmed by two negative semen analyses. 
 
Only in part II of the trial:  
 
Availability of archival ovarian cancer tissue for central histopathological review and p53 
mutational analysis 
 
7.4.1.2 Exclusion criteria 
 
Patients who meet any of the following criteria will be excluded from study entry: 
 
CANCER-RELATED: 
 
Ovarian tumours with low malignant potential (i.e. borderline tumours) 
 
Carcinosarcoma of the ovary 
 
Primary platinum-refractory disease (progression during primary platinum-based 
chemotherapy) 
 
PRIOR, CURRENT OR PLANNED TREATMENT: 
 
Previous treatment with > 2 chemotherapy regimens in the platinum-resistant setting 
(excluding targeted and endocrine therapies). 
 
Previous weekly paclitaxel in relapse treatment 
 
More than 4 previous lines of chemotherapy.  
 
Any prior radiotherapy to the pelvis or abdomen. 
 
Surgery (including open biopsy and traumatic injury) within 4 weeks prior to first dose of 
ganetespib, or anticipation of the need for major surgery during study treatment 
 
Minor surgical procedures, within 24 hours prior to the first study treatment 
 
Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment 
with aspirin (>325 mg/day) 
 
Chronic daily treatment with corticosteroids (dose >10 mg/day methylprednisolone 
equivalent), excluding inhaled steroids. 
 
PRIOR OR CONCOMITANT CONDITIONS OR PROCEDURES: 
 
Patients with a history of prior malignancies, except: 
o disease-free time-frame of ≥ 3 years prior to randomisation. 
 
Patients with prior in-situ carcinomas, except: 
o  complete removal of the tumour is given 
 
Known history of severe (grade 3 or 4) allergic or hypersensitivity reactions to excipients 
(e.g. polyethylene glycol [PEG] 300 and Polysorbate 80)  
 
History of intolerance or hypersensitivity to paclitaxel and/or adverse events related to 
paclitaxel that resulted in paclitaxel being permanently discontinued 
 
Peripheral neuropathy of grade > 2 per NCI CTCAE, version 4.03, within 4 weeks prior to 
randomisation 
 
Clinically significant gastro-intestinal (GI) tract abnormalities that may increase the risk for 
GI bleeding and/or perforation including but not limited to: active peptic ulcer disease, 
known intraluminal metastatic lesion/s with risk of bleeding, inflammatory bowel disease 
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first study treatment (excluding postoperative, i.e. within 4 weeks post-surgery), other GI 
condition with increased risk of perforation such as a recurrence deeply infiltrating into 
the muscularis or mucosa of the rectosigmoid or the mucosa of the bladder, or history of 
abdominal fistula, gastrointestinal perforation or intra-abdominal abscess 
 
Non-healing wound or non-healing bone fracture 
 
Patients with symptomatic brain metastases  
 
Left ventricular ejection fraction defined by ECHO below the institutional lower limit of 
normal 
 
Cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or sub- 
arachnoid haemorrhage within ≤6 months prior to first study treatment 
 
Significant cardiac disease: New York Heart Association (NYHA) Class 3 or 4; 
myocardial infarction within the past 6 months; unstable angina; coronary angioplasty or 
coronary artery bypass graft (CABG) within the past 6 months; or uncontrolled atrial or 
ventricular cardiac arrhythmias. 
 
History of prolonged QT syndrome, or family member with prolonged QT syndrome 
 
QTc interval > 470 msec when 3 consecutive ECG values are averaged 
 
Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a 
Class Ia antiarrhythmic drug (e.g. quinidine, procainamide, disopyramide) or Class III 
antiarrhythmic drug (e.g. sotalol, amiodarone, dofetilide). Use of other antiarrhythmic 
drugs is permitted 
 
Second- or third-degree atrioventricular (AV) block, except: 
o treated with a permanent pacemaker 
 
Complete left bundle branch block (LBBB) 
 
History of evidence of hemorrhagic disorders, patients with active bleeding or pathologic 
conditions that carry high risk of bleeding, such as known bleeding disorders, 
coagulopathy, or tumour involving major vessels 
 
Any other condition that, in the opinion of the investigator, may compromise the safety, 
compliance of the patient, or would preclude the patient from successful completion of 
the study. 
 
Participation in another clinical study with experimental therapy within 28 days before 
start of treatment.  
 
Women who are pregnant or are lactating 
 
 
7.5 
Study duration 
Part I: dose escalation/de-escalation phase I 
 
Active study participation for the individual study participant in phase I will consist of at least 
two 4-weeks cycles of ganetespib and paclitaxel (administered on days 1, 8 and 15) and a 
safety follow-up 28 days after the last IMP application. Consequently the duration of study 
participation for each patient in phase I is at least 10 weeks. Patients who continue receiving 
experimental therapy beyond the two cycles will actively participate in phase I until 
discontinuation of experimental therapy and a safety follow-up 28 days after the last IMP 
application. 
 


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Part II: randomised phase II 
 
Once the DSMC has reviewed the applicable data from part I of the trial and determined the 
ganetespib dose to be used in part II, the phase II trial will start.  Two hundred and twenty-
two patients will be enrolled into the randomised phase II trial over a time-frame of active 
enrolment of approximately 2.5 years.  
Analysis of the phase II endpoints (apart from PFS-rates at 6 months) will be performed 
approximately 1.5 years after enrolment of the last patient into phase II. This is estimated to 
be approximately 4 years after the randomisation of the first patient, unless all patients in part 
II have been lost to follow-up, withdrawn consent, or died, or the trial is prematurely 
terminated by the sponsor or the DSMC. 
7.6 
End of study 
The GANNET53 clinical trial ends after approximately 5.5 years. 
 
Part I (phase I):  
The phase I study ends when a total of six patients have received at least two cycles of 
experimental therapy at the ganetespib dose level to be used in the phase II trial and after all 
participating patients have discontinued experimental therapy and had a safety follow-up 28 
days after the last IMP application, unless the trial is prematurely terminated by the sponsor 
or the DSMC. 
 
Part II (phase II):  
Part II of the study ends approximately 18 months after the last patient was randomised, or 
when all subjects are lost to follow-up, have withdrawn consent, or died, or if the trial is 
prematurely terminated by the sponsor or the DSMC, whichever occurs first. 
7.6.1 
Premature termination of the study 
The trial or single dose steps in part I (phase I) can be terminated prematurely by the 
sponsor or the DSMC in the following cases: 
 
If adverse events occur which are so serious that the risk-benefit ratio is not 
acceptable 
 
If the number of dropouts is so high that a proper completion of the trial cannot 
realistically be expected 
In that case the Independent Ethics Committee (IEC) and the competent regulatory authority 
must be informed within 15 days of early termination. 
 
Every effort should be made to follow-up phase II patients until progression in case they have 
dropped out before progression. Especially the safety follow-up should be completed in 
phase I and phase II patients who have dropped out of the trial. 
 


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7.6.1.1 Study site discontinuation 
The Sponsor has the right to terminate this study or discontinue a site participating in this trial 
at any time. Reasons for terminating the study or discontinuing a site participation may 
include, but are not limited to, the following: 
 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients (recommendation of the DSMC) 
 
Patient enrolment is unsatisfactory. 
 
Administrative reasons 
The Sponsor will notify the investigator if the study is placed on hold, or if the sponsor 
decides to discontinue the study or the participation of a study site. 
7.6.2 
Withdrawal and replacement of subjects 
Criteria for withdrawal 
 
Subjects have the right to withdraw fully or partially from the study at any time and for any 
reason without prejudice to their future medical care by the physician or at the institution. 
Withdrawal of full consent for a study means that the subject does not wish to receive further 
investigational treatment and does not wish or is unable to continue further study 
participation. Subject data up to withdrawal of consent will be included in the subject’s study 
data, but no further information will be collected unless a separate consent has been given. 
Any subject may withdraw full consent to participate in the study at any time during the study. 
The investigator will discuss with the subject appropriate procedures for withdrawal from the 
study. 
 
Withdrawal of partial consent means that the subject does not wish to take protocol-specified 
product(s) any longer but is still willing to collaborate in providing further data by continuing 
on study (e.g., participate in the EOT or safety follow-up visit, provided samples can be 
evaluated and do not need to be destroyed and/or provide overall survival information). 
 
Should a subject (or a legally acceptable representative) request or decide to withdraw from 
the study, all efforts will be made to complete and report the observations as thoroughly as 
possible up to the date of withdrawal. All information and the primary reason for withdrawal 
should be reported on the applicable eCRFs. 
 
Reasons for removal from investigational treatment or observation might include: 
• 
progression of disease 
• 
withdrawal of consent 
• 
administrative decision by the investigator 
• 
pregnancy  
• 
significant protocol deviation 
• 
subject noncompliance 
• 
adverse event 
• 
other safety concern of the investigator or sponsor 
• 
death 
• 
lost to follow-up. 
 


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For any patient who has received IMP and withdrew prematurely from the study every effort 
should be made for attendance of the safety follow-up visit 28 days after the last dose of 
IMP. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. Patients will not be followed for any reason after consent has been 
withdrawn, unless a separate consent has been given for further survival data collection.  
7.6.2.1 Discontinuation from IMP or non-IMP 
The investigator has the right to discontinue a patient from IMP or non-IMP or withdraw a 
patient from the study at any time. In addition, patients have the right to voluntarily 
discontinue IMP or non-IMP or withdraw from the study at any time for any reason. Reasons 
for discontinuation of IMP and non-IMP or withdrawal from the study may include, but are not 
limited to, the following: 
 
Patient withdrawal of consent at any time. 
 
Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if she continues in the study. 
 
Investigator or sponsor determines it is in the best interest of the patient. 
 
More detailed information on IMP and non-IMP modifications and discontinuation is found in 
section 10.1 
Patients who discontinue IMP and non-IMP prematurely (i.e., before disease progression) 
will receive local standard of care according to physician’s choice, should undergo the safety 
follow-up visit 28 days after the last dose of IMP and may undergo follow-up assessments.  
The primary reason for premature IMP or non-IMP discontinuation should be documented on 
the appropriate eCRF.  
7.6.2.2 Replacement of patients during part I of the trial 
If a patient discontinues study participation for reasons unrelated to an adverse event, an 
additional patient must be enrolled to replace that subject in the cohort. 
 
7.6.2.3 Replacement of patients during part II of the trial 
There will be no replacement of subjects who withdraw after they have been randomised for 
part II of this trial. 
 
7.7 
Study objectives 
7.7.1 
Part I: dose escalation/de-escalation phase I study 
The primary aim of the phase I study is to determine the safety of ganetespib in combination 
with weekly paclitaxel and also to determine the ganetespib combination dose to be used in 
the randomised phase II study. 
 
Primary endpoint: 


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 
Safety: Adverse events (AEs) (measure according to NCI CTCAE, version 4.03), 
laboratory parameters, Eastern Cooperative Oncology Group (ECOG) performance 
status (PS), vital signs 
 
Secondary endpoint: 
 
Objective response rate (ORR) 
 
Progression-free survival (PFS) 
7.7.2 
Part II: randomised, open-label, two-arm, phase II study 
The primary aim of the phase II study is to determine efficacy of ganetespib in combination 
with weekly paclitaxel compared to weekly paclitaxel alone. 
 
Primary endpoint: 
• Progression-free survival (PFS) and PFS rates at 6 months 
 
Secondary endpoints:  
• Overall survival (OS) 
• Objective response rate (ORR): best ORR, confirmed ORR 
• Post-progression PFS (PFS II) 
• Patient-reported outcome: EORTC C30, EORTC OV28, and additional items 
• Safety: AEs (according to NCI CTCAE, version 4.03), laboratory parameters, ECOG PS, 
vital signs 
• Pharmacokinetics (only in 30 patients in selected sites) 
o evaluate the possible effects of paclitaxel on ganetespib pharmacokinetics 
o evaluate the possible effects of ganetespib on paclitaxel pharmacokinetics 
o quantify ganetespib and ganetespib metabolite exposures in the presence of 
paclitaxel  
 
Exploratory endpoints 
• Molecular efficacy analysis 
• Biomarker analysis e.g. p53 status on DNA, RNA and protein level 
7.8 
Randomisation and stratification  
In phase I no randomisation will take place. However, patients will be allocated into the 
respective cohort via the electronic CRF system after verification of inclusion and exclusion 
criteria and after all screening assessments have been performed. 
 
Randomisation of the phase II study will be performed in a 1:2 ratio stratified by 1) sites and 
2) duration of platinum-free interval (PFI): PFI < 3 months (including secondary platinum-
refractory cases with no platinum-free interval) versus PFI ≥ 3 months.  
Platinum free interval is defined as the interval between the date of the last platinum dose 
until the date the progression of disease is documented. 
The randomisation code will be generated by the study statistician using permutated blocks 
and implemented into the electronic CRF system. Patients will be randomised automatically 
via the electronic CRF system after verification of inclusion and exclusion criteria as well as 
stratification status and after all screening assessments have been performed.  


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7.9 
Statistical analysis 
7.9.1 
Analysis populations 
The following populations will be used for statistical analysis 
 
Safety population 
The safety population will include all patients who received at least one dose of study drug. 
In the safety analyses, patients will be included in the treatment arm into which they have 
actually been randomised. This study population refers to phase I and phase II study parts. 
 
Intention-to-treat population 
The intention-to-treat (ITT) population will consist of all randomised patients. Analyses of this 
population will assign patients the treatment they were scheduled to receive, regardless of 
any errors of dosing or dose modifications. This study population refers to the randomised 
phase II study.  
 
Per-protocol population 
The per-protocol (PP) population will include all patients who received at least one dose of 
study treatment without major protocol deviations. Major protocol deviations will be 
determined and documented prior to database lock. This study population refers to phase I 
and phase II study part. 
7.9.2 
Part I statistical analysis 
In phase I, a 3+3 dose escalation/de-escalation study will be performed.  
The primary aim of the phase I study is to determine the safety of ganetespib in the new 
combination with paclitaxel weekly.  
For the determination of the ganetespib combination dose in phase II, the endpoint of interest 
in phase I is whether or not a patient experiences a DLT. The observation period for DLT 
lasts from the first day (D1) of cycle 1 to the last day (D28) of cycle 2. The 3+3 design is rule-
based with a statistical power of greater than 87% to detect at least one out of three patients 
with a DLT when the probability for a DLT is 50%. 
 
Further analyses in the phase I study include a description of toxicities in regards to 
frequency, grade, cycle and dose. Efficacy measures (objective response rate and 
progression-free survival) will be reported in per-patient listings. All analyses will be in a 
descriptive way. 
Analyses will be performed for the safety and PP population. 
7.9.3 
Part II statistical analysis (including sample size calculation) 
In phase II, a randomised, open-label, two-arm study will be performed. Group allocation 
ratio will be 1:2. Twice as many patients will be on ganetespib combination treatment as are 
in the paclitaxel alone treatment group. 
The primary aim of the phase II study is to determine the efficacy of the new agent regarding 
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Efficacy analysis 
Progression-free survival (PFS) serves as the primary endpoint of the phase II study. PFS is 
defined as the days between randomisation and the date of documented progression or 
death of any cause. For patients whose progression status cannot be determined, their PFS 
data will be censored at the last assessment date that the patient is confirmed to have no 
progression. Additionally post-progression PFS (PFS II) will be analysed as a secondary 
endpoint. 
 
Hypothesis testing between the two treatment arms will be performed using a log-rank test. 
For each treatment arm the median time to progression will be estimated using the Kaplan-
Meier method and the 95% confidence interval of the median will be reported. The restricted 
mean as a measure for PFS will be calculated using the area under the survival curve (AUC) 
at 6 months (24 weeks) after randomisation and at the end of the study (approximately 18 
months after the last patient was randomised). 
 
Overall survival (OS), objective response rate (ORR: best and confirmed ORR), post 
progression PFS (PFS II), and patient-reported outcome (PRO) serve as secondary 
endpoints with respect to efficacy. 
OS is defined as the days between randomisation and the date of documented death from 
any cause. For patients whose survival status cannot be determined, their OS data will be 
censored at the last documented date that the patient is confirmed to be alive. Statistical 
analysis of OS will be carried out in the same way as described for PFS. 
 
ORR will be estimated as the proportion of responders, defined as a patient whose best 
overall response is partial response (PR) or complete response (CR) during the treatment 
period (best ORR). ORR is considered confirmed when the result is repeated in the following 
efficacy assessment, no less than four weeks later. Hypothesis regarding ORR testing 
between the two treatment arms will be performed using a Mantel-Haenszel test. The odds 
ratio and 95% confidence interval of the odds ratio will be presented. 
 
Post progression PFS (PFS II) is defined as the days between randomization to the date of 
progression or death following the first recorded progression (PFS).  
Patients will be followed-up for secondary progression status regularly following the 
progression event used for the primary variable PFS (PFS). Patients alive and for whom a 
second disease progression has not been observed should be censored at the date of the 
last known tumour assessment.  
 
PRO will be assessed using validated questionnaires and additional items. Statistical 
analysis of PRO will be based on linear mixed models. These models will include the PRO 
scales as dependent variables, study group and time point as fixed effects, a random 
intercept on patient level and an unstructured covariance matrix. In the case of non-ignorable 
drop-outs (e.g., patients with low PRO are more likely to die), a joint model of longitudinal 
and survival data will be estimated. This modelling approach allows to simultaneously 
analyse a continuous longitudinal PRO response with time to progression or overall survival. 
Sensitivity analyses will be done using different methods for data imputation, to investigate 
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Efficacy analyses will be performed on the ITT and PP populations. The analysis of the ITT 
population will be considered as the primary analysis. All statistical tests are two-sided with a 
significance level of 0.05. 
 
Safety analysis 
Safety evaluations will be based on the incidence, type, severity and consequences (e.g. 
study discontinuation) of an adverse event (AE) as well as on clinically significant changes in 
the patient’s physical examination, vital signs, and clinical laboratory results. Statistical 
analysis includes tabulation per treatment group using descriptive measures which are 
absolute and relative frequencies for categorical data and means, standard deviations, 
medians and interquartile ranges for continuous data. 
 
