Conditions: Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Carcinoma
Keywords: Ganetespib Niraparib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 122
Healthy volunteers: no

Brief summary:
This study will be performed in women with platinum-sensitive, high-grade serous, high-grade endometrioid, undifferentiated epithelial ovarian cancer, carcinosarcoma, fallopian tube or primary peritoneal cancer (proven by central histo-pathological review).

A total of 120 subjects will be randomized (1:1:1) to three different treatment arms: (A) Standard arm (arm A): Carboplatin (AUC5 d1, q3w i.v.) in combination with Paclitaxel (175 mg/m² d1, q3w i.v.) or Carboplatin (AUC4 d1, q3w i.v.) in combination with Gemcitabine (1000 mg/m² d1, d8, q3w i.v.) followed by maintenance therapy with Niraparib (200/ 300 mg oral daily, q4w) // (B) First experimental arm (arm B): Ganetespib (150 mg/m2, d1, q3w) in combination with Carboplatin (AUC5 d1, q3w i.v.) followed by maintenance treatment with Niraparib (200/ 300 mg oral daily, q4w) // (C) Second experimental arm (arm C): Ganetespib (150 mg/m² d1, q3w i.v.) plus Carboplatin (AUC5 d1, q3w i.v.) followed by Ganetespib (100 mg/m² d1, d8, d15, d22, q4w i.v.) and Niraparib (200 mg oral daily, q4w).

Chemotherapy treatment will be given for 6 cycles, maintenance treatment with Ganetespib will be given for a maximum of 9 months or until disease progression, maintenance treatment with Niraparib can continue until disease progression.

Detailed description:

Arms:
arm 1: Carboplatin (AUC5 d1, q3w i.v.) in combination with Paclitaxel (175 mg/m² d1, q3w i.v.) or Carboplatin (AUC4 d1, q3w i.v.) in combination with Gemcitabine (1000 mg/m² d1, d8, q3w i.v.) followed by maintenance therapy with Niraparib (200/ 300 mg oral daily, q4w) arm 2: Ganetespib (150 mg/m2, d1, q3w) in combination with Carboplatin (AUC5 d1, q3w i.v.) followed by maintenance treatment with Niraparib (200/ 300 mg oral daily, q4w) arm 3: Ganetespib (150 mg/m² d1, q3w i.v.) plus Carboplatin (AUC5 d1, q3w i.v.) followed by Ganetespib (100 mg/m² d1, d8, d15, d22, q4w i.v.) and Niraparib (200 mg oral daily, q4w)

Interventions: intervention 1: Ganetespib intervention 2: Niraparib intervention 3: Carboplatin intervention 4: Paclitaxel intervention 5: Gemcitabine
Intervention descriptions: intervention 1: Ganetespib dose during chemotherapy will be 150mg/m² (q3w) Ganetespib dose during maintenance treatment will be 100mg/m² (q1w) intervention 2: Niraparib starting dose during maintenance treatment will be 200mg or 300mg depending on subject's body weight and subject neutrophil count (QD) intervention 3: In combination with Gemcitabine: Carboplatin dose will be AUC4 (q3w) In combination with Paclitaxel: Carboplatin dose will be AUC5 (q3w) intervention 4: Paclitaxel dose will be 175mg/m² (q3w) intervention 5: Gemcitabine dose will be 1000mg/m² (q3w, d1 \& d8)

Protocol document:
Prot_SAP_000.pdf: 
EUDARIO 
 
 
EUDRACT Nr: 2017-004058-40 
Confidential 
 
 
Date: 12Nov2020 
Version 4.0 Page 1 of 155 
 
 
 
 
 
A multicentre, open-label, three-arm randomised Phase II trial 
assessing the safety and efficacy of the HSP90 inhibitor Ganetespib 
in combination with Carboplatin followed by maintenance treatment 
with Niraparib versus Ganetespib plus Carboplatin followed by 
Ganetespib and Niraparib versus Carboplatin in combination with 
standard chemotherapy followed by Niraparib maintenance 
treatment in platinum-sensitive ovarian cancer patients 
 
 
EUDARIO: European Trial on enhanced DNA Repair Inhibition in Ovarian 
Cancer  
 
A seventh framework programme (FP7) project of the European Union 
(Grant agreement no 602602) 
 
 
EUDRACT Number: 2017-004058-40 
 
 
      
 
  
   
 
 
 
 


EUDARIO 
 
 
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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 Belgian BGOG trial 
centre, except to the extent necessary to obtain informed consent from those persons to whom 
the study drug may be administered. 
 


EUDARIO 
 
 
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1 CONTACTS & SIGNATURES SPONSOR  
Sponsor  
KU Leuven, UZLeuven – BGOG, Belgium, Department of Gynaecological Oncology, 
Herestraat 49, 3000 Leuven, Belgium 
Phone: +32 16 34 74 19/+32 16 34 29 96, Fax: +32 16 34 76 87,  
E-mail: joke.deroover@uzleuven.be / ellen.reynders@uzleuven.be  
 
 
_____________________________________ 
 
 
___________________ 
Signature (Prof. Dr. Ignace Vergote) 
 
 
Date 
 
 
_____________________________________ 
 
 
___________________ 
Signature (Joke De Roover)  
 
 
 
Date 
 
Coordinating investigator  
Univ.-Prof. Dr. Nicole Concin 
Department of Gynaecological Oncology, Catholic University of Leuven, Belgium 
Department of Gynaecology and Obstetrics, Medical University of Innsbruck, Austria  
Phone: +43-699 12787212, Fax: +32 16 34 76 87 
E-mail: nicole.concin@uzleuven.be, nicole.concin@i-med.ac.at  
 
 
____________________________________ 
 
 
___________________ 
Signature (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 
 


EUDARIO 
 
 
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 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 
Prof. Dr. Ignace Vergote 
 
 
 
Place, Date, Signature 
Coordinating investigator 
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. 
 
 
 
 


EUDARIO 
 
 
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Protocol authorisation – Investigator 
Study title 
 
Eudario 
A multicentre, open-label, three-arm randomised Phase II trial assessing the safety and 
efficacy of the HSP90 inhibitor Ganetespib in combination with Carboplatin followed by 
maintenance treatment with Niraparib versus Ganetespib plus Carboplatin followed by 
Ganetespib and Niraparib versus Carboplatin in combination with standard chemotherapy 
followed by Niraparib maintenance treatment in platinum-sensitive ovarian cancer patients 
 
Version: 4.0 
EudraCT Number: 2017-004058-40 
 
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: ___________________________________________         


EUDARIO 
 
 
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2 TABLE OF CONTENTS  
 
1 
CONTACTS & SIGNATURES SPONSOR .......................................................... 3 
 
Declaration of the sponsor and the coordinating investigator ........................ 4 
2 
TABLE OF CONTENTS ...................................................................................... 6 
3 
LIST OF TABLES .............................................................................................. 10 
4 
PROTOCOL SYNOPSIS ................................................................................... 13 
5 
SCHEMATIC DIAGRAM OF THE STUDY DESIGN .......................................... 19 
6 
ABBREVATIONS AND DEFINITIONS .............................................................. 20 
7 
BACKGROUND AND STUDY RATIONALE ..................................................... 23 
 