All safety analyses will be performed on the safety population. 
 
Pharmacokinetics 
PK analysis will be performed in a subgroup of phase II patients (n=15 per treatment group). 
Plasma samples will be analysed for ganetespib concentrations using a validated liquid 
chromatography-mass spectrometry / mass spectrometry (LC-MS/MS) method. Plasma 
samples may be analysed for ganetespib metabolites. Ganetespib and metabolite 
concentrations (if available) will be summarized descriptively. 
Plasma samples will also be analysed for paclitaxel concentrations using a validated liquid 
chromatography-mass spectrometry / mass spectrometry (LC-MS/MS) method. 
For both ganetespib and paclitaxel, concentration-versus-time curves for plasma 
concentrations will be displayed. Noncompartmental parameters for ganetespib and 
paclitaxel will include: maximum concentrations achieved (Cmax), elimination rate constant 
(ke), half-life (t1/2), clearance (CL), volume of distribution (Vss), and area-under-the-
concentration 
time 
curve 
(AUC). 
Other 
parameters 
may 
also 
be 
computed. 
Noncompartmental parameters will be computed using WinNonlin software version 6.3 or 
later (Pharsight Inc, Mountain View, CA). Pharmacokinetic parameters may also be 
computed for ganetespib metabolites, data permitting.  
 
Paclitaxel parameters from the experimental arm (ganetespib + paclitaxel) will be compared 
to paclitaxel parameters from the active comparator arm (paclitaxel alone). Ganetespib 
parameters from this study will be compared to historical data. Other analyses 
methodologies may also be utilized such as modelling, possibly in conjunction with PK data 
of other studies. 
 
Comparability of treatment arms 
The two treatment arms will be assessed descriptively for comparability of demographic and 
baseline characteristics. Administered study treatment, medical history, disease duration, 
use of prior treatments and concomitant medications will be summarised by treatment arm 
using descriptive statistics.  
 
Subgroup analysis 
Efficacy analyses will also be done for a subgroup of patients with tumours harbouring 
proven p53 mutations and for the subgroup of patients with tumours harbouring missense 


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p53 mutations. Furthermore, efficacy analyses will be performed in subgroups of primary 
platinum-resistance, of secondary platinum-resistance (including and excluding secondary 
platinum-refractory cases) and of secondary platinum-refractory cases (if case numbers are 
sufficient). 
 
Interim analysis 
No interim analysis will be performed. 
 
Sample size estimation 
Sample size estimation was performed for the primary endpoint PFS and for the secondary 
endpoint OS. The study is sufficiently powered to show superiority for both of these 
endpoints. 
 
Endpoint PFS: When the sample size in the treatment groups is 64 versus 128 patients (a 
total of n=192 patients), the study design provides 80% power to detect a PFS hazard ratio 
(HR) of 0.65 with 2-sided log-rank test and α=0.05 after 185 events, assuming a median PFS 
of 4 months with paclitaxel weekly alone and 6.2 months with paclitaxel weekly in 
combination with ganetespib. 
Endpoint OS: When the sample size in the treatment groups is 63 versus 126 patients (a 
total of n=189 patients), the study design provides 80% power to detect a OS hazard ratio 
(HR) of 0.6 with 2-sided log-rank test and α=0.05 after 126 events, assuming a median OS of 
14 months with paclitaxel weekly alone and 23.3 months with paclitaxel weekly in 
combination with ganetespib. 
 
In order to ensure a power of 80% for the study subpopulation with proven p53 mutations 
(more than 95% of all included type II EOC patient are expected to have mutp53 tumours) 
and to account for drop-out-rate of approximately 15%, the aspired patient number is 
expanded to a final sample size of 74 versus 148 patients (a total of n=222) in the two 
treatment arms, respectively. 
 
7.10 
Risk-benefit considerations 
Ovarian cancer patients with mutp53 platinum-resistant tumours face a dismal prognosis. 
The aim of the GANNET53 trial is to improve the wellbeing and survival in this subgroup of 
ovarian cancer patients by destabilising mutp53 using the most advanced Hsp90 inhibitor 
ganetespib. This aim links the awareness of human dignity, quality of patient’s life and the 
patient’s best interest, as pronounced in the Declaration of Helsinki (§3 - §5) and the Charter 
of Fundamental Rights of the European Union (2000/C 364/01; Article 1-3). 
 
The risk to harm patients in the phase II trial is minimised by the preceding phase I trial. Our 
guiding principle for the design of phase I dose escalation/de-escalation trial is to avoid 
exposing too many patients to subtherapeutic doses while preserving safety. The first three 
patients will receive 2/3 of the recommended combination ganetespib dose in solid tumours 
(the recommended combination dose is 150 mg/m2). Only after a waiting period and 
assurance that no significant serious adverse effect has occurred, a further cohort of three 
patients will be treated at an increased ganetespib dose level, namely at the recommended 


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ganetespib combination dose in solid tumours of 150 mg/m2. The observation time-frame for 
dose limiting toxicity has been set relatively long (compared to general practice in phase I 
trials), namely at a total of two cycles of treatment covering two months in the present phase 
I trial. This also decreases the risk of exposing subsequent patients to harmful effects in 
phase II by choosing the safest dosage observed.  
There is a risk in the GANNET53 trial by treating patients with ganetespib who may not 
benefit from this treatment but may experience adverse effects due to the experimental 
therapy. This risk is opposed by a potential benefit for these patients in terms of a possible 
survival advantage and a possibly higher life quality through better symptom control derived 
from this new therapeutic approach. Furthermore, the particular dismal prognosis of this 
specific subgroup of ovarian cancer patients and the lack of an efficient “golden standard 
therapy” has to be integrated into the risk-benefit considerations. Finally, the shown well 
tolerability of the combination-therapy of ganetespib with the taxane docetaxel (and the 
hypothesised better tolerability of the ganetespib combination with the taxane paclitaxel) 
together with the demonstrated efficacy of the ganetespib-docetaxel combination in NSCLC 
(in the GALAXY-1 trial, please see 6.3.3.1) clearly shifts the risk-benefit ratio in favour of a 
potential benefit dominance. A Data and Safety Monitoring Committee (DSMC) consistent of 
4 independent experts in the field of gynaecologic oncology and statistics will closely and 
continuously monitor patient safety and trial development. The DSMC can, if required, 
amend the protocol and in case the risk to the patients outweighs the potential benefit end 
the study prematurely. 
8. 
STUDY PROCEDURES 
See Appendix A for treatment schedules for part I and for part II. 
 
General rules for trial procedures 
 
All study measures like blood sampling and measurements (vital parameters, ECG, etc.) 
have to be documented at least with date (dd:mm:yyyy) and where appropriate with time.  
 
In case several study procedures are scheduled at the same time point, there is no 
specific sequence that should be followed, although e.g. blood drawing etc. should be 
done after ECGs. 
 
The dates of all procedures should be according to the protocol. The time frames 
mentioned in the study flow chart are admissible. If for any reason a study procedure is 
not performed within scheduled time frame a protocol deviation must be noted, and the 
procedure must be performed as soon as possible or as adequate. 
 
If it is necessary for organisational reasons, it is permissible to perform procedures which 
are scheduled for a single visit at two different time points. However, allowed time frames 
should not be exceeded. 
 
After patients have received the last study drug due to any reason, any cancer-related 
treatment is according to physician’s choice but should be recorded in the eCRF.  
 
Only the most recent available values should be documented for screening. 


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8.1 
Before treatment start/screening (days -28 to -1) 
All subjects must provide written informed consent before any study-specific assessments or 
procedures are performed. 
The screening examinations must be performed between 1 and 28 days before being 
assigned into a cohort in part I and prior to randomisation in part II. Only subjects who fulfil all 
the inclusion and none of the exclusion criteria will be accepted into the study. 
 
An Eligibility Screening Form (ESF) documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. In addition a screen failure log must be maintained by the 
investigator. 
 
The following study screening assessments are to be completed within 4 weeks (28 days) 
prior to study entry.  
 
 
Signed and dated informed consent 
 
Verification of inclusion and exclusion criteria 
 
Medical history including ovarian cancer history, significant diseases and medical 
procedures (at Investigator’s discretion) and concurrent illnesses 
 
Urine/serum pregnancy test in WOCBP (for definition see section 5)  
 
Demographic data (date of birth, ethnicity) 
 
Physical examination including  
o Height 
o Weight 
o Performance status (ECOG, see Appendix B) 
 
Vital signs 
o Heart rate 
o Blood pressure  
o Temperature 
 
Laboratory 
o Haematology  
 
Haemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, 
differential (%)†, platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
o Biochemistry panel 
 
Sodium, potassium, calcium 
 
Serum albumin, serum urea 
 
ALT, AST, LDH, alkaline phosphatase (AP), total bilirubin 
 
Creatinine 
o Urinanalysis or urine dipstick for proteinuria should be < 2+. Patients with ≥ 2+ 
on dipstick should undergo 24-hour urine collection and must demonstrate < 1 
g of protein/24 hours, except the proteinuria is clearly related to a catheter in 
the urinary system.  
 
Tumour marker:  


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Part I: CA-125 will be measured twice during the screening period; collections should 
be at least 1 day apart. One sample needs to be drawn within 1 week of treatment 
start. 
Part II: CA-125 will be measured at least once during the screening period. One of 
these samples must be taken within 2 weeks before treatment start. 
 
Concomitant medications  
 
Electrocardiogram (ECG; average of triplicate ECG recording) 
 
Left ventricular ejection fraction (LVEF) by ECHO  
 
Tumour assessment which is not older than 28 days at the time of randomisation: 
chest, abdomen and pelvis CT scan or MRI and chest CT/MRI or X-ray. Pre-operative 
chest X-ray is allowed. PET scans are allowed; the same technique is to be used for 
all assessments.  
 
For part II additionally: 
 
Additional demographic data (marital status, highest level of education, current 
employment status) 
 
Archival tissue samples sent to central histopathological review (for confirmation of 
high-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, 
fallopian tube or primary peritoneal carcinoma) and for biomarker analysis such as 
p53 mutational status. 
 
Whenever technically feasible CT- or sonographically-guided biopsy samples of the 
actual relapse are to be performed after informed consent has been obtained but 
prior to the first study drug administration. Biopsy tissue of the actual relapse will be 
collected in all patients. 
 
The collection of ascites is highly recommended 
 
Completion of PRO [EORTC QLQ-C30, EORTC QLQ-OV28, and additional items 
(Appendix D)]. 
 
8.2 
Treatment period 
Note: as of Amendment 4, enrolment for the phase I dose escalation/de-escalation study has 
been completed. The description of planned assessments for these patients is retained in the 
protocol for completeness.  
 
Laboratory tests from screening can be used for treatment day 1 of cycle 1, if drawn within 
the 3 days range. 
 
Part I 
In part I of the trial the treatment will start after the patient has been allocated to a treatment 
cohort after screening. Treatment will last for 2 treatment cycles. If the patient has had a 
benefit from the treatment, continued administration of ganetespib and paclitaxel at the prior 
received dosage is allowed at the physician’s discretion. After six cycles of ganetespib 
combination therapy, the physician is allowed to discontinue paclitaxel (e.g. in case of 
peripheral neuropathy) and to continue maintenance therapy with ganetespib (i.e. ganetespib 
once a week for 3 out of 4 weeks; at the dose level previously used in the combination or re-
escalated to the ganetespib dose level 0. 
 


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One treatment cycle will consist of 28 days with the following schedule: 
 
 
Strongly recommended: Loperamide 2 mg 1-2 hours prior to ganetespib 
administration. And every 4 hours for the first 12 hours.  
 
Ganetespib infusion given intravenously over 1 hour on days 1, 8, 15 per (28-day) 
cycle.  
 
Premedication according to hospital standards (e.g. Dexamethasone 20 mg 30 min 
prior to each paclitaxel-infusion), see section 10.3 
 
Paclitaxel on days 1, 8, 15 as a 1 hour infusion, per 28 day cycle. The sequence of 
administration will be ganetespib followed by paclitaxel 
 
The following parameters have to be gathered within 3 days prior to IMP administration: 
 
Physical examination including  
o Weight 
o Heart rate 
o Blood pressure  
o Temperature 
 
Laboratory 
o Haematology  
 
Haemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, 
differential (%)†, platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
o Biochemistry panel (on day 1 of every cycle) 
 
Sodium, potassium, calcium 
 
Serum albumin, serum urea 
 
ALT, AST, LDH, AP, total bilirubin 
 
Creatinine 
 
Concomitant medications  
 
Adverse event evaluation using the NCI-CTCAE criteria, version 4.03 (Appendix C) 
 
Performance status according to ECOG Performance Status (Appendix B) 
 
Additional assessments:  
 
The tumour marker (CA-125) will be evaluated monthly (on day 1 of each cycle; +/- 
7 days). 
 
Pre-ganetespib dose ECG will be performed, in patients who receive ganetespib. In 
addition, a 24-hours post-ganetespib-dose ECG (+/- 4 hours) will be performed on 
day 1 of cycle 1. Furthermore, a 24-hours post-ganetespib dose ECG (+/- 4 hours) 
is strongly recommended on day 1 of each subsequent cycle. 
 
A urine/serum pregnancy test will be performed monthly (on day 1 of each cycle; +/- 
7 days) in WOCBP. 
 
Tumour assessments for response and progression require CT scans of the pelvis 
and abdomen and (by X-ray or preferably by CT scan) of the chest. MRI scans can 
be used for patients who are allergic to radiographic contrast agents. Throughout 
the study, the same assessment technique must be used. Ultrasound scanning is 
not an acceptable substitute for CT scanning. This assessment should be performed 
every 8 weeks, +/- 1 week, starting from date of cohort assignment or if recurrence 
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Part II 
In part II of the trial treatment will start after central histopathological review has confirmed 
high-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian or fallopian 
tube or primary peritoneal cancer and the patient has been randomised into one of the two 
treatment arms. 
 
Treatment should begin within 7 days of randomisation.  
 
Treatment will be administered until progression or drop out of the trial. A minimum of six 
cycles of ganetespib and paclitaxel combination therapy will be administered. Thereafter, 
paclitaxel may be discontinued and ganetespib may be administered as a mono therapy at 
the same dosage level as used in the combination therapy or re-escalated to the ganetespib 
dose level 0. 
 
For treatment schedule please refer to Appendix A.  
 
One treatment cycle will consist of 28 days with the following schedule: 
 
 
Strongly recommended for patients receiving ganetespib: Loperamide 2 mg 1-2 
hours prior to ganetespib administration. And every 4 hours for the first 12 hours.  
 
Ganetespib infusion given intravenously over 1 hour on days 1, 8, 15 per 28-day 
cycle.  
 
Paclitaxel premedication will be given according to hospital standards (with the 
exception of day 1 cycle 1 in patients participating in PK analysis; for 
standardised paclitaxel premedication scheme in PK patients, please see section 
9.8). 
Of note, in patients receiving ganetespib, paclitaxel premedication schemes must 
exclude any QTc interval prolonging medications with known risk for Torsade de 
Pointes (see APPENDIX F; for example but not exclusively: do not use granisetron 
in the paclitaxel premedication scheme). 
 
Paclitaxel on days 1, 8, 15 as a 1 hour infusion, per 28-day cycle. The sequence of 
administration will be ganetespib followed by paclitaxel. 
 
The following parameters have to be gathered within 3 days prior to IMP administration: 
 
Physical examination including  
o Weight 
o Heart rate 
o Blood pressure   
o Temperature 
 
Laboratory 
o Haematology  
 
Haemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, 
differential (%)†, platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
o Biochemistry panel (only on day 1 of each cycle) 
 
Sodium, potassium, calcium 
 
Serum albumin, serum urea 


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 
ALT, AST, LDH, AP, total bilirubin 
 
Creatinine 
 
Concomitant medications  
 
Adverse event evaluation using the NCI-CTCAE criteria 4.03 (see Appendix C) 
 
Performance status according to ECOG Performance Status (Appendix B) 
 
Additional assessments: 
 
Pharmacokinetics (30 patients, 15 in each study arm, at selected sites), see section 
9.8  
 
Blood sampling for biomarker analysis (e.g. for circulating tumour cells [CTCs]) in all 
part II patients: 
o Blood collection will be performed before and 24 hours after (+/- 3 hours) the 
administration of study drug on day 1 of cycle 1 (the sample time is relative 
to the start of the study drug infusion). On day 1 of cycles 2 and 3 blood 
collection will be performed exclusively before the study drug administration. 
After cycle 3, blood collection will take place on day 1 of every other cycle 
(i.e. cycles 5, 7, 9 etc.) prior to administration of study drug. 
 
Completion of PRO [EORTC QLQ-C30, EORTC QLQ-OV28, and additional items 
(Appendix D)] will be performed on day 1 and day 15 of each cycle prior to IMP 
administration. 
 
The tumour marker (CA-125) will be evaluated monthly (on day 1 of each cycle; +/- 
7 days). 
 
On day 1 of cycle 1 a pre-ganetespib dose ECG (day 1 cycle 1, or one day prior to 
day 1 cycle 1), a 24-hours post-ganetespib dose ECG (+/- 4 hours) and on day 1 of 
each subsequent cycle a pre-dose ECG is performed in patients who receive 
ganetespib. 
o A risk-based ECG monitoring will be followed after evaluation of the day 1 
cycle 1 ECG findings according to section 9.5. 
 
A urine/serum pregnancy test will be performed monthly (on day 1 of each cycle; +/- 
7 days) in WOCBP (for definition see section 5). 
 
Tumour assessments for response and progression require CT scans of the pelvis 
and abdomen and (by X-ray or preferably by CT scan) of the chest. MRI scans can 
be used for patients who are allergic to radiographic contrast agents. Throughout 
the study, the same assessment technique must be used. Ultrasound scanning is 
not an acceptable substitute for CT scanning. This assessment should be performed 
every 8 weeks, +/- 1 week, starting from date of randomisation until progression, 
regardless of any study interruptions, or if recurrence is suspected. 
 
The collection of ascites (for tumour cell isolation of the actual relapse and 
biomarker analysis) is highly recommended and will be collected at the time of 
occurrence. 
 
 
 
 


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8.3 
Part I & II end of treatment/Safety follow-up  
End of treatment will be after last dose of study drug.  
All patients receiving ganetespib will receive a safety follow-up 28 days (+/- 7 days) after the 
last dose of the IMP ganetespib or prior to initiation of a new anti-cancer treatment, 
whichever occurs earlier.  
 
Safety follow-up includes the following: 
 
Physical examination including  
o Weight 
o Heart rate 
o Blood pressure  
 
Laboratory 
o Haematology  
 
Haemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, 
differential (%)†, platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
o Biochemistry panel  
 
Sodium, potassium, calcium 
 
Serum albumin, serum urea 
 
ALT, AST, LDH, AP, total bilirubin 
 
Creatinine 
 
Tumour marker CA-125 
 
Electrocardiography (ECG) 
 
LVEF 
 
Concomitant medications  
 
Adverse event evaluation using the NCI-CTCAE criteria, version 4.03 (see Appendix 
C) 
 
Performance status according to ECOG Performance Status (see Appendix B) 
 
A urine/serum pregnancy test will be performed monthly (on day 1 of each cycle; +/- 7 
days) in WOCBP (for definition see section 5) 
 
For part II additionally: 
 
Patient-reported outcome questionnaire: EORTC QLQ-C30, EORTC QLQ-OV28, and 
additional items (Appendix D)  
8.4 
Part I and II long-term follow-up 
In all patients a long-term follow-up period will be performed after the EOT and the safety 
follow-up visit.  
In patients who had end of treatment due to progression of disease, the following 
assessments should be recorded in three-monthly intervals (+/- 14 days) until death of the 
patient or the end of study, whichever occurs first. 
 
Part I 
 
Survival status 
 
Additional cancer therapy 


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Part II 
 
Survival status 
 
Additional cancer therapy 
 
Date of next progression following the subsequent cancer therapy 
 
Patient-reported outcome questionnaire: EORTC QLQ-C30, EORTC QLQ-OV28, 
and additional items (Appendix D)  
8.4.1 
Long-term FU in patients who discontinues treatment prior to 
progression 
Patients who discontinue study treatment without having developed progressive disease 
will first continue to be followed as listed below until progression and will then continue with 
long-term follow-up as described above after progression. 
 
Tumour assessments through CT scans of the pelvis and abdomen and (by X-ray 
or preferably by CT scan) of the chest. MRI scans can be used for patients who 
are allergic to radiographic contrast agents. Throughout the study, the same 
assessment technique must be used. Ultrasound scanning is not an acceptable 
substitute for CT scanning. This assessment should be performed every 8 weeks, 
+/- 1 week or if recurrence is suspected, until progression. 
 
Tumour marker: CA-125 every 4 weeks (+/- 1 week) 
 
Additional cancer therapy 
 
Date of progression  
And for patients in part II additionally: 
 
Patient-reported outcome questionnaire: EORTC QLQ-C30, EORTC QLQ-OV28, 
and additional items (Appendix D) every 2 weeks 
 
9. 
STUDY ASSESSMENTS 
Details of the timing of assessments are presented in the Schedule of Assessments 
(Appendix A). 
9.1 
Tumour response assessment 
Patients will be assessed for disease response or progressive disease throughout the clinical 
trial. 
Response or progression will be evaluated in this study according to RECIST 1.1 (see 
Appendix E), CA-125 (GCIG criteria (30)) and by the investigator on the basis of physical 
and/or gynaecological examinations.  
 
Evidence of progressive disease is considered clear radiological, clinical, or symptomatic 
evidence. CA-125 elevation alone is not defined as disease progression. An objective 
response should be confirmed by repeated assessment not earlier than 4 weeks after initial 
documentation (e.g. CA-125 measurement) or at the next scheduled tumour assessment if it 
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9.1.1 
Radiologic tumour assessments 
Tumour assessments require CT scans of the pelvis and abdomen and (by X-ray or 
preferably by CT scan) of the chest. MRI scans can be used for patients who are allergic to 
radiographic contrast agents. The same method of tumour assessment and the same 
technique should be used to characterise each identified and reported lesion at baseline and 
during follow-up. Positron emission technology scans are not acceptable for monitoring 
target lesions. At the investigator’s discretion, CT scans may be repeated at any time if 
progressive disease is suspected. 
 
Baseline tumour assessment of the chest (by X-ray of preferably by CT scan), abdomen and 
pelvis by CT scan (or MRI scan in case of allergic reactions to radiographic contrast agents) 
must be performed within a maximum of 28 days before first dose of study drug treatment. 
Already existing CT scan can be used as screening CTs, if not older than 28 days at the time 
of randomisation.  
Post baseline assessments are to be performed every 8 weeks (+/- 1 week) from date of 
randomisation and/or cohort assignment, (e.g. on day 1 of cycle 3, 5, 7, 9, 11 etc.) 
independent of any treatment interruptions using the same imaging technique as used during 
screening until disease progression. 
If there is suspicion of disease progression based on clinical or laboratory findings before the 
next scheduled assessment, an unscheduled assessment should be performed. 
9.1.2 
GCIG criteria  
CA-125 elevation alone is not defined as disease progression unless accompanied by clear 
radiological, clinical or symptomatic progression. Patients on treatment who are well but have 
rising CA-125 levels should continue protocol treatment until RECIST 1.1 defined 
radiological, clinical or symptomatic progression of disease. 
Patients can be evaluated according to CA-125 (30) only if they have a pre-treatment sample 
that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment. 
 
CA-125 response is defined as at least a 50% reduction in CA-125 levels from a pre-
treatment sample.  
The date when the CA-125 level is first reduced by at least 50% is the date of the CA-125 
response. However, the response must be confirmed and maintained for at least 28 days. 
The (28-day) confirmatory sample must be less than or equal to (within an assay variability of 
10%) the previous sample for to be a confirmed response.  
 
Patients are not evaluable by CA-125 if they have received mouse antibodies or if there has 
been medical or surgical interference with their peritoneum or pleura during the previous 28 
days. 
 
Timing of CA-125 measurements 
 
Part I: two CA-125 blood samples prior to treatment, 
 
Part II: one CA-125 blood sample prior to treatment. One of these samples must 
be taken at least 2 weeks prior to treatment start 
 
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For each patient the same assay method must be used. The assay must be tested in a 
quality control scheme. 
 
9.2 
Patient-reported outcome (PRO) 
9.2.1 
PRO instruments 
The following PRO questionnaires will be used in both study arms in part II / phase II of this 
study: EORTC QLQ-C30, EORTC QLQ-OV28, and additional items (Appendix D). 
 
The EORTC QLQ-C30, an internationally validated and widely used cancer-specific QOL-
instrument, assesses various facets of functioning and symptoms common in cancer 
patients. It comprises five functioning scales (physical, social, role, emotional, cognitive), a 
scale for global QOL, and nine symptom scales (fatigue, nausea/vomiting, pain, dyspnoea, 
sleeping disturbances, appetite-loss, constipation, diarrhoea, and financial impact). 
 
The QLQ-OV28 module is a supplement of the QLQ-C30 for assessing issues relevant to 
ovarian cancer patients. The module covers abdominal/gastrointestinal symptoms, peripheral 
neuropathy, other chemotherapy side-effects, hormonal/menopausal symptoms, body image, 
attitude to disease/treatment and sexual functioning. 
 
Additional items for the assessment of distress associated with diarrhoea and constipation 
are added in line with the EORTC item format. 
 
All scales are scored according to EORTC guidelines resulting in a score range from 0 to 100 
points. 
9.2.2 
PRO assessment schedule 
The PRO questionnaires should be given to the patient to complete during their visit (i.e. 
patients should not be sent home with the questionnaires to complete and return at their next 
visit), but prior to administration of investigational product. These will be assessed during 
screening, on day 1 and day 15 of each cycle. After end of therapy and safety visit PRO 
assessments will be continued in both study arms in three-monthly intervals (+/- 14 days) 
until death of the patient or the end of study, whichever occurs first.  
Patients who had EOT prior to progression will have PRO assessments every 2 weeks (+/- 1 
week) until progression and thereafter in three-monthly intervals (+/- 14 days) until death of 
the patient or the end of study, whichever occurs first. 
9.2.3 
PRO assessment procedure 
The patient will be approached by a study nurse or an investigator and will be asked to 
complete the PRO questionnaires on her own. The PRO assessments will take place prior to 
patient-clinician consultation to avoid the immediate impact of issues discussed in the clinical 
encounter. A quiet place providing sufficient privacy will be provided to the patient for 
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arising during questionnaire completion. In case of problems with reading (e.g. due to limited 
literacy or impaired eyesight) the questionnaire will be conducted as a structured interview. 
 
9.3 
Concomitant medications/therapies 
All medication (other than study drug) and significant non-drug therapies (including, but not 
limited to, herbal/natural medications and blood transfusions) will be recorded at Screening 
and on an ongoing basis thereafter. Any surgical and medical procedures (i.e. paracentesis) 
will also be recorded. 
 
9.4 
Physical examination 
Physical examinations will be performed by trained medical personnel at the time points 
specified in Appendix A. 
Vital signs (blood pressure, heart rate and temperature, as appropriate) and body weight will 
be measured per institutional standards as part of the physical examination. Height will be 
measured only at Screening. All physical examinations occurring on dosing days must be 
performed prior to study drug administration. Any treatment-emergent abnormal findings will 
be recorded as AEs. 
Heart rate and blood pressure will be measured after patient has been in a seating position 
for 10 minutes. 
9.5 
Electrocardiography and LVEF 
ECG: 
A standard 12-lead ECG assessment will be performed at screening and at EOT/safety 
follow-up in both parts of the trial. 
 
For part I of the trial further ECG assessments will be performed on day 1 of each cycle (on 
the day of medication dosing, or one day prior) in patients who receive ganetespib. In 
addition, a 24-hours post-ganetespib-dose ECG (+/- 4 hours) will be performed on day 1 of 
cycle 1. A 24-hours post-ganetespib-dose ECG (+/- 4 hours) is strongly recommended to be 
performed on day 1 of each subsequent cycle. 
 
In part II of the trial a pre-ganetespib dose ECG will be performed on day 1 of each cycle (on 
the day of medication dosing, or one day prior), in patients who receive ganetespib. In 
addition, a 24-hours post-ganetespib-dose ECG (+/- 4 hours) will be performed on day 1 of 
cycle 1. Furthermore on day 1 of each subsequent cycle a pre-dose ECG is performed in 
patients who receive ganetespib. 
 
 
In case of normal findings on the day 1 cycle 1 pre- and 24-hours post-
ganetespib dose ECGs (option 1 in Figure 8), further standard ECG 
monitoring will be performed consisting of pre-ganetespib dose ECGs on 
days 1 of all following cycles. 
 
In case of QT prolongation in the initial 24-hours post-ganetespib dose ECG 
only (option 2 in graph, Figure 8), another pre- and 24-hours post-ganetespib 


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dose ECG will be performed at the following dosing of ganetespib (day 8 of 
cycle 1).  
 
In case of QT prolongation in the initial pre-ganetespib dose ECG only (option 
3 in Figure 8), another pre-ganetespib dose ECG will be performed before the 
following dosing of ganetespib (day 8 of cycle 1). 
 
In case of QT prolongation in both (option 4 in Figure 8), the initial pre-
ganetespib dose and the 24-hours post-ganetespib dose ECG, another pre- 
and 24-hours post-ganetespib dose ECG will be performed at the following 
dosing of ganetespib (day 8 of cycle 1). 
 
For options 2, 3 and 4 thereafter, the principal investigator of each clinical centre will 
decide on a possible necessity for further intensified ECGs based on previous ECG 
findings and after thorough review of the patients’ medical history including 
concomitant medication. At least the standard ECG monitoring needs to be performed 
(pre-dose ECGs on days 1 of all following cycles).  
Thus, an individual risk-adjusted ECG monitoring will be performed (see Figure 8). 
 
Figure 8: risk-adjusted ECG schedule 
 
ECGs for each patient should be obtained from the same machine whenever possible. A 
consistent method of QTc calculation must be used for each patient’s QTc measurements. 
QTcF (Fridericia’s formula) is preferred. For the screening ECG averaged values of triplicate 
recordings are necessary. 
To minimise variability, it is important that patients be in a resting position for ≥ 10 minutes 
prior to each ECG evaluation. Body position should be consistently maintained for each ECG 
evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, 
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recording. ECGs should be performed prior to any scheduled vital sign measurements and 
blood draws. 
For safety monitoring purposes, the investigator or designee must review, sign, and date all 
ECG tracings. Paper copies will be kept as part of the patient's permanent study file at the 
site. Digital recordings will be stored at site as part of the patient’s file.  
 
LVEF:  
Cardiac ejection fraction will be assessed by transthoracic echocardiography (ECHO) at the 
time points specified in Appendix A (Schedule of assessments). 
9.6 
Laboratory assessments 
Samples for laboratory tests will be analysed at the local laboratory of each participating site. 
 
Blood analysis will be done as part of regular safety assessments at screening/baseline, 
every treatment cycle (prior to study drug administration), and at the post-treatment safety 
follow-up. Assessments must be performed at each cycle within 3 days (with results 
available) prior to the administration of study medication. 
Blood samples for the analysis of biomarkers (including CTCs analysis) will be taken before 
and during experimental therapy with ganetespib in all phase II patients (both arms; one arm 
for control) as outlined in section 8.2. 
9.7 
Biomarker analysis in part II  
The following samples will be collected to determine the p53 status and other potential 
biomarkers (such as other HSP90 clients) and to confirm high-grade serous, high-grade 
endometrioid or undifferentiated EOC in patients of part II of the trial: 
 
 
Mandatory archival tumour tissue (formalin-fixed paraffin-embedded tissue)  
 
Mandatory blood collection before and during experimental therapy as previously 
specified (topic 8.2). 
 
It is strongly recommended to prospectively collect ascites 
 
Whenever technically feasible it is mandatory to collect biopsy tissue of the actual 
platinum-resistant relapse in all phase II patients. Biopsy tissues will be collected 
using CT-guided or sonography-guided biopsy collection after informed consent has 
been obtained but prior to the first study drug application.  
 
Samples remaining after completion of biomarker studies and prospectively collected 
biomaterials will be stored in a biobank. Tumour samples from screen-failed patients will also 
be included in a biobank. 
Details of tissue requirements, processing, and handling instructions are given separately in 
the Sample Handling Manual and Logistics Manual. 
9.7.1 
Determination of p53 status and other biomarkers in collected 
biomaterials in phase II 
The availability of archival tissues (FFPE) is mandatory for inclusion of patients into phase II. 
In addition, tissues and/or tumour cells of the actual platinum-resistant relapse (biopsy tissue 


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and/or ascites) will be collected. DNA, RNA and/or protein will be extracted from the 
respectively collected biomaterials. The p53 status (e.g. genomic mutations, isoforms, splice 
variants, protein) and other biomarkers analyses (e.g. analysis of the p53-homologues p73 
and p63, or other HSP90 clients) will be performed. 
Ascites fluid from phase II patients will be collected and isolated for epithelial cells to be 
cultured in the presence or absence of ganetespib to investigate the interaction of p53 with 
Hsp90 in vitro. Alternatively to ascites, biopsy tissue of the actual platinum-resistant relapse 
site tissue can be used. To this end, fresh tumour biopsies will be disaggregated into single-
cell suspensions, incubated in the presence or absence of ganetespib and subsequently 
analysed (molecular efficacy analysis).  
Blood samples for biomarker analysis including e.g. circulating tumour cells (CTCs) will be 
taken before and during experimental therapy with ganetespib in all phase II patients (both 
arms; one arm for control).  
9.8 
Pharmacokinetic (PK) analysis in Phase II, at selected centres 
PK samples will be collected from 30 patients (15 paclitaxel, 15 ganetespib + paclitaxel) at 
selected sites in phase II. 
 
o Ganetespib + paclitaxel patients: on day 1 to day 3 of cycle 1, blood samples 
will be drawn at 0 (pre-dose), 1, 1.5, 2.5, 3.5, 4.5, 6.5, 8, 24, and 55 hours 
following the start of the ganetespib infusion. The 0 (pre-dose) sample is to 
be taken immediately prior the start of the ganetespib infusion. The 1-hour 
and 2.5 hour nominal time samples are to be taken prior to stopping the 
ganetespib and paclitaxel infusion, respectively and may be drawn as early 
as 55 ± 5 minutes. The day 2 and day 3 samples (24 and 55 hour time 
points) may be drawn ± 2 hours from the nominal times. 
All samples are to be drawn contralateral to the infusion. All sample times 
are relative to the start of the ganetespib infusion (i.e.: ganetespib infusion 
start is defined as time zero) and presume the paclitaxel infusion starts 30 
minutes after termination of the 1-hour ganetespib infusion In the 30 min 
between ganetespib and paclitaxel infusion a standardised paclitaxel pre-
medication will be administered, please see below. 
 
o Paclitaxel-only patients: on day 1 to day 3 of cycle 1, blood samples will be 
drawn at 0 (pre-dose), 1, 2, 3, 5, 6.5, 22.5, and 53,5 hours following the start 
of the paclitaxel infusion. The 0 (pre-dose) sample is to be taken after the 
application of the standardised paclitaxel premedication scheme immediately 
before the start of the paclitaxel infusion. The 1-hour nominal time samples 
are to be taken prior to stopping the paclitaxel infusion and may be drawn as 
early as 55 ± 5 minutes. The Day 2 and Day 3 samples (22.5 and 53.5 hour 
time points) may be drawn ± 2 hours from the nominal times. All samples are 
to be drawn contralateral to the infusion. All sample times are relative to the 
start of the paclitaxel infusion (i.e.: paclitaxel infusion start is defined as time 
zero; immediately prior to the start of the paclitaxel infusion is pre-dose).  
 