Ovarian cancer ............................................................................................ 23 
 
Study Rationale ........................................................................................... 24 
 
Rationale for Combination of Carboplatin with Ganetespib ..............................24 
 
Rationale for Combination of Ganetespib with PARP-inhibitor Niraparib .........25 
Rationale to test our approach in a p53 mutant background ..........................................26 
8 
INFORMATION ON THE INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) 
GANETESBIP .......................................................................................................... 28 
 
Name and Chemical Information ................................................................. 28 
 
Preclinical experience .................................................................................. 28 
 
Clinical experience ...................................................................................... 29 
 
General clinical experience with Ganetespib ...................................................29 
 
Phase I/II GANNET53 trial in platinum-resistant ovarian cancer patients 
(EUDRACT 2013-003868-31) ........................................................................................30 
 
Phase I/II MESO-02 trial in patients with malignant pleural mesothelioma 
(EudraCT No.: 2012-001598-10) ...................................................................................30 
 
Ganetespib Safety Profile ................................................................................32 
 
Clinical Pharmacokinetics ............................................................................ 45 
9 
INFORMATION ON THE INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) 
NIRAPARIB .............................................................................................................. 47 
 
Name and Chemical Information ................................................................. 47 
 
Preclinical experience .................................................................................. 47 
 
Clinical experience ...................................................................................... 47 
 
Phase III NOVA trial in relapsed platinum-sensitive ovarian cancer patients 
(EudraCT No.: 2013-000685-11) ...................................................................................47 
 
Niraparib Safety Profile ...................................................................................48 
 
Clinical Pharmacokinetics ............................................................................ 50 
 
Absorption .......................................................................................................50 
 
Distribution ......................................................................................................50 
 
Metabolism ......................................................................................................50 
 
Elimination ......................................................................................................50 
 
Specific Populations ........................................................................................51 
10 
INFORMATION ON THE COMPARATOR PRODUCTS (NON-IMP) ............. 51 


EUDARIO 
 
 
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Study treatment with Ganetespib will be compared to two different options of 
standard treatment which are combined with Carboplatin in arm A. Therefore these 
products are investigational products, however treatment with these will be 
performed according to the local standard of care of the hospital. ........................ 51 
 
Gemcitabine ............................................................................................. 51 
 
Paclitaxel .................................................................................................. 51 
11 
INFORMATION ON THE NON-INVESTIGATIONAL PRODUCT (NON-IMP) 51 
 
Carboplatin ............................................................................................... 51 
12 
STUDY DESIGN ............................................................................................. 52 
 
Description of study .................................................................................. 52 
 
Subject population .................................................................................... 53 
 
Subject eligibility ....................................................................................... 53 
 
Study duration .......................................................................................... 57 
 
End of study ............................................................................................. 57 
 
Premature termination of the study ..................................................................57 
 
Study site discontinuation ................................................................................57 
 
Withdrawal and replacement of subjects .........................................................57 
 
Discontinuation from IMP or non-IMP ..............................................................58 
 
Study objectives ....................................................................................... 59 
 
Randomisation and stratification .............................................................. 60 
13 
STATISTICAL ANALYSIS ............................................................................. 61 
 
Analysis populations................................................................................. 61 
 
Sample size calculation ............................................................................ 61 
 
Efficacy analysis ....................................................................................... 61 
 
Safety analysis ......................................................................................... 64 
 
Subgroup analysis .................................................................................... 64 
 
Comparability of treatment arms .............................................................. 64 
 
Interim analysis ........................................................................................ 64 
14 
RISK-BENEFIT CONSIDERATIONS ............................................................. 65 
15 
STUDY PROCEDURES ................................................................................. 67 
 
Before treatment start/screening (days -28 to -1) ..................................... 67 
 
Treatment period ...................................................................................... 70 
 
Chemotherapy Arm A: Carboplatin and Gemcitabine (Standard platinum-based 
chemotherapy, investigators choice) .............................................................................70 
 
Chemotherapy Arm A: Carboplatin and Paclitaxel (standard platinum-
chemotherapy, investigators choice) .............................................................................73 
 
Chemotherapy based treatment Arms B and C: Carboplatin and Ganetespib 
(experimental platinum-combination) .............................................................................75 
 
Maintenance treatment in arms A and B: Niraparib single agent .....................77 
 
Maintenance Treatment Arm C: combination maintenance treatment Niraparib 
and Ganetespib .............................................................................................................80 
 
End of treatment / Safety Follow-up ......................................................... 83 
 
Longterm FU prior to progression ............................................................ 83 
 
Longterm FU after progression ................................................................ 84 
16 
STUDY ASSESSMENTS................................................................................ 85 


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Tumour response assessment ................................................................. 85 
 
Patient-reported outcome (PRO) .............................................................. 86 
 
PRO instruments .............................................................................................86 
 
PRO assessment schedule .............................................................................86 
 
Concomitant medications/therapies ......................................................... 87 
 
Physical examination ................................................................................ 87 
 
Electrocardiography (ECG) and Left ventricular ejection fraction (LVEF). 87 
 
Laboratory assessments .......................................................................... 88 
 
Biomarker analysis ................................................................................... 88 
17 
STUDY MEDICATION .................................................................................... 89 
 
Dosage and Administration ...................................................................... 89 
18 
DOSING SELECTION/ DOSE MODIFICATION/ DELAYS ............................ 91 
 
Dose modifications for Carboplatin and Gemcitabine (Arm A) ................. 91 
 
Haematologic toxicity ......................................................................................91 
 
Non-haematologic toxicity ...............................................................................92 
 
Hypersensitivity to Carboplatin (regardless of combination) ............................93 
 
Dose modifications for Carboplatin/Paclitaxel (Arm A) ............................. 93 
 
Haematologic toxicity .......................................................................................94 
 
Non-haematologic Toxicity ..............................................................................96 
 
Dose modification for Carboplatin/Ganetespib combination ..................... 98 
 
Haematologic Toxicity .....................................................................................98 
 
Non-haematologic Toxicity ............................................................................ 100 
 
Dose Modification for Niraparib single agent in maintenance treatment (Arm 
A and B) .............................................................................................................. 100 
 
Dose modification of Niraparib for non-haematologic parameters .................. 100 
 
Dose modifications for haematologic parameters for Niraparib single agent 
treatment in maintenance (arms A and B) ................................................................... 102 
 
Dose Modification for Niraparib and Ganetespib in maintainance treatment 
(arm C) 104 
 
Dose modifications for Niraparib plus Ganetespib combination treatment in 
maintenance (arm C) ................................................................................................... 104 
 
Management guidelines of the most significant AE diarrhoea ........................ 110 
 
Study drug interruption or discontinuation .............................................. 111 
 
Summary of known and potential risks of the study drug Ganetespib .... 111 
 
Summary of known and potential risks of the study drug Niraparib ........ 114 
 
Summary of known and potential risks of non IMPs ............................... 114 
 
Paclitaxel, Gemcitabin, Carboplatin ............................................................... 114 
 
Study drug delivery & drug storage conditions ............................................... 115 
 
Study drug packaging and labelling ............................................................... 117 
 