Of note, all patients participating in PK analysis (both arms: ganetespib plus 
paclitaxel and paclitaxel only) will receive a standardised (regarding drug, 


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dosage, application form, timing of application) premedication for paclitaxel 
on day 1 of cycle 1.  
For all further dosings of study treatment in PK patients, paclitaxel premedication 
can be given according to hospital standards. However, in patients receiving 
ganetespib the premedication must be excluding any QTc interval prolonging 
medications with known risk for Torsade de Pointes (see APPENDIX F). 
 
The standardised paclitaxel premedication scheme in PK patients consists of: 
1) Dexamethason 20 mg i.v. (in 100 ml NaCl), 30 min prior to the start of the 
paclitaxel-infusion (given as i.v. infusion over 10 min) 
2) Diphenhydraminhydrochlorid 50 mg tablets orally; 30 min prior to start of the 
paclitaxel infusion. 
3) Ranitidine 50 mg i.v. (in 20 ml NaCl), 20 min prior to the start of the paclitaxel-
infusion (given as iv bolus-injection over a minimum of 2 and a maximum of 10 
min) 
 
 
 


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10. 
STUDY MEDICATION 
The test drug used in the GANNET53 trial, ganetespib, is a 2nd generation Hsp90 inhibitor 
(synthetic small molecule). 
10.1 
Dosage and administration 
The route of administration of ganetespib and paclitaxel is intravenously. The agents will be 
administered as two separate 1-hour infusions. The sequence of administration will be 
ganetespib followed by paclitaxel.  
Paclitaxel premedication can be given according to local standards with the exception of day 
1 cycle 1 in patients participating in PK analysis (in this situation a standardised paclitaxel 
premedication is necessary, see section 9.8). Drugs which prolong QTc interval and have a 
known risk to cause Torsade de Pointes (TdP, see APPENDIX F), are to be avoided and 
drugs which prolong QTc interval and have a possible risk to cause TdP (see APPENDIX G) 
are to be used with caution in patients receiving ganetespib. 
 
Prophylactic medication with loperamideLoperamide 2 mg is strongly recommended 
in all patients who receive ganetespib and should be given 1-2 hours before 
ganetespib administration, to be repeated every 4 hours for the first 12 hours. 
Sufficient hydration should be provided in all patients. 
 
Part I: The first 3 patients will be treated with a starting dose of ganetespib of 100 mg/m2 in 
combination with paclitaxel (80 mg/m2, fixed dose). If this dose does not cause significant 
side effects (DLT) in the first cohort during cycle 1 (weeks 1-4), ganetespib will be escalated 
to 150 mg/m2, as a second cohort takes part in the study. If the dose of 150 mg/m2 does not 
cause significant side effects (DLT), it will be used in the GANNET53 phase II trial.  
 
In case of significant side effects (DLT) in the cohorts in phase I dose reductions of 
ganetespib are planned and described in section 7.2.  
 
Each patient will receive at least two cycles of experimental therapy and may continue 
treatment according to physician’s choice. If a patient did benefit from the experimental 
therapy it is recommended to continue treatment at dosage received until progression. 
 
Part II: An expected number of 222 patients will be treated with either the combination of 
ganetespib weekly (150 mg/m²) in combination with paclitaxel (80 mg/m2) or with paclitaxel 
(80 mg/m2) alone. Patients will receive the respective therapy until disease progression. 
 
After at least six cycles of ganetespib combination therapy, the physician is allowed to 
discontinue paclitaxel (e.g. in case of peripheral neuropathy) and to continue maintenance 
therapy with ganetespib (i.e. ganetespib once a week for 3 out of 4 weeks, at the same dose 
as used in the combination or re-escalated to the ganetespib dose level 0). 
 
The IMP ganetespib must be diluted prior to administration. The drug product is a clear, 
colourless-to-pale-yellow solution. The appropriate drug administration instructions per the 
preparation guidelines must be carefully followed prior to use.  


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The use of vascular access devices (VADs) such as ports and peripherally-inserted central 
catheters (PICCS) containing silicone for ganetespib/paclitaxel administration is permitted. 
Use of VADs made of any other material is not permitted. Following ganetespib 
administration through a VAD, care should be taken to flush the line after each dose of study 
drug. 
 
Ganetespib dose is calculated based on the patient’s body surface area (BSA). No dose 
capping will be performed in case of greater BSA. 
 
Please refer to the Pharmacy Manual for detailed ganetespib preparation guidelines.  
10.1.1 
Dose reduction levels for ganetespib 
DLT for phase I is defined in section 10.1.6. 
 
Ganetespib dose reductions in the first 2 cycles of phase I are detailed in section 7.2.1.  
If a patient stays on experimental treatment for more than 2 cycles in the phase I study, 
please follow the dose reduction and dose modification guidelines for ganetespib and 
paclitaxel described below (as in phase II). 
Patients in phase II of the trial, requiring a ganetespib dose reduction will be de-escalated 
one dose level with a maximum of three dose reductions allowed.  
A further indication for dose reduction will result in the patient being taken off study, see 
below.  
 
No dose re-escalation will be allowed with the exception of those who permanently 
discontinued paclitaxel, in which circumstance ganetespib may be re-escalated to 
dose level 0 at the discretion of the investigator.  
 
Dose delay and dose modification guidelines for specific ganetespib-related toxicity are 
described below. 
 
Table 3: Dose reduction levels for ganetespib 
DOSE LEVEL 
GANETESPIB DOSE 
0 
baseline dose (depending on cohort in phase I and 
established dose for phase II) 
Dose -1 
minus 25 mg/m2* 
Dose -2 
minus 25 mg/m2 further* 
Dose -3 
minus 25 mg/m2 further* 
Indication for further dose reduction 
off study 
* if dosage to be reduced should be 75 mg/m², then no further reduction is possible. 
 
In addition to the specific toxicities presented in the tables in section 10.1.3, if a patient 
develops any other significant and clinically relevant grade 3 or 4 toxicity thought to be 
related specifically to ganetespib, ganetespib will be held until the symptoms resolve to grade 
 1 or to the baseline grade. When treatment is resumed, ganetespib dose is reduced by 1 
dose level or discontinued if the patient is already receiving 75 mg/m2. 


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If grade  3 toxicity persists for more than 2 weeks from the last planned study drug 
administration or recurs after the maximum dose reduction, the patient will discontinue 
ganetespib treatment and receive a safety follow-up and will continue to be followed for 
unresolved adverse events and SAEs. The patient will receive long-term follow-up according 
to Appendix A. 
 
For Ganetespib no dose reduction is necessary due to a body surface area (BSA) above 2.0. 
10.1.2 
Dose reduction levels for paclitaxel 
Dose delay and dose modification guidelines for specific paclitaxel-related toxicity are 
described in the tables below.  
No re-escalation of paclitaxel dose will be allowed. 
Patients who permanently discontinue paclitaxel may continue ganetespib. Only these 
patients may be allowed to escalate ganetespib to dose level 0, per the clinical judgment of 
the investigator. 
 
Table 4: Dose reduction levels for paclitaxel 
 
DOSE  
LEVEL 
PACLITAXEL  
DOSE 
0 
80 mg/m2 
Dose -1 
60 mg/m2 
Dose -2 
40 mg/m2 
Indication for further dose reduction 
off paclitaxel 
 
 
In addition to the specific toxicities presented in the tables in section 10.1.3, if a patient 
experiences any other significant and clinically relevant grade 3 or 4 toxicity thought to be 
related to paclitaxel, paclitaxel will be held until symptoms resolve to grade  1 or to the 
baseline grade. When treatment is resumed, the paclitaxel dose will be reduced by 1 dose 
level permanently, or Paclitaxel will be discontinued if the patient is already receiving 40 
mg/m2. 
 
If grade  3 toxicity persists for more than 2 weeks from the last planned study drug 
administration or recurs after the maximum dose reduction, the patient will discontinue 
paclitaxel treatment. 
 
 
 
 
 
 
 


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10.1.3 
Dose modifications  
10.1.3.1 Dose modification for hypertransaminasaemia (AST/ALT) 
 
Grade 2 
(AST/ALT) 
Grade 3 
(AST/ALT) 
Grade 4 
(AST/ALT) 
Ganetespib treat at same dose 
level   
1st occurrence 
hold dose; reduce one dose level 
when recovered to ≤ grade 2  
hold dose; reduce 
one dose level 
when recovered to 
≤ grade 2  
 
2nd occurrence 
hold dose; reduce one dose level 
when recovered to ≤ grade 2 
Paclitaxel 
hold dose; treat at 
same dose level 
when recovered to 
≤ grade 1 
hold dose; reduce one dose level 
when recovered to ≤ grade 1 
Discontinue  
Patients who experience a grade  3 hepatic adverse event should have their liver enzymes 
and/or bilirubin checked twice per week until they are stable or recovered to  grade 2. 
 
10.1.3.2 Dose modification for neutropenia 
 
Grade 2 
neutropenia 
Grade 3 
neutropenia 
Grade 4 
neutropenia 
Ganetespib treat at same 
dose level 
1st or 2nd occurrence 
hold dose; treat at same 
dose level when recovered 
to ≥ 1,000 cells/mm3 
1st occurrence 
hold dose; treat at the same 
dose level when recovered to ≥ 
1,000 cells/mm3 
3rd occurrence 
hold dose; reduce one dose 
level when recovered to ≥ 
1,000 cells/mm3 
2nd occurrence  
hold dose; treat at same dose of 
ganetespib when recovered to ≥ 
1,000 cells/mm3 
Paclitaxel 
treat at same 
dose level  
 
1st occurrence 
Hold dose, treat at the same 
dose level when recovered 
to ≥ 1,000 cells/mm3 
 
1st occurrence 
Hold dose, if recovery to ≥ 1,000 
cells/mm3 occurs, by the next 
scheduled dose (or within 7 
days) reduce one dose level. 
If prolonged (14 days) 
neutropenia of < 1,000 
cells/mm³ occurs, discontinue 
paclitaxel 
2nd occurrence 
Discontinue  
2nd occurrence 
Discontinue  
 
In case of severe neutropenia paclitaxel will be reduced one dose level first, before reducing 
ganetespib. 
 


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10.1.3.3 Dose modification for hyperbilirubinaemia 
 
Grade 1 
hyperbilirubinaemia 
Grade 2 
hyperbilirubinaemia 
Grade 3 
hyperbilirubinaemia 
Grade 4 
hyperbilirubinaemia 
Ganetespib treat at same 
dose level 
hold dose; treat at 
same dose level 
when recovered 
to ≤ grade 1 
hold dose; reduce 
one dose level when 
recovered to ≤ grade 
1 or baseline  
hold dose; 
reduce one 
dose level when 
recovered  to ≤ 
grade 1 or 
baseline 
Paclitaxel 
treat at same 
dose level 
hold dose; treat at 
same dose level 
when recovered 
to ≤ grade 1 
hold dose; reduce 
one dose level when 
recovered to ≤ grade 
1 or baseline  
Discontinue 
Patients who experience a grade  3 hepatic adverse event should have their liver enzymes 
and/or bilirubin checked twice per week until they are stable or recovered to  grade 2. 
 
10.1.3.4 Dose modification for thrombocytopenia 
 
Grade 2 
thrombocytopenia 
Grade 3 
thrombocytopenia 
Grade 4 
thrombocytopenia 
Ganetespib treat at same 
dose level 
1st or 2nd occurrence 
hold dose; treat at same 
dose level when recovered to 
≤ grade 2 
1st occurrence 
hold dose; treat at the same 
dose level when recovered 
to ≤ grade 2  
3rd occurrence 
hold dose; reduce one dose 
level when recovered to ≤ 
grade 2  
 
2nd occurrence, currently 
on concurrent paclitaxel  
hold dose; treat at same 
dose of ganetespib when 
recovered to ≤ grade 2 
(paclitaxel discontinued as 
described below)  
2nd cumulative 
occurrence, currently on 
single agent ganetespib 
hold dose; reduce one dose 
level when recovered to ≤ 
grade 2 
Paclitaxel 
treat at same 
dose level when 
recovered to ≥ 
100,000 
cells/mm³  
1st occurrence 
Hold dose, treat at the same 
dose level when recovered to 
≥ 100,000 cells/mm³  
1st occurrence 
Hold dose, reduce one dose 
level when recovered to ≥ 
100,000 cells/mm³. 
2nd occurrence 
Hold dose; reduce one dose 
level when recovered to ≥ 
100,000 cells/mm³ 
2nd occurrence 
Discontinue  
In case of severe thrombocytopenia paclitaxel will be reduced one dose level first, before 
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10.1.3.5 Dose modification for peripheral neuropathy 
 
Grade 2 
peripheral neuropathy 
Grade 3 or 4 
peripheral neuropathy 
Ganetespib 
treat at same dose level 
hold dose; treat at same dose 
level when recovered to ≤ grade 2  
Paclitaxel 
treat, hold or discontinue at investigators 
discretion, if recurrent can also consider 
dose reduction  
Discontinue 
 
10.1.3.6 Dose modification for ganetespib-related gastrointestinal toxicity 
 
Grade 2 
gastrointestinal toxicity 
Grade 3 or 4 
gastrointestinal toxicity 
Ganetespib 
treat at same dose level 
hold dose; treat at same dose level 
when recovered to ≤ grade 2  
2nd occurrence: 
consider one dose level reduction 
Ensure that optimal prophylactic and therapeutic measures are taken (e.g. 
loperamideLoperamide). 
 
10.1.3.7 Dose modification for ganetespib-related QTc prolongation 
 
Grade 2 
QTc prolongation 
Grade 3 (> 500 ms on average of triplicate ECGs) 
or repeated grade 3 
or grade 4 
QTc prolongation 
Ganetespib 
treat at same dose 
level 
Discontinue 
 
Patients with reported QTc >500 ms (QTc prolongation Grade 3 severity) or with reported 
Grade 4 QTc prolongation (QTc >500 ms or >60 ms change from baseline and Torsades de 
Pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia) at 
any of the specified ECG time points (average of triplicate recordings) must discontinue 
treatment with ganetespib.  
Close cardiac monitoring should be ensured in case of a grade 3 QTc prolongation 
occurrence by: 
 
patient hospitalisation 
 
cardiac monitoring 
 
discharge of the patient after specialist review 
 
Drugs which prolong QTc interval and have a known risk to cause Torsade de Pointes (TdP, 
see APPENDIX F), are to be avoided and drugs which prolong QTc interval and have a 
possible risk to cause TdP (see APPENDIX G) are to be used with caution in patients  
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10.1.4 
Management guidelines of the most significant AE diarrhoea  
For diarrhoea the postulated mechanism of action is inhibition of EGFR in enterocytes that 
line the GI tract, leading to a transient secretory diarrhoea, limited to 24-48 hours following 
ganetespib infusion.  
This AE is readily manageable by antidiarrheal medication (loperamideLoperamide). 
Prophylactic use of loperamideLoperamide can reduce the occurrence of diarrhoea to 
approximately 40%. 
 
In the GANNET53 trial prophylactic medication with loperamideLoperamide is highly 
recommended. Loperamide 2 mg should be given prophylactically to patients 
receiving ganetespib before the onset of diarrhoea, starting approximately 1-2 hours 
before ganetespib administration, to be repeated every 4 hours for the first 12 hours.  
 
In the event of diarrhoea it is highly recommended to apply therapeutic medication with 
loperamideLoperamide.  
Patients should take loperamideLoperamide at an initial 4 mg dose (irrespective of the 
timing of the last prophylactic dose), followed by 2 mg doses every 4 hours. In the 
presence of uncomplicated grade 1 or 2 diarrhoea, loperamideLoperamide should be 
continued until the patient is free from diarrhoea for 12 hours. Total daily dose should 
not exceed 16 mg (eight capsules). 
 
For grade 3 or 4 diarrhoea or complicated grade 1 or 2 (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. 
 
In addition, due to the potential for dehydration, patients will be advised to maintain 
appropriate hydration. Blood chemistries, including electrolytes, will be regularly monitored 
and corrected as appropriate. 
10.1.5 
Study drug interruption or discontinuation 
The investigator must temporarily interrupt or permanently discontinue the study drug if 
continued administration of the study drug is believed to be contrary to the best interests of 
the patient. 
The interruption or premature discontinuation of study drug might be triggered by an AE, a 
diagnostic or therapeutic procedure, an abnormal assessment (e.g., laboratory abnormalities; 
see chapter 11.5.3), or for administrative reasons, in particular withdrawal of the patient’s 
consent. 
The reason for study drug interruption or premature permanent discontinuation must be 
documented in the CRF. 
 
The patient has to be taken off study drug permanently if interruption (time between two 
study drug applications) is longer than 4 weeks. It is permitted to omit 1 cycle during 
ganetespib maintenance therapy (after termination of paclitaxel after 6 cycles in phase I or 
phase II) in case of patients wish (e.g. because of vacation). An interruption of more than 1 
cycle during ganetespib maintenance must be discussed with the sponsor. 


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Study drug premature permanent discontinuation  
In case of premature permanent discontinuation of study treatment for any reason, the 
patient should have an EOT/safety follow-up visit with all the assessments performed 28 
days (+/- 7 days) after last administration of IMP or, if the decision was reached after this 
time frame, on day of decision for discontinuation.  
10.1.6 
Dose-limiting toxicity (DLT) in phase I  
For the phase I trial DLT will be defined as any of the following: 
 
NON-HAEMATOLOGIC adverse events: 
Any significant, clinically relevant grade > 3 adverse event, excluding: 
 
alopecia 
 
grade > 3 nausea 
 
vomiting and diarrhoea. These will only be considered a DLT if they occurred 
despite of optimal prophylactic measures (e.g. loperamideLoperamide) 
Fatigue must be grade 4 to be considered a DLT.  
 
Any grade ≥ 3 adverse event not improving to baseline or grade ≤ 1 within 21 days of last 
treatment dose and despite adequate supportive care/toxicity management. 
The following adverse events are always considered a DLT:  
 
Any grade ≥ 3 elevation of serum bilirubin  
 
> 10x ULN elevation of hepatic transaminases (AST or ALT), or > 10x ULN 
elevation of alkaline phosphatase (ALP) 
 
Any > 5-10 x ULN elevation of hepatic transaminases (ALT or AST) or ALP not 
improving to ≤ 5 x ULN (grade ≤ 2) by day 7 
 
HAEMATOLOGIC adverse events: 
 
Grade 4 thrombocytopenia 
 
Any grade 3 thrombocytopenia that has not recovered to grade  2 by day 7 of AE 
onset 
 
Grade 4 neutropenia lasting  7 days  
 
Febrile neutropenia 
 
OTHER adverse events: 
 
Any treatment-related toxicity prompting a dose reduction of ganetespib during 
the DLT observation period (D1 of cycle 1 to D28 of cycle 2) 
 
Grade ≥ 3 laboratory toxicity that are thought by the principal investigator (of the 
respective trial site) to be clinically insignificant or related to an underlying 
condition will not be considered as a DLT but will be forwarded to the DSMC. 
 
Adverse events that have an outcome of death and are considered possibly 
related to the study drug will be considered as DLTs. The possible relation to the 
study drug will be determined by the principal investigator.  
 
Adverse events related to disease progression or clearly are not study drug-
related will not be considered as DLTs. 
 


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Note: A dose hold of ganetespib during the DLT observation period does not 
constitute a DLT.  
 
Delayed toxicities will be carefully monitored and documented and will be included in the 
assessment of the recommended phase II dose of the combination. 
 
Toxicity will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03. 
 
 


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Table 5: Criteria for DLTs  
 
Adverse Event 
Grade Comment 
DLT (yes/no) 
NON-HAEMATOLOGIC 
any  
(with exceptions) 
4 
significant, clinically relevant 
Yes 
with the exceptions of  
1. alopecia 
2. nausea and 
3. vomiting without optimal 
prophylactic measures 
alopecia 
4 
 
no 
nausea 
4 
 
no 
vomiting 
4 
occurred despite optimal 
prophylactic measures (e.g. 
antiemesis, 
loperamideLoperamide) 
yes 
4 
no optimal prophylactic 
measures applied 
no 
diarrhoea 
4 
occurred despite optimal 
prophylactic measures (e.g. 
loperamideLoperamide) 
yes 
4 
no optimal prophylactic 
measures applied 
no 
fatigue 
4 
 
yes 
1, 2, 3 
 
no 
any  
3, 4 
Not improving to baseline or 
grade ≤ 1 within 21 days of last 
treatment dose and despite 
adequate supportive 
care/toxicity management 
yes 
elevation of serum 
bilirubin 
4 
 
yes 
elevation of AST, 
ALT, or ALP 
 
> 10 x ULN 
yes 
 
> 5-10 x ULN and not improving 
to ≤ 5 x ULN (grade ≤ 2) by day 
7 
yes 
 
> 5-10 x ULN which improved to 
≤ 5 x ULN (grade ≤ 2) by day 7 
no 
any AEs 
 
Related to disease progression 
or considered to be clearly not 
study drug-related 
no 
 
 
 


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HAEMATOLOGIC 
thrombocytopenia 
4 
 
yes 
thrombocytopenia 
3 
if not recovered to ≤ 2 by day 7 of AE 
onset 
yes 
3 
if recovered to ≤ 2 by day 7 of AE 
onset 
no 
neutropenia 
4 
If lasting ≥ 7 days 
yes 
4 
If lasting less than 7 days 
no 
febrile neutropenia any 
grade 
 
yes 
OTHER 
any toxicities  
 
Which are treatment-related and 
prompt a dose reduction of ganetespib 
during DLT observation time* 
yes 
Laboratory toxicity 
3, 4 
Considered as clinically insignificant 
by the PI or related to an underlying 
condition 
no 
any death 
 
Which is considered possibly related 
to the study drug (determined by the 
PI) 
yes 
 
Which is considered not related to the 
study drug (determined by the PI) 
no 
any AEs 
 
Related to disease progression or 
considered to be clearly not study 
drug-related 
no 
any dose hold 
during DLT 
observation time* 
 
 
no 
 
* DLT observation time: D1 of cycle 1 to D28 of cycle 2 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.2 
Summary of known and potential risks of the study drug ganetespib 
For the most up-to-date information on the safety profile of ganetespib, the list of expected 
AEs and those considered listed for regulatory purposes, please refer to the current version 
of the Investigator’s Brochure. The safety information in the Investigator’s Brochure is 
continually updated as the toxicity profile of ganetespib is refined. 
Ganetespib is well tolerated with most reported adverse events (AEs) being mild or 
moderate and readily manageable. In addition, there has been no observed pattern of 
specific target organ severe toxicity. 
 
The most frequently reported AEs (taking as reference the largest pooled data set of 
single agent studies, n=402 patients) were related to gastrointestinal (GI) toxicity and 
included diarrhoea (80.1%), nausea (44.5%), decreased appetite (31.6%), vomiting (27.4%), 
constipation (21.9%), and abdominal pain (20.9%). 
Non-GI-related events that occurred frequently included fatigue (53.5%), anaemia (21.1%), 
headache (20.4%), insomnia (21.1%), dyspnoea (17.4%), back pain (15.7%), blood alkaline 
phosphatase (AP) increase (15.9%), aspartate aminotransferase (AST) increase (16.2%), 
alanine 
aminotransferase 
(ALT) 
increase 
(15.4%), 
hypokalaemia 
(13.7%), 
and 
hyponatraemia (13.7%).  
 
AEs of grade 3 or higher [National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTC AE)], were seen in 275 patients (68%), and 126 patients (31%) 
had an AE deemed related to treatment (defined as possibly, probably, or definitely related to 
treatment). The most common treatment-related ≥ grade 3 AEs were diarrhoea (10%), 
fatigue (6%), increased lipase and hyponatraemia (3%), and hypophosphatemia, nausea, 
increased ALT and increased AST (2% each). 
 
160 patients (40%) experienced a treatment-emergent AE that was assessed as serious 
(SAE). 33 (8%) patients had an SAE deemed related to treatment. The most common 
treatment-related SAE was diarrhoea, which occurred in 7 (2%) patients. All other treatment-
related SAEs occurred in <1% of study patients. 
 
Note new safety information GIP (gastrointestinal perforation): 
GIP is a hole that for example develops through the wall of the oesophagus, stomach, small 
intestine, large bowel, rectum, or gallbladder. According to the Ganetespib Safety Update 
letter (dated 28-Sep-2015) 11 cases out of 1.509 patients (0.7%) exposed to ganetespib 
were identified with GIP overall. In the GANNET53 trial, which is including patients with 
platinum-resistant ovarian cancer, GIP has been observed in 2 of 65 patients (3.1%; cut-off 
date 15-Jan-2016). 
GIP was therefore identified as a new safety finding and as such has been added to the 
reference safety information of the Investigators Brochure (edition 11, dated 13-Nov-2015). 
 
 


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10.2.1 
Medications used with caution 
10.2.1.1 Inhibitors of P-glycoprotein efflux Transporters 
Concomitant medications that are strong inhibitors of P-glycoprotein efflux transporters 
should be used with caution during the study; examples of these medications include 
ritonavir, cyclosporine, verapamil, erythromycin, ketoconazole, itraconazole, quinidine, and 
elacridar. 
10.2.1.2 Medications associated with QTc interval prolongation 
Drugs which prolong QTc interval and have a known risk to cause Torsade de Pointes (TdP, 
see APPENDIX F), are to be avoided in patients receiving ganetespib. 
Medications that have the potential of prolonging the QTc interval but that are not linked to 
the occurrence of Torsades de Pointes (i.e. drugs with possible Torsades de Pointes risk) 
should also be avoided or used with caution (see APPENDIX G) in patients receiving 
ganetespib. The decision whether or not such a medication with possible Torsades de 
Pointes risk may be used will be made by the investigator, taking into consideration the 
patient’s medical history and current QTc values. 
10.2.1.3 Substrates of CYP3A4 or CYP2C19 
Preliminary results of a clinical drug-drug interaction study, examining the effect of 
ganetespib on the pharmacokinetics of the CYP2C19-sensitive probe omeprazole, show a 
modest (20%) increase in omeprazole exposure when co-administered with ganetespib. In 
vitro data implies expectation of greater interaction with CYP2C19 substrates than with 
CYP3A4 substrates. Caution is advised when sensitive narrow therapeutic range CYP3A4 or 
CYP2C19 substrates are concomitantly administered.  
 
Examples of compounds frequently used in oncology and metabolised predominantly by 
CYP3A4 or CYP2C19 are provided in Table 7.  
 


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Table 6: List of medications frequently used in oncology treatment that are substrates 
of CYP3A4 or CYP2C19 
Drug Class 
Drug 
Washout 
CYP3A4 substrate examples 
antibiotics (macrolide) 
clarithromycin 
17 hours 
 
erythromycin 
8 hours 
antifungals 
ketoconazole 
16 hours 
 
itraconazole 
4 days 
antiretrovirals 
amprenavir 
2 days 
 
indinavir 
16 hours 
 
lopinavir 
1 day 
 
nevirapine 
9 days 
 
ritonavir 
1 day 
 
saquinavir 
2 ½ days 
 
nelfinavir 
1 day 
Benzodiazepines  
midazolam 
10 hours 
 
alprazolam 
2 ½ days 
 
triazolam  
15 hours 
calcium channel blockers 
diltiazem 
1 day 
 
felodipine 
3 days 
 
nifedipine 
9 hours 
 
verapamil 
1 day 
Gastrointestinal (GI) Agents 
aprepitant 
1 week 
CYP2C19 substrate examples 
anticonvulsants 
phenytoin 
5 days 
antifungals 
voriconazole 
1 day 
antiretrovirals 
nelfinavir 
1 day 
 
 
10.3 
Summary of known and potential risks of paclitaxel 
Current information on the safety profile of paclitaxel is provided in detail in the Summary of 
Product Characteristics (SmPC). Investigators should refer to the SmPC for warnings and 
precautions particular to paclitaxel therapy. 
 
Premedication 
Due to the known potential for allergic reaction to paclitaxel and/or the cremophor vehicle, 
premedications should be administered in accordance with local standard of care in order 
to prevent severe hypersensitivity reactions.  
 
Of note, drugs which prolong QTc interval and have a known risk to cause Torsade de 
Pointes (TdP, see APPENDIX F) are to be avoided and drugs which prolong QTc interval 
and have a possible risk to cause TdP (see APPENDIX G) are to be used with caution in 
patients receiving ganetespib. 
 


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Therefore, for patients receiving ganetespib an example of a possible paclitaxel 
premedication containing no QT interval prolonging medications with known Torsade de 
Pointes risk is as follows: 
 
Dexamethasone  
 
 
20 mg i.v.  
 
30 minutes prior to paclitaxel 
Diphenhydraminhydrochlorid  
30 mg i.v.  
 
20 minutes prior to paclitaxel 
Ranitidine  
 
 
 
50 mg i.v.  
 
20 minutes prior to paclitaxel 
 
And patients participating in PK analysis in phase II will receive a standardised pre-
medication scheme see section 9.8. 
 
Investigators may use their discretion in determining the regimen to be used according to 
institutional guidelines or practice. 
 
Since significant hypersensitivity reactions may occur, appropriate supportive equipment 
should be available. 
Significant hypersensitivity reactions as characterised by dyspnoea and hypotension 
requiring treatment, angiooedema, and generalised urticaria have occurred in <1% of 
patients receiving paclitaxel after adequate premedication. 
These reactions are probably histamine-mediated. 
 
In the case of severe hypersensitivity reactions, paclitaxel infusion should be 
discontinued immediately, symptomatic therapy should be initiated and the patient 
should not be rechallenged with paclitaxel. 
 
34% of patients receiving paclitaxel (17% of all courses) experienced minor hypersensitivity 
reactions. These minor reactions, mainly flushing and rash, did not require therapeutic 
intervention nor did they prevent continuation of paclitaxel therapy. 
 
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-
limiting toxicity. Frequent monitoring of blood counts should be instituted during paclitaxel 
treatment. Patients should not be treated with paclitaxel in case neutrophil count is < 1,000 
cells/mm3 and platelet count is < 100,000 cells/mm3. 
 
Severe conduction abnormalities have been documented in <1% of patients during paclitaxel 
therapy and in some cases requiring pacemaker placement. If patients develop significant 
conduction abnormalities during paclitaxel infusion, appropriate therapy should be 
administered and continuous cardiac monitoring should be performed during subsequent 
therapy with paclitaxel. 
10.3.1 
Study drug delivery & drug storage conditions 
The IMP ganetespib will be provided by Synta Pharmaceuticals Corp. (Lexington, MA, USA) 
at no charge. Paclitaxel is considered an NIMP and will be supplied and covered by the local 
hospital/health insurer.  
The IMP ganetespib is a concentrate for solution for infusion provided in a single-use vial.  
 


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The IMP is supplied as ganetespib drug product, 25 mg/mL, 300 mg/vial (identified with a 
dark blue colour 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, colourless-to-
pale-yellow solution essentially free of visible particles. 
The 300 mg/vial drug products are shipped at ambient temperatures. No temperature 
monitoring devices are utilized during the shipping of this drug product. 
Storage of the 300 mg/vial drug product should be at 20-25°C (68°F to 77°F) with excursions 
allowed between 15°C and 30°C (59°F and 86°F). Alternatively, ganetespib drug product 
may be stored in a cool place between 8°C (46°F) and 20°C (68°F). DO NOT FREEZE. 
Infusion solutions must be stored at room temperature and exposure to direct light should be 
avoided.  
Please refer to the Pharmacy Manual for detailed information. 
10.3.2 
Study drug packaging and labelling 
Drug labelling, storage and distribution to the patient-recruiting sites will be done in 
accordance with all local legal requirements and conducted according to Good 
Manufacturing Practice. 
10.4 
Concomitant medications 
Throughout the study, investigators are permitted to use their clinical judgement when 
prescribing concomitant medications and treatments for trial patients. Local prescribing 
information and institutional guidelines should be followed as applicable. In all cases, 
concomitant medications and treatments should only be used with the intention of either 
maintaining existing medical conditions, or controlling cancer-related symptoms or treatment-
related complications. Caution should be exercised when using treatments that could 
potentially interfere with any of the study medications or the interpretation of the study 
results. For specific information, please refer to the ganetespib Investigators’ Brochure and 
the local prescribing information for whichever chemotherapy is being used. 
• 
The use of erythropoietin or other specific red blood cell growth factors and red blood 
cell transfusions will be permitted as clinically indicated during the study after 
documentation of anaemia secondary to the study treatment. These agents cannot be 
used prior to this occurrence. 
• 
The use of bone marrow colony-stimulating factors (such as granulocyte colony-
stimulating factor or granulocyte-macrophage colony-stimulating factor) is permitted as 
clinically indicated after documentation of neutropenia secondary to the study treatment. 
These agents cannot be used prior to this occurrence.  
• 
However, during the DLT observation time in Phase I (day 1 of cycle 1 through day 28 of 
cycle 2) these bone marrow colony-stimulating factors (such as granulocyte colony- 
stimulating factor or granulocyte-macrophage colony-stimulating factor) should not be 
used in order not to bias the lasting of e.g. neutropenia. 
• 
Other concomitant medications may be given as clinically indicated 
• 
A standard 3-5 day course of dexamethasone following the institutions standard of care 
for the prevention of chemotherapy-induced nausea and vomiting is allowed; steroids 
(inhaled, topical, or for physiologic replacement, or for short-term treatment of conditions 


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such as allergic reactions and asthma flares, or for appetite stimulation) and 
glucocorticoid daily doses (oral) ≤ 1.5 mg dexamethasone (or equivalent) are allowed. 
• 
Also see section “Medications Used with Caution” (section 10.2.1). 
Not allowed are: 
 
Use of medications associated with a high incidence of QTc prolongation and known risk 
of TdP in subjects receiving ganetespib should be avoided and drugs with QTc 
prolongation and possible risk of TdP should also be avoided or used with caution. See 
Appendix F and Appendix G, respectively.  
 
Treatment with other systemic anticancer agents (e.g., chemotherapy, hormonal therapy, 
and immunotherapy) or other treatments not part of protocol-specified anticancer therapy.  
 
Any oral, injected or implanted hormonal methods of contraception. The use of non-
hormonal contraceptives is required for WOCBP, as per the inclusion criteria in Section 
7.4.1.1. 
 
Concurrent investigational agents of any type. 
 
Use of herbal remedies for cancer treatment. 
 
The following treatments should be avoided because of the risk of immunosuppression: 
 
 
Chronic or high-dose oral corticosteroid therapy. 
 
Tumour necrosis factor-α inhibitors. 
 
Anti-T cell antibodies. 
 
 
 


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11. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Safety assessments will consist of monitoring and recording AEs, including SAEs; 
measurement of protocol-specified vital signs deemed critical to the safety evaluation of the 
study. 
 
11.1 
Adverse events 
It is the responsibility of the investigator(s) to report all adverse events in the eCRF. 
 
An AE is any untoward adverse change from the subject's baseline condition, i.e. any 
unfavourable and unintended sign including an abnormal laboratory finding, symptom or 
disease which is considered to be clinically relevant by the physician that occurs during the 
course of the study, whether or not considered related to the study drug. 
 
Adverse events include: 
 
Worsening or increase in frequency or intensity of a pre-existing disease or medical 
condition. 
 
Abnormal laboratory tests (see section 11.5.3). 
 
Adverse events do not include:  
 
Pre-planned interventions/hospitalisations (see also section 11.2.1) 
 
Medical or surgical procedures, e.g. surgery, endoscopy, tooth extraction, 
transfusion. However, the event leading to the procedure is an AE. If this event is 
serious, the procedure must be described in the SAE narrative. 
 
Pre-existing disease or medical condition that does not worsen. 
 
Overdose of either study drug or concomitant medication without any signs or 
symptoms.  
 
11.2 
Serious adverse events (SAEs) 
A serious adverse event (SAE) is defined by the International Conference on Harmonisation 
(ICH) guidelines and WHO GCP guidelines as any AE fulfilling at least one of the following 
criteria: 
 
Results in death. 
 
Life-threatening – defined as an event in which the subject was, in the judgment of 
the investigator, at risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death had it been more severe. 
 