Concomitant medications ....................................................................... 117 
19 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ................... 118 
 
Adverse events ...................................................................................... 118 
 
Serious adverse events (SAEs) ............................................................. 119 
 
Hospitalisation – Prolongation of existing hospitalisation ............................... 119 
 
Treatment-Emergent Adverse Event (TEAE) ................................................. 120 
 
Adverse Events of Special Interest ................................................................ 120 


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Suspected unexpected serious adverse reactions (SUSARs) ....................... 120 
 
Pregnancy ..................................................................................................... 120 
 
Severity of adverse events/Grading ....................................................... 121 
 
Relationship to study drug ...................................................................... 122 
 
Expectedness ......................................................................................... 123 
 
Collection and recording of adverse events ........................................... 123 
 
Follow-Up of Adverse Events ........................................................................ 124 
 
Diagnosis versus signs and symptoms .......................................................... 124 
 
Persistent or recurrent adverse events .......................................................... 124 
 
Abnormal laboratory values or vital signs ...................................................... 124 
 
Progression of underlying malignancy ........................................................... 125 
 
Reporting procedures ............................................................................. 125 
 
Reporting procedures for SAEs and SUSARs ............................................... 126 
 
Reporting to TESARO and Aldeyra Therapeutics .......................................... 127 
 
Adverse event reporting period ..................................................................... 128 
 
Handling of safety parameters ............................................................... 128 
 
Treatment and follow-up of adverse events ................................................... 128 
 
Follow-up of abnormal laboratory test value .................................................. 128 
 
Special Situations: Abuse, Misuse, Medication Errors, Overdose, and 
Accidental or Occupational Exposure .................................................................. 128 
 
Reporting Product Complaints for Niraparib ........................................... 129 
20 
DOCUMENTATION AND DATA MANAGEMENT ....................................... 130 
 
Retention of documents/Investigator site file .......................................... 130 
 
Case report form (CRF) ................................................................................. 130 
 
Independent Data and Monitoring committee (IDMC) ............................ 130 
 
Quality control and quality assurance..................................................... 131 
 
Periodic monitoring ....................................................................................... 131 
 
Audit and inspections .................................................................................... 131 
 
Reporting and publications ..................................................................... 131 
 
Reports ......................................................................................................... 131 
 
Publication of study results ............................................................................ 132 
21 
ETHICAL AND LEGAL ASPECTS .............................................................. 132 
 
Informed consent of subjects ................................................................. 132 
 
Acknowledgement/Approval of the study ............................................... 133 
 
Insurance ............................................................................................... 133 
 
Study Data ............................................................................................. 134 
 
Collection of investigator’s personal data ............................................... 134 
 
Ethics and Good Clinical Practice (GCP) ............................................... 134 
22 
REFERENCES ............................................................................................. 135 
23 
APPENDICES .............................................................................................. 137 
 
 
 
 


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3 LIST OF TABLES 
 
Table 1: Summary of Adverse events (AEs) (NCI CTCAE v4.03) which occurred in >1 patients 
in the Phase I dose escalation/de-escalation study (Total number of patients N=10) ...........34 
Table 2: Summary of preliminary results (as of 23.08.2017) of related Adverse events (AEs) 
Grade 1-2 (NCI CTCAE v4.03) which occurred in >10 % of patients in the Phase II study; 
included were all patients who received at least one dose of study medication in the 
experimental arm P+G. (Total number of patients N=86) ......................................................35 
Table 3: Summary of preliminary results (as of 23.08.2017) of realated Adverse events (AEs) 
Grade 3 – 5 (NCI CTCAE v4.03); included were all patients who received at least one dose of 
study medication in the experimental arm P+G (Total number of patients N=86). .................36 
Table 4: Number of patients experiencing AEs of maximum grade 2 (NCI CTCAE v4.0) in 
treatment cycles 1 and 2 ......................................................................................................37 
Table 5: Number of patients experiencing AEs of maximum grade 3 or 4 (NCI CTCAE v4.0) in 
treatment cycles 1 and 2 ......................................................................................................38 
Table 6: Number of patients experiencing AEs of maximum grade 2 (NCI CTCAE v4.0) at any 
time ......................................................................................................................................39 
Table 7: Number of patients experiencing AEs of maximum grade 3 or 4 (NCI CTCAE v4.0) at 
any time................................................................................................................................40 
Table 8: Screening Schedule of Events ................................................................................68 
Table 9: Carboplatin Gemcitabine Schedule of Events (arm A, Investigator`s choice) ..........72 
Table 10: Carboplatin Paclitaxel Schedule of Events (arm A, investigators choice) ..............74 
Table 11: Carboplatin Ganetespib Schedule of Events (Arm B and C) .................................76 
Table 12: Niraparib single agent Maintenance Schedule of Events (Arm A and B) ...............79 
Table 13: Niraparib + Ganetespib Maintenance Schedule of Events (Arm C) .......................82 
Table 14: Longterm follow-up Schedule of Events ................................................................84 
Table 15 Niraparib dosing for arm A and arm B ....................................................................90 
Table 16: Dose levels for Gemcitabine and Carboplatin .......................................................91 
Table 17: Recommendations for Gemcitabine dose adjustments on day 8 for haematologic 
toxicities ...............................................................................................................................92 
Table 18: Dose reduction levels for Paclitaxel and Carboplatin ............................................93 
Table 19: Guidelines for Paclitaxel and Carboplatin dose modification for delayed 
haematologic recovery according to the blood test on day 22...............................................94 
Table 20: Guidelines for Paclitaxel and Carboplatin dose modification due to dose-limiting 
toxicity ..................................................................................................................................95 
Table 21: Dose reduction levels for Ganetespib and Carboplatin given in combination ........98 
Table 22: Dose modifications for the combination therapy of Carboplatin and Ganetespib on 
day 21 (q3w) ........................................................................................................................98 
Table 23: Dose reduction levels of Niraparib ...................................................................... 100 
Table 24 Niraparib Dose modification for Other Non-haematologic Adverse Reactions ...... 101 
Table 25: Dose modification for hypertransaminasaemia (AST/ALT) .................................. 101 
Table 26: Dose modification/reduction for Haematologic toxicitities of Niraparib on day 28 
(q4w) .................................................................................................................................. 102 
Table 27: Dose modification for Niraparib and Ganetespib in maintenance treatment on day 
28 (q4w) ............................................................................................................................. 105 
Table 28: Dose modification for hypertransaminasaemia (AST/ALT) .................................. 107 
Table 29: Dose modification for hyperbilirubinaemia .......................................................... 108 
Table 30: Dose modification for Ganetespib-related gastrointestinal toxicity ....................... 109 


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Table 31: Dose modification for Ganetespib related QTc prolongation ............................... 110 
Table 32: List of medications frequently used in oncology treatment that are substrates of 
CYP3A4 or CYP2C19......................................................................................................... 113 
Table 33 Grading AEs not listed in the CTCAE v5.0 ........................................................... 122 