Requiring subject's hospitalisation or prolongation of existing hospitalisation – 
inpatient hospitalisation refers to any inpatient admission, regardless of length of stay. 
 
Resulting in persistent or significant disability or incapacity (i.e. a substantial 
disruption of a person’s ability to conduct normal life functions). 
 
Congenital anomaly or birth defect. 
 
Is medically significant or requires intervention to prevent at least one of the 
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Important medical events that may not immediately result in death, be life-threatening, or 
require hospitalisation may be considered as SAEs when, based upon appropriate medical 
judgement, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definitions above. 
11.2.1 
Hospitalisation – Prolongation of existing hospitalisation 
Hospitalisation is defined as an overnight stay in a hospital unit and/or emergency room. 
An additional overnight stay defines a prolongation of existing hospitalisation. 
 
The following is not considered a SAE and should be reported as an AE only: 
 
Treatment on an emergency or outpatient basis for an event not fulfilling the definition 
of seriousness given above and not resulting in hospitalisation. 
 
The following reasons for hospitalisation are not considered AEs or SAEs: 
 
Hospitalisation for cosmetic elective surgery, social and/or convenience reasons. 
 
Standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g. hospitalisation for coronary angiography in a subject with stable angina 
pectoris. 
 
Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g. hospitalisation for chemotherapy for cancer, elective hip replacement for arthritis. 
 
Placement of a central venous catheter (e.g. port-a-cath) as a routine intervention 
11.2.2 
Suspected unexpected serious adverse reactions (SUSARs) 
SUSARs are serious adverse reactions with a suspected causal relationship to the study 
drug that is unexpected (not previously described in the SmPC - Summary of Product 
Characteristics or Investigator’s Brochure) and serious.  
11.2.3 
Pregnancy 
Any pregnancy that occurs during study participation must be reported to the 
investigator/sponsor immediately. If a pregnancy is confirmed during the study, the continued 
use of the study drug must be immediately evaluated. If a pregnancy should be confirmed 
after informed consent has been obtained, but prior to the initiation of the study drug, the 
patient must be excluded from the trial. 
 
The pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child. Pregnancy complications (including spontaneous abortions) 
and elective terminations must be reported as an AE or SAE. 
 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the investigational product, must be promptly reported to the principal 
investigator/sponsor. 
 
 


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11.3 
Severity of adverse events/Grading 
Intensity of all adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version v4.03 on a five-point scale (grade 1 to 5) and 
reported in detail on the eCRF. 
 
Adverse events not listed in the CTCAE v4.03 should be graded as follows: 
 
CTC grade  Equivalent 
to 
Definition 
Grade 1  
Mild  
Discomfort noticed but no disruption of normal daily activity 
Grade 2  
Moderate  
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated although this 
could improve the overall wellbeing or symptoms of the patient. 
Grade 3  
Severe  
Inability to work or perform normal daily activity; treatment or 
medical intervention is indicated in order to improve the overall 
wellbeing or symptoms; delaying the onset of treatment is not 
putting the survival of the patient at direct risk. 
Grade 4  
Life 
threatening/
disabling  
An immediate threat to life or leading to a permanent mental or 
physical condition that prevents work or performing normal 
daily activities; treatment or medical intervention is required in 
order to maintain survival. 
Grade 5  
Death  
AE resulting in death 
 
11.4 
Relationship to study drug 
Medical judgment should be used to determine the cause of the AE, considering all relevant 
factors such as (but not limited to) the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication. 
 
Is there a reasonable possibility that the study drug caused the event? 
Answer YES (possibly, probably or definitely related) if one or more of the following criteria 
apply: 
 
The event follows a reasonable temporal sequence from administration of study drug. 
 
The event could not be reasonably attributed to the known characteristics of the 
patient’s clinical state, environmental or toxic factors or other modes of therapy 
administered to the patient. 
 
The event follows a known pattern of response to study drug. 
The event disappears or decreases on cessation or reduction in dose of the study 
drug. (It should be noted that in some situations an AE will not disappear or decrease 
in intensity upon discontinuation of study drug despite other clear indications of 
relatedness). 
 
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11.5 
Procedures for recording of adverse events 
Investigators should use correct medical terminology/concepts when recording AEs on the 
Adverse Event eCRF. Avoid lay terminology and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. See 
section 11.1 for the definition of an AE. 
11.5.1 
Diagnosis versus signs and symptoms 
Infusion-associated reactions 
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction. 
 
Other adverse events 
For AEs other than infusion-associated reactions, a diagnosis (if known) should be recorded 
on the Adverse Event eCRF rather than individual signs and symptoms (e.g. record only liver 
failure or hepatitis rather than jaundice and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterised as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded on 
the Adverse Event eCRF. If a diagnosis is subsequently established, all previously reported 
AEs based on signs and symptoms should be nullified and replaced by AE report based on 
the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
11.5.2 
Persistent or recurrent adverse events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points. Such events should only be recorded once on the Adverse Event 
eCRF. The initial severity (mild, moderate, severe, life-threatening/disabling) of the event 
should be recorded, and the severity should be updated to reflect the most extreme severity 
any time the event worsens. If the event becomes serious, the Adverse Event eCRF should 
be updated to reflect this. 
A recurrent AE is one that resolves between patient evaluation time points and subsequently 
recurs. Each recurrence of an AE should be recorded separately on the Adverse Event 
eCRF. 
11.5.3 
Abnormal laboratory values or vital signs 
Not every laboratory abnormality qualifies as an AE. A laboratory test result/vital sign should 
be reported as an AE if it meets any of the following criteria: 
 
Accompanied by clinical symptoms. 
 
Results in a change in study treatment (e.g. dosage modification, treatment 
interruption, or treatment discontinuation). 
 
Results in a medical intervention (e.g. potassium supplementation for hypokalaemia) 
or a change in concomitant therapy. 
 
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It is the investigator’s responsibility to review all laboratory findings/vital signs. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality or vital sign should be classified as an AE. 
If a clinically significant laboratory abnormality or vital sign is a sign of a disease or syndrome 
(e.g. alkaline phosphatase and bilirubin 5 times the ULN associated with cholecystitis), only 
the diagnosis (i.e. cholecystitis) should be recorded on the Adverse Event eCRF. The 
supporting laboratory abnormalities should be included in the event description if the event 
qualifies as a SAE. 
11.5.4 
Progression of underlying malignancy 
Progression of underlying malignancy and clinical symptoms of progression (e.g. ileus, sub-
ileus, vomiting)  are not reported as an adverse event if it is clearly consistent with the 
suspected progression of the underlying cancer as defined by RECIST 1.1 criteria or GCIG 
criteria for CA-125. Clinical symptoms of disease progression may be reported as adverse 
events if the symptom cannot be determined as exclusively due to the progression of the 
underlying malignancy or does not fit the expected pattern of progression for the disease 
under trial. Hospitalisation due solely to the progression of underlying malignancy should 
NOT be reported as a serious adverse event. 
If there is any uncertainty about an adverse event being due only to the disease under the 
clinical trial it should be reported as an AE or SAE. 
11.6 
Reporting procedures 
A special section is designated to adverse events in the case report form where the following 
details must be entered: 
 
Type of adverse event (diagnosis or syndrome; if not known signs or symptoms) 
 
Start (date) 
 
End (date) 
 
Severity (mild, moderate, severe, life-threatening/disabling, death) 
 
Serious (no / yes) 
 
Unexpected (no / yes)  
 
Outcome (resolved, ongoing, ongoing – improved, ongoing – worsening) 
 
Action taken (none, study medication dose reduced, study medication interrupted, 
study 
medication 
discontinued, 
medication 
therapy, 
surgical 
procedure, 
hospitalisation, other) 
 
Relation to study drug (possibly, probably or definitely related or unlikely, probably not 
related or definitely not related) 
 
Certain events require immediate reporting to allow the sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report such 
events to the sponsor immediately; under no circumstances should reporting take place more 
than 24 hours after the investigator learns of the event. The following is a list of events that 
the investigator must report to the sponsor within 24 hours after learning of the event, 
regardless of relationship to study drug: 
 
Serious adverse events. 
 
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The investigator must report new significant follow-up information for these events to the 
sponsor immediately (i.e. no more than 24 hours after becoming aware of the information). 
New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis. 
 
Significant new diagnostic test results. 
 
Change in causality based on new information. 
 
Change in the event’s outcome, including recovery. 
 
Additional narrative information on the clinical course of the event. 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
11.6.1 
Reporting procedures for SAEs and SUSARs 
In the event of a serious adverse event, the investigator has to use all supportive measures 
for best patient treatment. And the SAE form must be completed by the investigator and 
reported no more than 24 hours after awareness of the event.  
 
The following details should be available with the initial report: 
 
Patient number  
 
Patient: date of birth, ethnic origin 
 
Name of investigator and investigating site 
 
Period of administration 
 
The suspected investigational medicinal product (IMP) 
 
The adverse event assessed as serious 
 
Concomitant disease and medication 
 
Relevant medical history 
 
Short description of the event and outcome 
o Description 
o Onset and if applicable, end 
o Therapeutic intervention 
o Causal relationship to each of the study drugs 
o Hospitalisation or prolongation of hospitalisation 
o Death, life-threatening, persistent or significant disability or incapacity 
 
If applicable, the initial report should be followed by the follow-up report, indicating the 
outcome of the SAE. 
 
For SAEs, SUSARs and pregnancies, the sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and 
outcome information (e.g. from hospital discharge summaries, consultant reports, autopsy 
reports) in order to perform an independent medical assessment of the reported case. A 
follow-up SAE form must also be completed and reported appropriately.  
 
SUSARs will be reported to the required regulatory authorities, investigators/institutions, and 
ethical committees in compliance with all reporting requirements according to local 
regulations and good clinical practice by the sponsor and/or its designees. 
 


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For detailed reporting procedures please refer to the SAE reporting manual. 
11.6.2 
Adverse event reporting period 
Investigators will seek information on AEs at each patient contact throughout the trial. All 
AEs, whether reported by the patient or noted by study personnel, will be recorded in the 
patient’s medical record and on the Adverse Event eCRF.  
 
After informed consent has been obtained but prior to initiation of the study drug, only 
SAEs considered to be related to a protocol-mandated intervention should be reported (e.g. 
SAEs related to invasive procedures such as biopsies). 
 
After initiation of study drug, all AEs and SAEs regardless of relationship to the study 
drug, will be reported until safety follow-up at 28 days after the last dose of IMP or EOT or 
until the event has resolved to baseline grade or better, the event is assessed as stable by 
the investigator, the patient is lost to follow-up, or the patient withdraws consent.  
After the safety follow-up, investigators should report any deaths, SAEs, or other AEs of 
concern that are believed to be related to prior treatment with the study drug.  
 
Any Serious Adverse Event (SAE) that is ongoing at the time of safety follow-up should be 
followed-up until resolved. If, after follow-up, return to baseline status or stabilization cannot 
be established, an explanation should be recorded on the Adverse Event eCRF. 
 
11.7 
Handling of safety parameters 
11.7.1 
Treatment and follow-up of adverse events 
Adverse events, especially those for which a relationship to study drug is suspected, should 
be followed up until they have stabilised or returned to baseline status. If a clear explanation 
is established it should be recorded on the eCRF. 
11.7.2 
Follow-up of abnormal laboratory test value 
In the event of unexplained and clinically significant laboratory test values, the tests should 
be repeated immediately if possible and followed up until they have returned to the normal 
range and/or an adequate explanation of the abnormality is found. If a clear explanation is 
established it should be recorded on the eCRF. 
 
 
 


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12. 
DOCUMENTATION AND DATA MANAGEMENT 
12.1 
Retention of documents/Investigator site file 
The sponsor must keep all essential documents of the clinical study after completion or 
discontinuation of the study for a minimum of 15 years. The sponsor must archive all study-
relevant documents in accordance with the legal regulation. 
 
The clinical trial centre is provided with an Investigator Site File (ISF). This contains all 
documents which are required for the clinical study. It is the responsibility of the investigator 
to file all documents in the ISF. During monitoring visits the ISF will be reviewed to verify 
accuracy and completeness in accordance with the regulations. After completion or 
discontinuation of the study this ISF has to be stored in a safe place for 15 years. 
 
The investigators must keep all records and documents, which are related to the study or the 
allocation of investigational medicinal products (e.g. data entry form, consent form, list of the 
allocations of investigational medicinal products and further relevant documents), for a 
minimum of 15 years. 
Medical records and other original data have to be kept for the longest possible duration, 
which the hospital, the institution or the private practice permits. 
12.1.1 
Case report form (CRF) 
For each patient enrolled, an eCRF must be completed and electronically signed by the 
principal investigator or authorised delegate from the study staff. This also applies to records 
for those patients who fail to complete the study (even during a pre-enrolment screening 
period if an eCRF was initiated). If a patient withdraws from the study, the reason must be 
noted on the eCRF. If a patient is withdrawn from the study because of a treatment-limiting 
AE, thorough efforts should be made to clearly document the outcome. 
The investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor in the eCRFs and in all required reports. 
 
12.2 
Data and safety monitoring committee (DSMC) 
The DSMC will be responsible for independently evaluating the safety of the patients 
participating in the trial. All captured adverse events and safety reports will be reported to the 
DSMC for assessment. All SAEs will be forwarded to the DSMC immediately after knowledge 
of it. The DSMC can, if required, amend the protocol and in case the risk to the patients 
outweighs the potential benefit end the study prematurely. 
The DSMC will meet (e.g. via teleconference) on a regular basis over the course of the study 
and may also meet on an unscheduled basis if any unexpected safety concerns arise.  


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12.3 
Quality control and quality assurance 
Monitorings and audits are performed for the quality assurance within the clinical study and 
the A-AGO trial centre and the project management team will continuously monitor the 
recruitment process. 
12.3.1 
Periodic monitoring 
It is understood that the responsible sponsor-assigned monitor (or designee) will contact and 
visit the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial (eCRFs, source notes, and other pertinent data), provided that patient 
confidentiality is maintained in accord with local requirements. 
Monitoring and auditing procedures developed or endorsed by the sponsor will be adhered 
to, in order to comply with ICH-GCP guidelines and local legal requirements to ensure 
acceptability of the study data.  
 
It will be the monitor's responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them, evaluation of the SAEs reports according to the 
regulations, evaluation of compliance. The monitor should have access to laboratory test 
reports and other patient records needed to verify the entries in the eCRF. The investigator 
(or his/her deputy) agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
12.3.2 
Audit and inspections 
Upon request, the investigator will make all study-related source data and records available 
to a qualified quality assurance auditor mandated by the sponsor or to competent authority 
inspectors. The main purposes of an audit or inspection are to confirm that the rights and 
wellbeing of the subjects have been adequately protected, and that all data relevant for 
assessment of safety and efficacy of the investigational product have appropriately been 
reported to the sponsor. 
12.4 
Reporting and publications  
12.4.1 
Reports 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 
individual. The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting). 
 
In addition to the requirements for reporting all AEs to the sponsor, investigators must 
comply with requirements for reporting SAEs within 24 hours after knowledge of which to the 
sponsor. Investigators may receive written safety reports or other safety-related 
communications from the sponsor. Investigators are responsible for ensuring that such 


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reports are reviewed and processed in accordance with health authority requirements and 
the policies and procedures established by their IRB/EC, and archived in the site’s study file. 
12.4.2 
Publication of study results  
The data from the whole trial will be reported together. Positive and inconclusive as well as 
negative results will be published or otherwise made publicly available.  
The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor and 
the coordinating investigator (A-AGO, Nicole Concin) prior to submission. 
The rights of the investigator and of the A-AGO with regard to publication and dissemination 
of the results of this trial are described in the Consortium Agreement.  
13. 
ETHICAL AND LEGAL ASPECTS 
13.1 
Informed consent of subjects 
Following comprehensive instruction regarding the nature, significance, impact and risks of 
this clinical trial, the patient must give written consent to participation in the study. 
During the instruction the trial participants are to be made aware of the fact that they can 
withdraw their consent – without giving any reasons – at any time without their further 
medical care being influenced in any way. 
In addition to the comprehensive instructions given to the trial participants by the investigator, 
the trial participants also receive a written patient information sheet in comprehensible 
language, explaining the nature and purpose of the study and its progress. 
The patients must agree to the possibility of study-related data being passed on to relevant 
authorities. 
The patients must be informed in detail of their obligations in relation to the trial participants 
insurance in order not to jeopardise insurance cover. The informed consent form has to be 
signed and dated by the patient and the investigator and stored in the Investigator Site File. 
One copy of the informed consent form has to be handed over to the patient. 
No study specific procedures are allowed to be carried out prior to signing of the informed 
consent form. 
13.2 
Acknowledgement/Approval of the study 
The study groups will submit this protocol and any related document provided to the subject 
(such as subject information used to obtain informed consent) to the responsible 
Independent Competent Authority (ICA) and Independent Ethics Committee (IEC) or 
Institutional Review Board (IRB) in their respective country according to legal requirements. 
Approval from the committee must be obtained before starting the study.  
The clinical trial shall be performed in full compliance with the legal regulations according to 
applicable local laws and regulatory requirements. 


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13.2.1 
Changes in the conduct of the study 
Protocol amendments 
Proposed amendments must be submitted to the appropriate competent authorities (CAs) 
and ECs. Substantial amendments may be implemented only after CA/EC approval has been 
obtained. Amendments that are intended to eliminate an apparent immediate hazard to 
subjects may be implemented prior to receiving CA/EC approval. However, in this case, 
approval must be obtained as soon as possible after implementation. 
 
Study termination 
If the sponsor or the investigator decides to terminate the study before it is completed, they 
will notify each other in writing stating the reasons of early termination. In terminating the 
study, the sponsor and the investigator will ensure the adequate consideration is given to the 
protection of the subject interests. The investigator/trial group or sponsor will notify the 
relevant CA and EC. Documentation will be filed in the Trial Master and Investigator Site 
Files. 
 
Clinical study report (CSR) 
Within one year after the final completion of the study, a full CSR will be prepared by the 
sponsor and submitted to the EC and the competent authority. 
The investigator will be asked to review and sign the final study report. 
 