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List of Figures 
 
Figure 1: Schematic diagram of the study design .................................................................19 
Figure 2: Hypothesized mechanism of action in Eudario Trial (5) .........................................24 
Figure 3: Chemical structure of Ganetespib ..........................................................................28 
Figure 4: Study design ..........................................................................................................52 
Figure 5: Combination of Ganetespib and Olaparib synergize in OvCa cells ...................... 153 
Figure 6: Combination treatment with Ganetespib and Olaparib leads to accumulation of DNA 
damage .............................................................................................................................. 154 
Figure 7: Combination treatment with Ganetespib and Olaparib leads to increased induction of 
apoptosis ............................................................................................................................ 154 
Figure 8: IF-Analysis, gammaH2AX, 96 well format ............................................................ 155 
 
 
 


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4 PROTOCOL SYNOPSIS 
Title 
A multicentre, open-label, three-arm randomised Phase II trial assessing 
the safety and efficacy of the HSP90 inhibitor Ganetespib in combination 
with Carboplatin followed by maintenance treatment with Niraparib 
versus Ganetespib plus Carboplatin followed by Ganetespib and 
Niraparib 
versus 
Carboplatin 
in 
combination 
with 
standard 
chemotherapy followed by Niraparib maintenance treatment in platinum-
sensitive ovarian cancer patients  
 
Short title 
EUDARIO 
EudraCT number 2017-004058-40 
Protocol 
version/date 
V 4.0 
12Nov2020 
Indication 
Women with platinum-sensitive, high-grade serous, high-grade 
endometrioid, 
undifferentiated 
epithelial 
ovarian 
cancer, 
carcinosarcoma,  fallopian tube or primary peritoneal cancer (proven by 
central histo-pathological review) 
Phase/Design 
 
 
 
 
 
 
 
 
This is an open-label, three-arm, randomised (1:1:1) Phase II study 
Safety run in: 
- 
For Ganetespib/Carboplatin combination (arms B and C): safety 
evaluation by IDMC will be performed 4 weeks after inclusion of 
6 and 12 patients, respectively (without recruitment stop).  
- 
For Ganetespib/PARPi combination (arm C): safety evaluation by 
IDMC will be performed 4 weeks after start of maintenance 
therapy of 6 and 12 patients, respectively (with stop of entering 
maintenance treatment in arm C).  
Non-
investigational 
treatment, dosing 
and 
pharma-
ceutical form 
 
Investigational 
treatment, dosing 
and 
pharmaceutical 
form 
Standard arm (arm A): Carboplatin (AUC5 d1, q3w i.v.) in combination 
with Paclitaxel (175 mg/m² d1, q3w i.v.) or Carboplatin (AUC4 d1, q3w 
i.v.) in combination with Gemcitabine (1000 mg/m² d1, d8, q3w i.v.) 
followed by maintenance therapy with Niraparib (200/ 300 mg oral daily, 
q4w) 
 
 
 
First experimental arm (arm B): Ganetespib (150 mg/m2, d1, q3w) in 
combination with Carboplatin (AUC5 d1, q3w i.v.) followed by 
maintenance treatment with Niraparib (200/ 300 mg oral daily, q4w)  
 
Second experimental arm (arm C): Ganetespib (150 mg/m² d1, q3w i.v.) 
plus Carboplatin (AUC5 d1, q3w i.v.) followed by Ganetespib (100 mg/m² 
d1, d8, d15, d22, q4w i.v.) and Niraparib (200 mg oral daily, q4w)  


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Ganetespib and Niraparib are investigational products and will be 
provided by Aldeyra Therapeutics and TESARO, respectively. 
 
 
Planned study 
duration 
First patient in: Nov 2018 
Last patient in: Feb2020 
Last patient last treatment (LPLT) with Ganetespib: May 2021 
Estimated End of study: Aug 2022  
 
Number of 
patients 
A total of 120 patients will be randomised, 40 patients per treatment-arm 
Sites / Countries  13 sites in 5 countries (Austria, Belgium, France, Germany, Italy) 
 
Inclusion criteria 
 
Patients must meet the following criteria to be eligible for study entry: 
 
Signed and dated written informed consent prior to admission to the 
study in accordance with ICH-GCP guidelines and with the local 
legislation. 
 
Female patients ≥18 years of age 
 
High-grade serous, high-grade endometrioid, undifferentiated 
epithelial ovarian cancer, carcinosarcoma, fallopian tube or primary 
peritoneal cancer  
 
Platinum-sensitive relapse >6months after previous platinum-based 
treatment (calculated from the first day of the last cycle of the last 
platinum-based chemotherapy until the date of progression 
confirmed according to RECIST 1.1 on imaging) 
 
No limits in number of prior lines 
 
Measurable or evaluable disease according to RECIST 1.1 
 
ECOG performance status 0-1 
 
Adequate functions of the bone marrow  
o Platelets ≥ 100 x 109/L  
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
o Hemoglobin ≥8.5 g/dl (patients may not receive a transfusion 
within 4 weeks prior to initiating study treatment) 
o  
 
Adequate function of the organs 
o Creatinine clearance ≥ 30ml/min, as calculated using the 
Cockroft-Gault equation Total bilirubin ≤ 1.5 x upper limit of 
normal (≤ 2.0 in patients with known Gilberts syndrome) OR 
direct bilirubin ≤ 1 x ULN 
o SGOT/SGPT (AST/ALT) ≤ 2.5 x upper limit of normal unless 
liver metastases are present, in which case they must be ≤ 5 
x ULN 


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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 parameter: 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). 
 
Participant 
receiving 
corticosteroids 
(dose 
< 
10 
mg/day 
methylprednisolone equivalent), including inhaled steroids, may 
continue as long as their dose is stable for at least 4 weeks prior to 
initiating protocol therapy. 
 
Participants must agree to not donate blood during the study or for 
90 days after the last dose of study treatment 
 
Female participant has a negative serum pregnancy test within 7 
days prior to taking study treatment if of childbearing potential and 
agrees to abstain from activities that could result in pregnancy from 
screening through 180 days after the last dose of study treatment, or 
is of nonchildbearing potential. Nonchildbearing potential is defined 
as follows (by other than medical reasons): 
o ≥ 45 years of age and has not had menses for >1 year 
o Patients who have been amenorrhoeic for < 2 years without 
history of a hysterectomy and oophorectomy must have a 
follicle stimulating hormone value in the postmenopausal 
range upon screening evaluation 
o Post-hysterectomy, post-bilateral oophorectomy, or post-
tubal ligation. Documented hysterectomy or oophorectomy 
must be confirmed with medical records of the actual 
procedure or confirmed by imaging. Tubal ligation must be 
confirmed with medical records of the actual procedure, 
otherwise the patient must be willing to use 2 adequate 
barrier methods throughout the study, starting with the 
screening visit through 180 days after the last dose of study 
treatment. See below for a list of acceptable birth control 
methods. Information must be captured appropriately within 
the site’s source documents. Note: Abstinence is acceptable 
if this is the established and preferred contraception for the 
patient. 
o Birth Control: Participants of childbearing potential who are 
sexually active and their partners must agree to the use of a 
highly effective form of contraception throughout their 
participation beginning with time of consent, during the study 
treatment and for 180 days after last dose of study 
treatment(s): 


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 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation: 
 
Oral route 
 
Intravaginal route 
 
Transdermal route 
 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation  
 
Oral 
 
Injectable 
 
Implantable 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Sexual abstinence, if the preferred and usual lifestyle 
of the subject 
 
Participant must agree to not breastfeed (or store breast milk for use) 
during the study or for 180 days after the last dose of study treatment. 
 
Able to take oral medications  
 
Availability of archival ovarian cancer tissue from primary diagnosis 
(delivery of FFPE block or slides is prerequisite for randomisation)  
 
Conditions for the start of maintenance therapy with Niraparib, or 
Ganetespib 
 
Before start of the maintenance therapy patients must have following lab 
values: 
        Absolute neutrophil count ≥ 1,500/µL 
        Platelets ≥ 100,000/µL 
        Hemoglobin ≥ 9 g/dL 
        Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated 
creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation 
        Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts 
syndrome) OR direct bilirubin ≤ 1 x ULN 
        Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x 
ULN unless liver metastases are present, in which case they must be ≤ 
5 x ULN 
 
 
Exclusion criteria 
 
Patients who meet any of the following criteria will be excluded from 
study entry: 
 
Ovarian tumours with low malignant potential (i.e. borderline 
tumours) 


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 
Any prior radiotherapy to the pelvis or abdomen, or any radiotherapy 
encompassing > 20 % of the bone marrow within 2 weeks, or any 
radiotherapy within 1 week prior to Day 1 of protocol therapy  
 
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 
 
Known history of myelodysplastic syndrome (MDS) or acute myeloid 
leukemia (AML). 
 
Any serious, uncontrolled medical disorder, non-malignant systemic 
disease, or active, uncontrolled infection. Examples include, but are 
not limited to, uncontrolled ventricular arrhythmia, recent (within 90 
days) myocardial infarction, chronic obstructive pulmonary disease, 
uncontrolled 
major 
seizure 
disorder, 
unstable 
spinal 
cord 
compression, superior vena cava syndrome, or any psychiatric 
disorder that prohibits obtaining informed consent. 
 
Current or recent (within 10 days prior to the first study drug dose) 
chronic daily treatment with aspirin (>325 mg/day). 
 
Patients with a history of diagnosis, detection or treatment of any 
prior malignancies ≤ 2 years prior to initiating protocol therapy, 
except: basal or squamous cell carcinoma of the skin and cervical 
cancer that has been definitively treated.  
 
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 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 or leptomeningeal metastases 
(patients who are asyptomatic since treatment of brain or 
leptomeningeal metastases, eg. after irradiation, are eligible) 
 
Left ventricular ejection fraction (LVEF) 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 Assiciation (NYHA) 
Class 3 or 4; myocardial infarction within the past 6 months; unstable 
angina; coronary angioplasty or coronary atrial or ventricular cardiac 
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 
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. sotalol, 
amiodarone, dofetilide). Use of other antiarrhythmic drugs is 
permitted 
 
Second- or third-degree atrioventricular (AV) block, except: treated 
with a permanent pacemaker 
 
Complete left bundle branch block (LBBB) 
 
Concomitant use of drugs which prolong QTc interval and have a 
known risk to cause Torsade de Pointes (see appendix F for a non-
exhaustive list) 
 
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. 
 
Participation in another clinical study with experimental therapy 
within 28 days or five half-lives (whichever is shorter) of experimental 
therapy before start of treatment. 
 
Participant must not be simultaneously enrolled in any interventional 
clinical trial. 
 
Women who are pregnant or are lactating 
 
Patients unable to be regularly followed for any reason (geographic, 
familiar, social, psychologic, housed in an institution eg. prison 
because of a court agreement or administrative order) 
 
Subjects that are dependent on the sponsor/CRO or investigational 
site as well as on the investigator. 
 
History of known hypersensibility against any medication used in the 
study 
 
Intolerance / Hypersensitivity reactions to components and exipients 
of study drugs  
 
Peripheral neuropathy of grade >2 per NCI CTCAE, version 5.0, 
within 4 weeks prior to randomization 
 
Administration of a live, attenuated vaccine within 30 days prior to 
Cycle1 Day 1 or anticipation that such a live attenuated vaccine will 
be required during the study. Examples of live vaccines include but 
are not limited to: measles, mumps, rubella, varicella zoster (chicken 
pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), typhoid 
and intranasal influenza vaccines (eg. Flumist®). Inactivated 
influenza vaccinations can be administered during the flu season. 
 
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 
 


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Endpoints 
 
Primary endpoint: 
Progression-free survival (PFS) by RECIST 1.1 
 
Secondary endpoints: 
PFS according to pre-defined subgroups  
Post-progression PFS (PFS2) 
Time to First Subsequent Therapy (TFST) 
Time to Second Subsequent Therapy (TSST) 
Safety: Adverse events (AEs), measure according to NCI CTCAE, 
version 5.0 
Objective response rate (ORR) 
Patient-reported outcome (PRO) 
Overall survival (OS) 
 
Experimental endpoints: 
Biomarker analysis on DNA, RNA and protein level (e.g. free circulating 
tumour DNA, circulating tumour cells etc.) 
 
5 SCHEMATIC DIAGRAM OF THE STUDY DESIGN 
 
Figure 1: Schematic diagram of the study design 
 
 


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6 ABBREVATIONS AND DEFINITIONS 
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) 
AML 
Acute Myeloid Leukemia 
ANC 
absolute neutrophil count 
AP 
alkaline phosphatase 
AST (SGOT) 
aspartate-aminotransferase 
ATPase 
adenosine triphosphatase 
AUC 
area under the curve  
bcr-abl 
fusion gene 
BP 
Blood pressure 
BRAF 
v-raf murine sarcoma viral oncogene homolog B 
BRCA 
Breast Cancer Gene 
BSA 
body surface area 
B-Raf 
proto-oncogene 
CA 
Competent Authority 
CA-125 
carbohydrate antigen 125 
CBC 
complete cell count 
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 
CR 
complete response 
CT 
computed tomography 
CTC 
circulating tumour cells  
CTCAE 
common terminology criteria for adverse events 
CTNNB1 
catenin (cadherin-associated protein), beta 1 
CYP 
cytochrome protein 
DEHP 
Di-Ethylhexyl Phthalate 
DLT 
dose-limiting toxicity 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
ECG 
electrocardiography 
ECOG PS 
Eastern Co-Operative Oncology Group performance status 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EOC 
epithelial ovarian cancer 
EORTC 
European Organisation for Research and Treatment of Cancer  


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EOS 
end of study 
EOT 
end of treatment 
EPO 
Erythropoietin 
ESF 
Eligibility Screening Form 
FDA 
Food & Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FPI 
first patient in 
GCIG 
Gynaecologic Cancer Intergroup 
GCP 
Good Clinical Practice  
G-CSF 
Granulocyte Colony Stimulating Factor 
GFR 
glomerular filtration rates 
GI 
gastrointestinal  
GIP 
Gastrointestinal perfusion 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
HGS 
high-grade serous  
HR 
hazard ratio 
HR 
Hard rate 
Hsp90 
heat shock protein 90 
Hsp90i 
Hsp90 inhibitor 
IB 
Investigator Brochure 
ICH 
International Conference of Harmonisation  
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IMP 
investigational medical product 
IRB 
institutional review board 
ISF 
Investigator Site File 
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 
LVEF 
left ventricular ejection fraction 
M 
month 
MDS 
Myelodysplastic Syndromes 
MTD 
Maximum Tolerated Dose 
MRI 
magnetic resonance imaging 
mutp53 
mutant p53 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association  
OC 
Ovarian cancer 
ORR 
objective response rate 
OS 
overall survival 
p53 
tumour protein 