13.3 
Insurance 
During their participation in the clinical trial the patients will be insured as defined by legal 
requirements. The sponsor is providing insurance in order to indemnify (legal and financial 
coverage) the investigator/trial centre against claims arising from the study, except for claims 
that arise from malpractice and/or negligence. The compensation of the subject in the event 
of study-related injuries will comply with the applicable regulations. 
 
13.4 
Ethics and Good Clinical Practice (GCP) 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the "Declaration of Helsinki" (as amended at the 56th WMA General Assembly, 
Tokyo, Japan, 2008) and with the laws and regulations of the country in which the clinical 
research is conducted. 
The investigator of the clinical trial shall guarantee that only appropriately trained personnel 
will be involved in the study. All studies must follow the ICH-GCP Guidelines (June 1996).  
 
 


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14. 
REFERENCES 
 
(1)  Oberaigner W, Minicozzi P, Bielska-Lasota M, Allemani C, de AR, Mangone L et al. 
Survival for ovarian cancer in Europe: the across-country variation did not shrink in 
the past decade. Acta Oncol 2012 April;51(4):441-53. 
 
(2)  Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G et 
al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011 December 
29;365(26):2484-96. 
 
(3)  du Bois A., Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of 
surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a 
combined exploratory analysis of 3 prospectively randomized phase 3 multicenter 
trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe 
Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les 
Etudes des Cancers de l'Ovaire (GINECO). Cancer 2009 March 15;115(6):1234-44. 
 
(4)  Schorge JO, Garrett LA, Goodman A. Cytoreductive surgery for advanced ovarian 
cancer: quo vadis? Oncology (Williston Park) 2011 September;25(10):928-34. 
 
(5)  Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD et al. 
Randomized phase III trial of gemcitabine compared with pegylated liposomal 
doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007 July 
1;25(19):2811-8. 
 
(6)  Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent 
epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal 
doxorubicin versus topotecan. J Clin Oncol 2001 July 15;19(14):3312-22. 
 
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patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial from 
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Ann Oncol 2013;23(2):346-52(2012 Feb). 
 
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single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol 
2002 May 1;20(9):2365-9. 
 
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insights and old challenges. Clin Cancer Res 2005 October 15;11(20):7273-9. 
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Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. 
J Pathol 2010 May;221(1):49-56. 
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genomic 
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carcinoma. 
Nature 
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30;474(7353):609-15. 
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p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 2004 
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15. 
APPENDICES 
Appendix A - VISIT AND ASSESSMENT SCHEDULE 
Part I 
Phase I trial 
SCREENING 
TREATMENT and OBSERVATION 
Safety 
FU1 
FOLLOW-
UP2 
Cycle 1 
Cycle 2 
OPTIONAL 
Cycle 3 
OPTIONAL 
 
Follow schedule of 
cycle 1 through 3 
for subsequent 
cycles until 
progression4; 
 
 after six cycles of 
combination 
treatment with 
ganetespib and 
paclitaxel, ganetespib 
mono therapy is 
allowed7 
week number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
Cycle day 
- 28 days 
1 
8 
15 
21 
1 
8 
15 
21 
1 
8 
15 
21 
  
 
Informed consent  
X 
  
  
  
No treatment 
  
  
  
No treatment 
  
  
  
No treatment 
  
 
Inclusion / Exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
 
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
 
Demographic data  
X 
 
 
 
 
 
 
 
 
 
 
 
CTa 
X 
 
 
 
 
 
 
X5 
 
 
 
(X) 
Physical examination incl. vital signsb (BP, HR, T)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGc 
X 
X6 
  
  
X 
  
  
X 
  
  
X 
 
LVEF 
X 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory testsd 
X 
X 
X3 
X3 
X 
X3 
X3 
X 
X3 
X3 
X 
 
CA-125e 
X 
X 
  
  
X 
  
  
X 
  
  
X 
(X) 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testf 
X 
X 
  
  
X 
  
  
X 
  
  
X 
 
Administration of ganetespib and paclitaxel 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Survival status, additional cancer therapy 
 
 
 
 
 
 
 
 
 
 
 
X 


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Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; CA = cancer antigen; CT = 
computerised tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organisation for Research and 
Treatment of Cancer; FACT = Functional Assessment of Cancer Therapy; FU = follow-up; GOG = Gynecologic Oncology Group; HR = heart rate; LVEF = left 
ventricular ejection fraction; m² = meter squared; MRI = magnetic resonance imaging; RBC = red blood cell(s); T = temperature; WBC = white blood cell(s) 
  
 
a Tumour assessments for response and progression require CT scans of the pelvis and abdomen and (by X-ray or preferably by CT-scan) of the chest. MRI 
scans can be used for patients who are allergic to radiographic contrast agents. Throughout the study, the same assessment technique must be used. 
Ultrasound scanning is not an acceptable substitute for CT scanning.  
b Blood pressure and heart rate will be measured after patient was in a sitting position for at least 10 minutes. 
c ECGs for each patient should be obtained from the same machine whenever possible. A consistent method of QTc calculation must be used for each patient’s 
QTc measurements. QTcF (Fridericia’s formula) is preferred. For the screening ECG averaged values of triplicate recordings are necessary. 
d Laboratory tests include assessment of  
                                    o Haematology  
                                                      § Haemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†, platelets 
 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
 
o Biochemistry panel 
 
 
 
 
 
 
 
§ Sodium, potassium, calcium 
 
 
 
 
 
§ Serum albumin, serum urea 
 
 
 
 
 
 
§ ALT, AST, LDH, AP, total bilirubin  
 
 
 
 
 
§ Creatinine 
 
 
 
 
 
 
 
  Laboratory assessments from screening can be used for day 1 of cycle one if not older than 3 days. 
e Measured twice during the screening period; collections should be at least 1 day apart, one sample needs to be within 1 week of treatment start. 
f Urine/serum pregnancy testing is not required in patients after surgical sterilisation or bilateral ovarectomy or hysterectomy; > 12 months amenorrhea, age > 60 
years. 
g Between consent and first study drug dose only SAEs that are protocol-related will be recorded. Thereafter all AEs until Safety FU and all SAEs through Safety 
FU until resolved. 
 
1 28 days (+/- 7 days) after last IMP administration, due to any reason 
2 Patients who had EOT of any reason prior to progression will have monthly (+/- 7 days) follow-up after EOT, incl. CA-125 and recording of additional cancer 
treatment, and a CT every eight weeks (± 7 days) until progression.  
All patients after progression will have only survival status and information to additional cancer therapy collected every 3 months (+/- 14 days) until death of 
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3 Haematology only 
4 Patients who show a benefit from the treatment can continue to receive ganetespib and/or paclitaxel according to physician’s choice. Treatment needs to be 
recorded in eCRF.  
5 CT should be done every 8 weeks (+/- 7 days) from date of cohort assignment regardless of any treatment delays or interruptions until progression 
6 additionally to the pre-dose ECG a 24-hours (+/- 4 hours) post-ganetespib-dose ECG will be performed on day 1 cycle 1; 24-hours post-ganetespib dose ECG 
is also strongly recommended to be performed at day 1 of each subsequent cycle. 
7After six cycles of ganetespib combination therapy, the physician is allowed to discontinue paclitaxel (e.g. in case of peripheral neuropathy) and to continue 
maintenance therapy with ganetespib (i.e. ganetespib once a week for 3 out of 4 weeks; at the dose level previously used in the combination or re-escalated to 
the ganetespib dose level 0) 
 
 


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Part II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase II trial 
SCREENING 
TREATMENT and OBSERVATION (-1/+2 days)  
Safety 
FU1 
FOLLOW
-UP2 
Cycle 1 
Cycle 2 
Cycle 3 
Follow schedule of  
cycle 1 through 3  
for subsequent cycles 
until progression 
 
 
Combination of 
paclitaxel+ganetespib 
should be 
administered for a 
minimum of 6 cycles, 
thereafter ganetespib 
mono therapy is 
allowed in 
experimental arm. 
 
 
week number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
Cycle day 
- 28 days 
1 
8 
15 
21 
1 
8 
15 
21 
1 
8 
15 
21 
 
 
Informed consent 
X 
 
 
 
No treatment 
 
 
 
No treatment 
 
 
 
No treatment 
 
 
Inclusion / Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination incl. vital signsa (BP, HR, T) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CT/MRIb 
X 
 
 
 
 
 
 
X 
 
 
 
(X) 
ECGc 
X 
X3 
 
 
X3 
 
 
X3 
 
 
X 
 
LVEF 
X 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory testsd 
X 
X 
X4 
X4 
X 
X4 
X4 
X 
X4 
X4 
X 
 
CA-125e 
X 
X 
 
 
X 
 
 
X 
 
 
X 
(X) 
Pregnancy testf 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
PRO questionnaireg 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Adverse eventsh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of ganetespib/paclitaxel or paclitaxel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Survival status, additional cancer therapy, date of 
subsequent progression  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Archival tissue samplesi  
X 
 
 
 
Biopsy of the actual relapsej 
X 
 
 
 
Collection of ascitesk 
X 
X 
 
 
Blood sample collection for biomarker analysisl 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Blood sample collection for PK analysis (selected 
sites only; in a subgroup of 30 patients)m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; CA = cancer antigen; CT = 
computerised tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organisation for Research and 
Treatment of Cancer; FACT = Functional Assessment of Cancer Therapy; FU = follow-up; GOG = Gynecologic Oncology Group; HR = heart rate; LVEF = left 
ventricular ejection fraction; m² = meter squared; MRI = magnetic resonance imaging; PRO = person reported outcome; RBC = red blood cell(s); T = 
temperature; WBC = white blood cell(s) 
 
a Blood pressure and heart rate will be measured after patient was in a sitting position for at least 10 minutes. 
b Tumour assessments for response and progression require CT scans of the pelvis and abdomen and (by X-ray or preferably by CT-scan) of the chest. MRI 
scans can be used for patients who are allergic to radiographic contrast agents. Throughout the study, the same assessment technique must be used. 
Ultrasound scanning is not an acceptable substitute for CT scanning.  
CTs will be performed every 8 weeks (+/- 7 days) starting from date of randomisation and/or cohort assignment regardless of any study drug interruptions until 
progression. 
c ECGs for each patient should be obtained from the same machine whenever possible. A consistent method of QTc calculation must be used for each 
patient’s QTc measurements. QTcF (Fridericia’s formula) is preferred. For the screening ECG averaged values of triplicate recordings are necessary. 
d Laboratory tests include assessment of 
 
o Haematology  
§ Haemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†, platelets 
 
 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
 
o Biochemistry panel 
 
 
 
 
 
 
 
§ Sodium, potassium, calcium 
 
 
 
 
 
                                                      § Serum albumin, serum urea 
 
 
 
 
 
§ ALT, AST, LDH, AP, total bilirubin  
 
 
 
 
§ Creatinine 
 
 
 
 
 
 
 
e Measured at least once during the screening period. One of these samples needs to be within 2 weeks of treatment start. 
f Urine/serum pregnancy testing is not required in patients after surgical sterilisation or bilateral ovarectomy or hysterectomy; > 12 months amenorrhea, age > 
60 years. 
g Questionnaires EORTC QLQ-C30, EORTC QLQ-OV28, and additional items  
h Between consent and first study drug dose only SAEs that are protocol-related will be recorded. Thereafter all AEs until Safety FU and all SAEs through 
Safety FU until resolved. 
i Archival tissue samples are mandatory for central histopathological review (for confirmation of high-grade serous, high-grade endometrioid, or undifferentiated 
epithelial ovarian, fallopian tube or primary peritoneal carcinoma) at screening and for the determination of p53 mutational status. 
j CT- or sonographically-guided biopsy samples of the actual relapse (after informed consent has been obtained, but prior to the first study drug administration) 


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is mandatory whenever technically feasible. Biopsy tissue of the actual relapse will be collected in all patients. 
k The collection of ascites is highly recommended at screening and during the course of treatment 
l Blood collection for biomarker analysis will be performed before and 24 hours after (+/- 3 h) the administration of study drug on day 1 of cycle 1 (the sample 
time is relative to the start of the study drug infusion). On day 1 of cycles 2 and 3 blood collection will be performed exclusively before the study drug 
administration. After cycle 3, blood collection will take place on day 1 of every other cycle (i.e. cycles 5, 7, 9 etc.) prior to administration of study drug. 
m Ganetespib+paclitaxel patients: on day 1 to day 3, blood samples will be drawn at 0 (pre-dose), 1, 1.5, 2.5, 3.5, 4.5, 6.5, 8, 24, and 55 hours following the 
start of the ganetespib infusion. The 1-hour and 2.5 hour nominal time samples are to be taken prior to stopping the ganetespib and paclitaxel infusions, 
respectively and may be drawn as early as 55 ± 5 minutes. The Day 2 and Day 3 samples (24 and 55 hour time points) may be drawn ± 2 hours from the 
nominal times. All samples are to be drawn contralateral to the infusion. All sample times are relative to the start of the ganetespib infusion and presume the 
paclitaxel infusion starts 30 min after termination of the 1-hour ganetespib infusion (i.e.: ganetespib infusion start is defined as time zero). In the 30 min 
between ganetespib and paclitaxel infusion a standardised paclitaxel pre-medication will be administered. 
Paclitaxel-only patients: on day 1 to day 3, blood samples will be drawn at 0 (pre-dose), 1, 2, 3, 5, 6.5, 22.5, and 53.5 hours following the start of the 
paclitaxel infusion. Sample 0 (pre-dose) is to be taken immediately prior to the start of the paclitaxel infusion, i.e. after the application of the standardised 
paclitaxel premedication. The 1-hour nominal time samples are to be taken prior to stopping the paclitaxel infusion and may be drawn as early as 55 ± 5 
minutes. The Day 2 and Day 3 samples (22.5 and 53.5 hour time points) may be drawn ± 2 hours from the nominal times. All samples are to be drawn 
contralateral to the infusion. All sample times are relative to the start of the paclitaxel infusion (i.e.: paclitaxel infusion start is defined as time zero). 
 
1 Safety follow-up to be performed 28 days (+/- 7 days) after last IMP (ganetespib) administration or drop out of the trial of any other cause 
2 Patients who had EOT of any reason prior to progression will have monthly (+/- 7 days) follow-up, incl. CA-125 and recording of additional cancer treatment 
until progression. PRO will be assessed every 2 weeks (+/- 7 days). 
All patients after progression will have only survival status, date of second progression, information to additional cancer therapy and PRO collected every 3 
months (+/- 14 days) until death of patient or end of study, whichever occurs first. 
3 ECGs during treatment period needs to be done only in patients who receive ganetespib. A pre-ganetespib dose ECG will be performed on day 1 of each 
cycle (on the day of medication dosing, or one day prior). In addition, a 24-hours post-ganetespib-dose ECG (+/- 4 hours) will be performed on day 1 of cycle 
1. In case of QTc prolongation on day 1 cycle 1 (pre- or post-dose), further intensified ECG monitoring will be performed at the next dosing of ganetespib (day 
8 cycle 1 according to Figure 8 options 2-4). In case of normal QTc findings on day 1 cycle 1 (pre- and post-dose), standard ECG monitoring will be performed 
consisting of pre-dose ECGs on days 1 of all following cycles (also see Figure 8, option 1) 
4 Haematology only 
 


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Appendix B – ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work  
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair  
5 
Dead  
* Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.:  
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-  
655, 1982.  
Also see: http://www.ecog.org/general/perf_stat.html (last accessed: 05.09.2013) 
 
 
 
 


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Appendix C – CTCAE (version 4.03) 
 
The NCI Common Terminology Criteria for Adverse Events version 4.03, instituted 14 June, 
2010, is available at:  
http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf  
(last accessed: 30. April 2014) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix D – Patient-reported outcome questionnaire, additional items 
 
These are the questionnaires in German. Questionnaires will be provided for each national 
language. 


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Two additional items have been added to the mentioned questionnaires: 
 
Did you have gastrointestinal problems during the past week? 
 Not at all 
 a little 
 quite a bit 
 very much 
 
If yes, have you been upset by your gastrointestinal problems during the past week? 
 Not at all 
  A little 
 Quite a bit 
 Very much 
 
 
 
 


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Appendix E – Tumour assessment (RECIST) 1.1 (Eisenhauer et al. 2009) 
 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable 
as follows: 
 
Measurable tumour lesions: Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum of: 
1. 10 mm by CT scan (CT scan slice thickness no >5 mm). 
2. 10 mm calliper measurement by clinical exam (lesions which cannot accurately be 
measured with callipers should be recorded as non-measurable). 
3. 20 mm by chest X-ray. 
 
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 >5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable lesions: All other lesions, including small lesions (longest diameter <10 
mm or pathological lymph nodes with P10 to <15 mm short axis) as well as truly non-
measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical exam and is not measurable by reproducible imaging techniques. 
 
Method of Assessment 
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than 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 and ≥ 10 mm diameter as assessed using callipers (e.g. skin nodules). For the 
case of skin lesions, documentation by colour photography including a ruler to estimate the 
size of the lesion is suggested. When lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness >5 mm, the minimum size for a measurable lesion should be twice the slice 
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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 utilisation of these techniques for objective tumour 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
 
Tumour markers: Tumour markers alone cannot be used to assess objective tumour 
response. If markers are initially above the upper normal limit, however, they must normalise 
for a patient to be considered in complete response. Because tumour markers are disease-
specific, instructions for their measurement should be incorporated into protocols on a 
disease-specific basis. 
 
Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumour types such as 
germ cell tumours, where known residual benign tumours can remain). When effusions are 
known to be a potential adverse effect of treatment (e.g., with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment can be considered if the measurable tumour has 
met criteria for response or SD in order to differentiate between response (or SD) and PD. 
 
Tumour response evaluation 
 
Assessment of overall tumour burden and measurable disease: To assess objective 
response or future progression, it is necessary to estimate the overall tumour burden at 
baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included in protocols where objective tumour 
response is the primary endpoint. 
Measurable disease is defined by the presence of at least one measurable lesion (as 
detailed above). In studies where the primary endpoint is tumour progression (either time to 
progression or proportion with progression at a fixed date), the protocol must specify if entry 
is restricted to those with measurable disease or whether patients having non-measurable 
disease only are also eligible. 
 