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PARP 
Poly(adenosine diphosphate-ribose) polymerase 
PCR 
polymerase chain reaction  
PD 
partial response 
PET 
positron emission tomography 
PFI 
Platinum-free interval 
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 
PLT 
Platelet 
PROC 
platinum-resistant ovarian cancer 
PRO 
patient-reported outcome 
PTEN 
phosphatase and tensin homolog 
Pt-R 
platinum-resistant 
PVC 
Polyvinyl Chloride 
QT 
interval between Q wave and T wave in the hearts electrical cycle 
RBC 
red blood cells 
RECIST 
response evaluation criteria in solid tumours 
RNA 
Ribonucleic Acid 
SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid  
SD 
stable disease 
SOP 
standard operating procedures 
SGOT 
serum glutamate-oxaloacetate-transaminase 
SGPT 
serum glutamate-pyruvate-transaminase 
SUSAR 
suspected unexpected serious adverse reaction 
T 
Temperature 
TCGA 
Cancer Genome Atlas Research Network  
TdP 
Torsades de Pointes 
TEAE 
Treatment-Emergent Adverse Event 
TMG 
Trial Management Group 
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 
 


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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.  
 
7 BACKGROUND AND STUDY RATIONALE 
 Ovarian cancer 
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy. Recent data 
from the EUROCARE database showed a 5-year relative survival for European women 
diagnosed with EOC of only 38 % (range 31-41 % by European region; (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 been shown recently to improve 
progression-free survival in women with ovarian cancer (2). 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. 
Treatment strategy for recurrent ovarian cancer depends on the platinum-free interval, which 
is the time between the last platinum-based therapy and the detection of relapse. If the 
progression of the disease is more than 6 months after the last platinum-based therapy, the 
tumour is considered to be platinum-sensitive and can be retreated with Carboplatin in different 
combinations such as with Paclitaxel, Gemcitabine or pegylated liposomal Doxorubicine 
(PLD).  
Recent data on Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor (PARPi) 
treatment have led to approval of Lynparza in the maintenance treatment of relapsed, platinum-
sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer with mutations in the 
BRCA1 or 2 genes in Europe (3). PARPi interfere with the repair mechanism of single strand 
DNA breaks, which allows DNA damage to progress and to result in double strand breaks. 
PARPi treatment of tumour cells with homologous recombination deficiency, for instance 
BRCA1/2 mutation, results in synthetic lethality. Furthermore, recently patients receiving 
Niraparib, a PARP1/2 inhibitor, as maintenance therapy, showed a significant longer 
progression free survival in the recently published NOVA study (4). This effect was 
independent of BRCA mutation status. 
 
 


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 Study Rationale 
In this study we will evaluate the therapeutic benefit of broad DNA repair pathway inhibition 
after induction of DNA damage.  
 
Figure 2: Hypothesized mechanism of action in Eudario Trial (5) 
This is achieved by combining 1) standard induction platinum-based chemotherapy with an 
HSP90 inhibitor on one hand and 2) maintenance PARP inhibitor treatment combined with an 
HSP90 inhibitor on the other hand. We use the clinically most advanced HSP90 inhibitor, 
Ganetespib. Our approach of broad DNA repair inhibition is applied in tumours with a mutant 
p53 background (corresponding to specific histological subtypes) to maximize potential 
therapeutic effects.  
 
 Rationale for Combination of Carboplatin with Ganetespib 
HSP90 inhibitors destabilise a number of HSP90 client proteins, such as those governing the 
Fanconi Anemia DNA repair pathway (e.g. FancA) and the G2/M checkpoint (e.g. Chk1 and 
Wee1). This raises the possibility for using HSP90 inhibitors in combination with DNA 
damaging chemotherapeutics to induce massive chromosome fragmentation followed by cell 
death. 
Carboplatin is used as first line therapy in ovarian cancer patients as well as in the platinum-
sensitive relapsed situation. It mainly acts by forming interstrand crosslinks (ICL) within the 
DNA double helix, which can only be removed by the Fanconi Anemia pathway. Since key 
proteins of the Fanconi Anemia pathway are HSP90 clients (e.g. FancA), HSP90 inhibitor 
Ganetespib virtually eliminates a functional Fanconi Anemia DNA repair complex, thereby 
preventing the repair of DNA interstrand crosslinks. In parallel, Ganetespib abrogates Chk1 
and Wee1 expression thereby circumventing a G2/M arrest of DNA-damaged tumour cells. 
Consequently, cells with unrepaired DNA damage rush into mitosis, thereby inducing massive 
tumour cell death.  


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Importantly, untransformed cells are protected against Carboplatin/Ganetespib induced cell 
death due to an intact G1 checkpoint triggering a transient cell cycle arrest rather than cell 
death. Thus, Ganetespib sensitizes ovarian carcinoma cells specifically towards ICL-inducing 
drugs such as Carboplatin, Cisplatin, or Mitomycin C, by inhibiting DNA repair and blocking 
the induction of a G2/M cell cycle arrest. 
Our publication by Kramer et al. 2016 (5) showed that the combination of Carboplatin and 
Ganetespib (CG) strongly decreases viability of a large panel of human ovarian cancer (OC)-
derived cell lines. Effects occur synergistically when compared to single-drug treatment. This 
was systematically quantified by the classic drug interaction algorithm of Chou and Talalay. By 
immunostaining and immunoblot analysis of phosphorylated histone H2AX and phospho-Kap1 
(markers for DNA damage) it was shown that the combination of Carboplatin and Ganetespib 
increased detectable DNA damage to a greater extent than the single drugs. Consequently, 
the combination of Carboplatin and Ganetespib induces cell death in OC cells more strongly 
than Carboplatin or Ganetespib alone. In metaphase spreads massive chromosome 
fragmentation induced by combined Carboplatin and Ganetespib but not by the individual 
drugs was observed. In in vivo studies with OC xenografts, the combination of Carboplatin and 
Ganetespib strongly synergises in the inhibition of tumour growth and induction of tumour cell 
death. Importantly, the synergy of Carboplatin and Ganetespib is far superior when compared 
to the combination of Paclitaxel and Ganetespib (see Fig. 6e in Kramer et al.(5)), the drug 
combination that did not lead to favourable clinical results in a premature interim analysis of 
the randomised Phase II GANNET53 trial. This data justifies a new trial testing the combination 
of Carboplatin plus Ganetespib. 
Another rationale for using Ganetespib as Fanconi Anemia (FA) repair inhibitor in the cohort 
of mutant p53 ovarian cancer patients studied in this clinical trial comes from recent studies by 
Jaber et al (6).This study shows in mouse and human tissues that wild type p53 downregulates 
the Fanconi Anemia DNA crosslink repair pathway by repressing 12 FA genes. The authors 
used the wtp53 activating drug Nutlin3a, as well as a knockin p53 delta 31 mouse expressing 
a truncated wt p53 which is missing the last 31 amino acids at the p53 C-terminus and 
generates a hyperactive (unregulated) “wt"p53. p53 delta 31 works by inducing repressive 
E2F4 binding at these 12 FA genes’ promoters.  
This data implies that mutp53 cancer cells have increased FA repair activity. Indeed, Jabner 
et al. also showed that human mutp53 tumours correlate with increased expression of FA 
genes.Thus, in mutp53 tumours Ganetespib counteracts the aberrant upregulation of FA repair 
factors by inducing their degradation. 
 
 Rationale for Combination of Ganetespib with PARP-inhibitor Niraparib 
The latest studies by Mirza et al. (4) suggest the use of PARP inhibitors (PARPis) to treat OC 
regardless of the BRCA status. Therefore, it will be more straight-forward to justify clinical 
studies using combinations of Ganetespib not only with Carboplatin but also with PARPis. We 
have addresses this in unpublished studies, as summarized in the attachment (APPENDIX H). 
PARPi and Ganetespib together induce more phosphorylated histone H2AX (indicative of DNA 
damage) than single drug treatment. This was observed by immunoblot analysis and by 
quantitative immunofluorescence. By Annexin V staining it was shown that PARPi and 
Ganetespib together induce apoptosis to a greater extent than each drug alone. 


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Mechanistically, we anticipate that Ganetespib and PARP inhibitors both inhibit multiple 
pathways required for repair of DNA damage caused by Carboplatin (e.g. Fanconi anemia, 
non-homologous end joining and homologous recombination). Of note, Ganetespib strongly 
reduces the amount of BRCA1 in the cell (2, 7). Thus, it creates a deficiency similar to BRCA1-
mutant OC cells, which have long been known for their exquisite sensitivity towards PARP 
inhibitors. Thus, Ganetespib will broaden the synergy of BRCA loss and PARPi to include 
ovarian carcinomas regardless of their BRCA status (broadening of the sensitive ovarian 
cancer spectrum). Furthermore combination of Ganetespib and PARPi would prevent the 
evolvement of possible BRCA re-expression leading to acquired PARPi resistance (8). 
All this argues for a combined treatment of HSP90 and PARP inhibitors. 
 
Rationale to test our approach in a p53 mutant background 
We will test our approach of broad DNA repair inhibition in ovarian carcinomas with a mutant 
p53 background (particular histological subtypes, ie. high-grade serous, high-grade 
endometrioid, undifferentiated, carcinosarcoma). This offers the highest potential for achieving 
the most profound survival benefit, as these tumours lack a functional G1 checkpoint. While in 
untransformed, wildtype p53 expressing cells GC treatment leads to the induction of an p53 
mediated G1 arrest, mutant p53 expressing cells lacking the option of a G1 arrest. 
Consequently lack of wildtype p53 leads to high sensitivity towards GC induced loss of G2/M 
and accumulation of unrepaired DNA damage. Moreover, wildtype p53 is capable of repressing 
several components of the Fanconi anemia (FA) DNA repair pathway Jaber et al. 2016 (6) the 
primary mechanism to eliminate Carboplatin-induced DNA crosslinks. Conversely, ovarian 
cancer cells lacking wildtype p53 are expected to have increased levels of FA pathway activity. 
This further supports the model of enhanced dependence of p53 mutant ovarian cancer cells 
on the FA pathway, especially in the context of Carboplatin treatment. Tumour cell addiction 
would thus increase their vulnerability towards Ganetespib, which strongly suppresses FA 
components and thus confers Carboplatin sensitivity. 
Data from clinico-pathological 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 tumourigenic pathways and not to 
specific histopathological patterns. 
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 the time of 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 or a subset of clear cell carcinomas. 
HGS carcinomas account for ~ 85% of all ovarian cancer deaths. 
Importantly, type II tumours are characterised by the near ubiquitous presence of p53 
missense mutations (mut p53) - their preeminent molecular hallmark. Mut p53 proteins highly 
stabilize in tumour cells and many of them actively promote oncogenicity (called Gain-of-
Function mutants). This strongly suggests that mut p53 is a central oncogenic driver in the 
pathogenesis of these tumours. Ahmed et al (11) sequenced exons 2-11 and intron-exon 
boundaries in 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 


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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. 
 
 


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8 INFORMATION 
ON 
THE 
INVESTIGATIONAL 
MEDICINAL 
PRODUCTS (IMPS) GANETESBIP 
For detailed information about Ganetespib please refer to the Investigator’s Brochure (IB). 
 
 Name and Chemical Information 
Ganetespib 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 mut p53 was recently found to be a Hsp90 client (14, 15). 
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 3: 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. 
 
 
 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 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. 
 
 
 


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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 were 
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).  
 Clinical experience 
 General clinical experience with Ganetespib 
Ganetespib has been studied in 11 completed Synta-sponsored clinical trials (Studies 9090-
01,9090-02, 9090-03, 9090-04, 9090-05, 9090-06, 9090-07, 9090-08, 9090-09, 9090-11 and 
9090-14), and 3 completed Synta-sponsored studies in normal healthy volunteers (9090-12, 
9090-13, and 9090-15). Ganetespib has also been studied in 27 ISTs. The majority of ISTs 
are proof-of-concept studies across a variety of tumour types as well as haematologic 
malignancies. The ISTs with active patients are Phase I/II studies. 
Since the submission of Development Safety Update Report (DSUR) Number 5, which was 
submitted by Aldeyra Therapeutics, Inc. on November 15, 2016, there have been two (2) 
additional patients exposed to Ganetespib (study 9090-IST-125) which brings the total 
estimated cumulative exposure to 1,611 individuals. 
As of 21 September 2016, 1,609 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. 
696 patients were enrolled in Study 9090-14, of which 338 received Ganetespib. In Synta-


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sponsored studies of normal healthy volunteers, 102 subjects have 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 (545) have been treated in ISTs. 
 Phase I/II GANNET53 trial in platinum-resistant ovarian cancer patients 
(EUDRACT 2013-003868-31) 
The clinical partners in this trial have gained extensive experience with the test drug 
Ganetespib in ovarian cancer in the Phase I and randomised Phase II GANNET53 trial. 
 
Phase I dose escalation/de-escalation GANNET53 trial 
Patients and Methods: Eligible patients had platinum resistant ovarian cancer (PROC). 
Patients with > 4 prior chemotherapy and low-grade carcinoma were not eligible. Weekly 
Paclitaxel (80 mg/m²) and increasing doses of Ganetespib (100, 150 mg/m²) were given i.v. on 
days 1, 8, 15 in a 28 days cycle until disease progression or unacceptable toxicity. A traditional 
3+3 design was applied with no intra-patient dose escalation. End points were safety and 
determination of phase II dose. Dose limiting toxicity (DLT) was defined as grade 4 toxicity 
(with exceptions) occurring in cycles 1 & 2.  
Results: In the Phase I dose escalation/de-escalation study a total of ten patients (median age 
57 years; range 43-70) were enrolled. No DLT occurred in cohort 1 (4 patients treated with 
Paclitaxel + Ganetespib 100 mg/m²), nor in cohorts 2 and 3 (6 patients treated with Paclitaxel 
+ Ganetespib 150 mg/m²). Ganetespib in combination with Paclitaxel has been generally well 
tolerated. 
 