Baseline documentation of ‘target’ and ‘non-target’ lesions: When more than one 
measurable lesion is present at baseline all lesions up to a maximum of five lesions total 
(and a maximum of two lesions per organ) representative of all involved organs should be 
identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and 
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Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance the 
next largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumour. Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis 
of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a 
node is involved by solid tumour. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 20 
mm·to 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In 
this example, 20 mm should be recorded as the node measurement. All other pathological 
nodes (those with short axis ≥10 mm but <15 mm) should be considered non-target lesions. 
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterise any objective 
tumour regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, ‘absent’, 
or in rare cases ‘unequivocal progression’. In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
Response criteria 
Evaluation of target lesions: 
• 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
• 
Partial response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
• 
Progressive disease (PD): At least a 20% increase in the sum of 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 reduction to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
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The best overall response is the best response recorded from randomisation into the trial 
until the end of treatment taking into account any requirement for confirmation. On occasion 
a response may not be documented until after the end of therapy so protocols should be 
clear if post-treatment assessments are to be considered in determination of best overall 
response. Protocols must specify how any new therapy introduced before progression will 
affect best response designation. 
The patient’s best overall response assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions. 
Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomised trials where 
response is the primary endpoint, confirmation of PR or CR is needed to deem either one the 
‘best overall response’. This is described further below. 
 
Reference 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
 
 


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Appendix F – List of drugs with known Torsades de Pointes risk 
 
This list was obtained from the Arizona Center for Education and Research on Therapeutics 
(AZCERT) website, accessed 18 February 2016. 
https://www.crediblemeds.org 
 
Substantial evidence supports the conclusion that these drugs, when used as directed in 
labelling, can prolong the QT interval and can have a risk of Torsades de pointes (TdP) in 
some patients. 
 
Therefore Drugs that prolong QTc interval and have a known risk to cause TdP 
should be avoided. 
 
Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Route 
Amiodarone 
Cordarone®, 
Pacerone®, Nexterone® 
Anti-arrhythmic Abnormal heart 
rhythm 
oral, 
injection 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiester
ase 3 inhibitor 
Thrombocythemia 
oral 
Arsenic trioxide  Trisenox® 
Anti-cancer 
Leukemia 
injection 
Astemizole * 
Hismanal® 
Antihistamine 
Allergic rhinitis 
oral 
Azithromycin 
Zithromax®, Zmax® 
Antibiotic 
Bacterial infection 
oral, 
injection 
Bepridil * 
Vascor® 
Anti-anginal 
Angina Pectoris 
(heart pain) 
oral 
Chloroquine 
Aralen® 
Anti-malarial 
Malaria infection 
oral 
Chlorpromazine Thorazine®, Largactil®, 
Megaphen® 
Anti-psychotic / 
Anti-emetic 
Schizophrenia/ 
nausea 
oral, 
injection, 
suppository 
Cilostazol 
Pletal® 
Phospodiestera
se 3 inhibitor 
Intermittent 
claudication 
oral 
Ciprofloxacin 
Cipro®, Cipro-XR®, 
Neofloxin® 
Antibiotic 
Bacterial infection 
oral, 
injection 
Cisapride * 
Propulsid® 
GI stimulant 
Heartburn 
 oral 
Citalopram 
Celexa®, Cipramil® 
Anti-
depressant, 
SSRI 
Depression 
oral 
Clarithromycin 
 Biaxin®, Prevpac® 
Antibiotic 
Bacterial infection 
oral 
Cocaine 
Cocaine 
Local 
anesthetic 
Topical anesthetic 
topical 
Disopyramide 
Norpace® 
Anti-arrhythmic Abnormal heart 
rhythm 
oral 
Dofetilide 
 Tikosyn® 
Anti-arrhythmic Abnormal heart 
rhythm 
oral 
Domperidone 
Motilium®, Motillium®, 
Motinorm Costi®, 
Nomit® 
Anti-nausea 
Nausea 
oral, 
injection, 
suppository 


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Dronedarone 
Multaq® 
Anti-arrhythmic Atrial Fibrillation 
oral 
Droperidol 
 Inapsine®, Droleptan®, 
Dridol®, Xomolix® 
Anti-psychotic / 
Anti-emetic 
Anesthesia adjunct, 
nausea 
 injection 
Erythromycin 
 E.E.S.®, Robimycin®, 
EMycin®, Erymax®, Ery-
Tab®, Eryc Ranbaxy®, 
Erypar®, Eryped®, 
Erythrocin Stearate 
Filmtab®, Erythrocot®, 
E-Base®, Erythroped®, 
Ilosone®, MY-E®, 
Pediamycin®, Zineryt®, 
Abboticin®, Abboticin-
ES®, Erycin®, PCE 
Dispertab®, 
Stiemycine®, Acnasol®, 
Tiloryth® 
Antibiotic 
Bacterial infection; 
increase GI motility 
oral, 
injection 
Escitalopram 
Cipralex®, Lexapro®, 
Nexito®, Seroplex®, 
Elicea®, Lexamil®, 
Lexam®  
 Anti-
depressant, 
SSRI 
Major depression/ 
Anxiety disorders 
oral 
Flecainide 
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine® 
Anti-arrhythmic Abnormal heart 
rhythm 
oral 
Fluconazole 
Diflucan®, Trican® 
Antifungal 
Fungal infection 
oral, 
injection 
Gatifloxacin * 
Tequin® 
Antibiotic 
Bacterial infection 
oral, 
injection 
Grepafloxacin 
Raxar® 
Antibiotic 
Bacterial infection 
oral 
Halofantrine 
Halfan® 
Anti-malarial 
Malaria infection 
oral 
Haloperidol 
Haldol®, Aloperidin®, 
Bioperidolo®, 
Brotopon®, Dozic®, 
Duraperidol®, Einalon 
S®, Eukystol®, 
Halosten®, Keselan®, 
Linton®, Peluces®, 
Serenace®, Serenase®, 
Sigaperidol® 
Anti-psychotic Schizophrenia, 
agitation 
oral, 
injection 
Ibutilide 
Corvert® 
Anti-arrhythmic Abnormal heart 
rhythm 
injection 
Levofloxacin 
Levaquin®, Tavanic® 
Antibiotic 
Bacterial Infection 
oral, 
injection 
Levomethadyl  Orlaam® 
Opiate 
Pain control, narcotic 
dependence 
oral 
Mesoridazine  
Serentil® 
Anti-psychotic Schizophrenia 
oral 
Methadone 
Dolophine®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, 
Heptadon® 
Opiate 
Pain control, narcotic 
dependence 
oral, 
injection 
Moxifloxacin 
Avelox®, Avalox®, 
Avelon® 
Antibiotic 
Bacterial infection 
oral, 
injection 


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Ondansetron 
Zofran®, Anset®, 
Ondemet®, Zuplenz®, 
Emetron®, Ondavell®, 
Emeset®, Ondisolv®, 
Setronax® 
Anti-emetic 
Nausea, vomiting 
oral, 
injection 
Oxaliplatin 
Eloxatin® 
Antineoplastic 
Agent 
Cancer 
injection 
Papaverine HCl none 
Vasodilator, 
Coronary 
Diagnostic adjunct 
injection 
Pentamidine 
Pentam® 
Antibiotic 
Pneumocystis 
pneumonia 
injection 
Pimozide 
Orap® 
Anti-psychotic Tourette's tics 
oral 
Probucol * 
Lorelco® 
Antilipemic 
Hypercholesterolemi
a 
oral 
Procainamide  
Pronestyl®, Procan® 
Anti-arrhythmic Abnormal heart 
rhythm 
injection 
Propofol 
Diprivan®, Propoven® 
Anesthetic, 
general 
Anesthesia 
injection 
Quinidine 
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, 
Cin-Quin®, Quinora® 
Anti-arrhythmic Abnormal heart 
rhythm 
oral, 
injection 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, 
general 
Anesthesia 
inhaled 
Sotalol 
Betapace®, Sotalex®, 
Sotacor® 
Anti-arrhythmic Abnormal heart 
rhythm 
oral 
Sparfloxacin * 
Zagam® 
Antibiotic 
Bacterial infection 
oral 
Sulpiride 
Dogmatil®, Dolmatil®, 
Eglonyl®, Espiride®, 
Modal®, Sulpor® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral 
Terfenadine * 
Seldane® 
Antihistamine 
Allergic rhinitis 
oral 
Thioridazine 
Mellaril®, 
Novoridazine®, Thioril® 
Anti-psychotic Schizophrenia 
oral 
Vandetanib 
Caprelsa® 
Anti-cancer 
Thyroid cancer 
oral 
 
* removed from market 
 


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Appendix G – List of drugs with possible Torsades de Pointes risk 
 
This list was obtained from the Arizona Center for Education and Research on Therapeutics 
(AZCERT) website, accessed 18 February 2016. 
https://www.crediblemeds.org 
 
Substantial evidence supports the conclusion that these drugs, when used as directed in 
labelling, can prolong the QT interval and can possibly have a risk of Torsades de pointes 
(TdP) in some patients. 
 
Therefore Drugs that prolong QTc interval and have a possible risk to cause 
TdP should be used with caution. 
 
Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Route 
Alfuzosin 
Uroxatral® 
Alpha1-blocker Benign prostatic 
hyperplasia 
oral 
Apomorphine 
Apokyn®, Ixense®, 
Spontane®, Uprima® 
Dopamine 
agonist 
Parkinson's disease 
injection 
Aripiprazole 
Abilify®, Aripiprex® 
Anti-psychotic, 
atypical 
Psychosis, Adjunct 
for Depression 
oral, 
injection 
Artenimol + 
piperaquine 
Eurartesim® 
Animalarial 
Malaria 
oral 
Asenapine 
Saphris®, Syscrest® 
Antipsychotics 
Schizophrenia 
oral 
Atazanavir 
Reyataz® 
Anti-viral 
HIV/AIDS 
oral 
Atomoxetine 
Strattera® 
Norepinephrin
e reuptake 
inhibitor 
ADHD 
oral 
Bedaquiline 
Sirturo® 
Antibiotic 
Tuberculosis, drug 
resistant 
oral 
Bortezomib 
Velcade®, Bortecad® 
Proteasome 
inhibitor 
Multiple 
Myeloma,lymphoma 
injection 
Bosutinib 
Bosulif® 
Tyrosine 
kinase inhibitor 
Leukemia 
oral 
Ceritinib 
Zykadia® 
Kinase 
Inhibitor 
Cancer (Lung) 
oral 
Clomipramine 
Anafranil® 
Antidepressant
, Tricyclic 
Depression 
oral 
Clozapine 
Clozaril®, Fazaclo®, 
Versacloz® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral 
Crizotinib 
Xalkori® 
Kinase 
inhibitor 
Anti-cancer 
oral 
Dabrafenib 
Tafinlar® 
Anti-cancer 
Melanoma 
oral 
Dasatinib 
Sprycel® 
Tyrosine 
kinase inhibitor 
Leukemia 
oral 
Delamanid 
Deltyba® 
Antibiotic 
Tuberculosis, drug 
resistant 
oral 
Desipramine 
Pertofrane®, 
Norpramine® 
Antidepressant
, Tricyclic 
Depression 
oral 
Dexmedetomi
dine 
Precedex®,  Dexdor®,  
Dexdomitor® 
Sedative 
Sedation 
injection 


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Dolasetron 
Anzemet® 
Anti-nausea 
Nausea, vomiting 
oral, 
injection 
Eribulin 
mesylate 
Halaven® 
Anti-cancer 
Metastatic breast 
neoplasias 
injection 
Famotidine 
Pepcid®, Fluxid®, 
Quamatel® 
H2-receptor 
antagonist 
Peptic ulcer/ GERD 
oral, 
injection 
Felbamate 
Felbatol® 
Anti-
convulsant 
Seizure 
oral 
Fingolimod 
Gilenya® 
Sphingosine 
phospate 
receptor 
modulator 
Multiple Sclerosis 
oral 
Foscarnet 
Foscavir® 
Anti-viral 
HIV/AIDS 
injection 
Gemifloxacin 
Factive® 
Antibiotic 
Bacterial infection 
oral 
Granisetron 
Kytril®, Sancuso®, 
Granisol® 
Anti-nausea 
Nausea, vomiting 
oral, 
injection, 
topical 
Hydrocodone 
- ER 
HysinglaTM ER, Zohydro 
ER 
Analgesic 
Pain, severe 
oral 
Iloperidone 
Fanapt®, Fanapta®, 
Zomaril® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral, 
injection 
Imipramine 
(melipramine) 
Tofranil® 
Antidepressant
, Tricyclic 
Depression 
oral 
Isradipine 
Dynacirc® 
Anti-
hypertensive 
High blood pressure 
oral 
Lapatinib 
Tykerb®, Tyverb® 
Anti-cancer 
Breast cancer, 
metastatic 
oral 
Lithium 
Eskalith®, Lithobid® 
Anti-mania 
Bipolar disorder 
oral, 
injection 
Mifepristone 
Korlym®, Mifeprex® 
Progesterone 
antagonist 
Pregnancy 
Termination 
oral 
Mirabegron 
Myrbetriq® 
Beta3 
adrenergic 
antagonist 
Overactive bladder 
oral 
Mirtazapine 
Remeron 
Anti-
depressant, 
Tetracyclic 
Depression 
oral 
Moexipril/HCT
Z 
Uniretic®, Univasc® 
Anti-
hypertensive 
High blood pressure 
oral 
Nicardipine 
Cardene® 
Anti-
hypertensive 
High blood pressure 
oral, 
injection 
Nilotinib 
Tasigna® 
Anti-cancer 
Leukemia 
oral 
Norfloxacin 
Noroxin®, Ambigram® 
Antibiotic 
Bacterial infection 
oral 
Nortiptyline 
Pamelor®, Sensoval®, 
Aventyl®, Norpress®, 
Allegron®, Noritren®, 
Nortrilen® 
Antidepressant
, Tricyclic 
Depression 
oral 
Ofloxacin 
Floxin® 
Antibiotic 
Bacterial infection 
oral, 
injection 
Olanzapine 
Zyprexa®, Zydis®, 
Relprevv® 
Anti-psychotic, 
atypical 
Schizophrenia, 
bipolar 
oral, 
injection 
Oxytocin 
Pitocin®, Syntocinon® 
Oxytocic 
Labor stimulation 
injection 


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Paliperidone 
Invega®, Xepilon® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral, 
injection 
Panobinostat 
Farydak® 
Antineoplastic 
agent 
Multiple myeloma 
oral 
Pasireotide 
Signifor® 
Somatostatin 
analog 
Cushings Disease 
injection, 
topical 
Pazopanib 
Votrient® 
Tyrosine 
kinase inhibitor 
Anti-cancer 
oral 
Perflutren 
lipid 
microspheres 
Definity® 
Imaging 
contrast agent 
Echocardiography 
injection 
Pipamperone  
Dipiperon (E.U) 
Antipsychotic 
Schizophrenia 
oral 
Promethazine 
Phenergan® 
Anti-psychotic 
/ Anti-emetic 
Nausea 
oral, 
injection, 
supposit
ory 
Ranolazine 
Ranexa®, Ranozex® 
Anti-anginal 
Chronic angina 
oral 
Rilpivirine 
Edurant®, Complera®, 
Eviplera® 
Anti-viral 
HIV/AIDS 
oral 
Risperidone 
Risperdal® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral, 
injection 
Roxithromycin  Rulide®, Xthrocin®, 
Roxl-150®, Roxo®, 
Surlid®, Rulide®, 
Biaxsig®, Roxar®, 
Roximycinv®, 
Roxomycin®, Rulid®, 
Tirabicin®, Coroxin® 
Antibiotic 
Bacterial infection 
oral 
Saquinavir 
Invirase®(combo) 
Anti-viral 
HIV/AIDS 
oral 
Sertindole 
Serdolect®, Serlect® 
Anti-psychotic, 
atypical 
Anxiety, 
Schizophrenia 
oral 
Sorafenib 
Nexavar® 
Tyrosine 
kinase inhibitor 
Anti-cancer 
oral 
Sunitinib 
Sutent® 
Anti-cancer 
Renal cell cancer, 
GIST 
oral 
Tacrolimus 
Prograf®, Prograf®, 
Advagraf®, Protopic® 
Immunosuppre
ssant 
Immune suppression oral, 
injection 
Tamoxifen 
Nolvadex®(discontinue
d 6/13), Istubal®, 
Valodex® 
Anti-cancer 
Breast cancer 
oral 
Telavancin 
Vibativ® 
Antibiotic 
Bacterial infection 
injection 
Telithromycin 
Ketek® 
Antibiotic 
Bacterial infection 
oral 
Tetrabenazine 
Nitoman®, Xenazine® 
Monoamine 
Transporter 
Inhibitor 
Chorea 
(Huntington’s 
disease) 
oral 
Tizanidine 
Zanaflex®, Sirdalud® 
Muscle 
relaxant 
Spasticity 
oral 
Tolterodine 
Detrol®, Detrusitol® 
Muscle 
relaxant 
Bladder spasm 
oral 
Toremifene 
Fareston® 
Estrogen 
agonist/antago
nist 
Anti-cancer 
oral 


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Trimipramine 
Surmontil®, 
Rhotrimine®, Stangyl® 
Antidepressant
, Tricyclic 
Depression 
oral 
Tropisetron 
Navoban®, Setrovel® 
Antiemetic 
Nausea, vomiting 
oral, 
injection 
Vardenafil 
Levitra® 
Phosphodieste
rase inhibitor 
Vasodilator 
oral 
Vemurafenib 
Zelboraf® 
Kinase 
inhibitor 
Anti-cancer 
oral 
Venlafaxine 
Effexor®, Efexor® 
Anti-
depressant, 
SNRI 
Depression 
oral 
Vorinostat 
Zolinza® 
Anti-cancer 
Lymphoma 
oral