Randomised, open label, multicentre Phase II GANNET53 trial 
Patients and Methods: Patients with high-grade serous, high-grade endometrioid or 
undifferentiated platinum resistant ovarian cancer were randomised in a 1:2 ratio and received 
either weekly Paclitaxel (80 mg/m²) or a combination of weekly Ganetespib (150 mg/m²) and 
Paclitaxel (80 mg/m²) i.v. on days 1, 8, 15 in a 28 days cycle. Patients received 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 was 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). The primary aim of 
the phase II study was to determine efficacy of Ganetespib in combination with weekly 
Paclitaxel compared to weekly Paclitaxel alone. 
Preliminary results: The trial is still active but recruitment was terminated early due to the 
decision of the company to stop the production of Ganetespib. In total 133 of the originally 
planned 222 patients were included. 90 patients were enrolled in the experimental arm 
Ganetespib plus Paclitaxel and 43 patients in the active comparator arm receiving single agent 
Paclitaxel.  
 Phase I/II MESO-02 trial in patients with malignant pleural mesothelioma 
(EudraCT No.: 2012-001598-10) 
The MESO-2 trial is a Phase I/II study of first line Ganetespib combined with Platinum in 
patients with malignant pleural mesothelioma. The Phase I dose-escalation trial was 
conducted at the University College London, UK (PI Prof. Dean Fennell). 
 


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Primary outcome measure of the Phase I trial was maximum tolerated dose (MTD) of 
Ganetespib. Primary endpoint of the Phase I trial was dose limiting toxicities (DLTs) for the 
Ganetespib, Cisplatin, Pemetrexed combination (during Cycles 1 and 2) and for Ganetespib, 
Carboplatin, Pemetrexed (during Cycle 1). 
 
The Phase I trial consisted of three Ganetespib dose cohort: 
- 
Cohort 1: 100 mg/m2 iv on day 1 and day 15 of each cycle 
- 
Cohort 2: 150 mg/m2 iv on day 1 and day 15 of each cycle 
- 
Cohort 3: 200 mg/m2 iv on day 1 and day 15 of each cycle 
 
Two experimental arms were investigated: 
1) Combination of Ganetespib with Cisplatin/Pemetrexed  
Cisplatin 75 mg/m2,          day 1 every 21 days (q3w) 
Pemetrexed 500 mg/m2,  day 1 every 21 days  (q3w) 
2) Combination of Ganetespib with Carboplatin/Pemetrexed  
Carboplatin AUC5,           day 1 every 21 days (q3w) 
Pemetrexed 500 mg/m2,   day 1 every 21 days (q3w) 
 
Dose-escalation in the Ganetespib with Cisplatin/Pemetrexed followed a classical 3+3 design 
(with expansion so that 9 patients would be treated at the MTD). Dose-escalation in the 
Ganetespib with Carboplatin/Pemetrexed followed an accelerated titration run-in stage using 
single patients, which switched to a classical 3+3 upon observing first DLT (also with expansion 
so that 9 patients would be treated at the MTD). 
 
Results of the Phase I trial: 
A total of 16 patients received Ganetespib/Cisplatin/Pemtrexed treatment (4 at 100 mg/m2, 3 
at 150 mg/m2, 9 at 200 mg/m2 Ganetespib respectively). 
A total of 11 patients received Ganetespib/Carboplatin/Pemtrexed treatment (1 at 100 mg/m2, 
1 at 150 mg/m2, 9 at 200 mg/m2). 
For both experimental treatment arms (Cisplatin and Carboplatin combination) MTD was 
established at 200 mg/m2 Ganetespib dose level, respectively. In the Cisplatin combination 
arm one DLT was observed in the 200 mg/m2 Ganetespib cohort, i.e. nausea, grade 3 lasting 
longer than 48 hours, respectively. In the Carboplatin combination arm the same DLT, nausea, 
grade 3 lasting longer than 48 hours was observed in one patient in the 200 mg/m2 Ganetespib 
cohort. Furthermore, a second DLT (infusion related reaction) was observed in the 200 mg/m2 
Ganetespib cohort in combination with Carboplatin/Pemetrexed. Two further patients 
experienced infusion related reactions in the 200 mg/m2 Ganetespib cohort in combination with 
Carboplatin/Pemetrexed, but were not classified as formal DLTs as observed outside of the 
DLT observation time-frame of cycle 1. 
In summary, the combination of Carboplatin and Ganetespib (and Pemtrexed as a third drug) 
was well tolerated in patients with malignant pleural mesothelioma. In the Carboplatin 
combination arm with Ganetespib two DLTs occurred at the identified MTD of Ganetespib (i.e. 
200mg/m2), which was nausea grade 3 lasting for more than 48 hours and one infusion related 
reaction, respectively. 
 


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 Ganetespib Safety Profile 
As of September 21, 2016 (data cut - off date for DSUR Number 5), 1,609 patients have been 
exposed to Ganetespib.  
TREATMENT-RELATED SERIOUS ADVERSE EVENTS: 
Single-agent Ganetespib (N=402): 
Treatment-related serious adverse events (expected serious adverse reactions) occurring in 
≥ 1% of patient are diarrhoea (1.7%), asthenia (1.0%) and vomiting (1.0%).  
 
Ganetespib+Docetaxel combination (most commonly applied Ganetespib combination to date, 
N=560): 
Treatment-related serious adverse events occurring in ≥1% of patients are febrile 
neutropenia (7.9%), diarrhoea (5.2%), neutropenia (3.8%), asthenia (1.6%), vomiting 
(1.4%), sepsis (1.3%), anemia (1.2%), dehydration (1.1%), and pneumonia (1.1%). 
 
 
TREATMENT-EMERGENT / TREATMENT-RELATED NCI CTAE ≥ Grade 3 ADVERSE 
EVENTS 
 
Single-agent Ganetespib (N=402): 
Treatment-related AEs ≥ Grade 3 occurring in ≥ 1% of patients were diarrhoea (9.7%), fatigue 
(6.0%), hyponatraemia (2.5%), lipase increased (2.5%), aspartate aminotransferase 
increased (2.0%), hypophosphataemia (2.0%), alanine aminotransferase increased 
(2.0%), nausea (2.0%), vomiting (1.7%), hypokalaemia (1.5%), lymphopenia (1.2%), 
asthenia (1.2%). 
 
Ganetespib+ Docetaxel combination (N=222) from Studies 9090-07 (phase I) and 9090-08 
(phase II)  
Treatment-emergent AEs Grade 4 occurring in ≥ 1% of patients were neutropenia (26.1%; in 
comparison to docetaxel alone in 18.8%), febrile neutropenia (5.0%; in comparison to 
docetaxel alone in 3.2%), and leukopenia (1.4%; in comparison to docetaxel alone in 0%). 
 
Ganetespib+ Docetaxel combination (N=338) from Studies 9090-14 (phase III)  
Treatment-emergent AEs Grade 4 occurring in ≥ 1% of patients were febrile neutropenia 
(3.0%; in comparison to docetaxel alone in <1%). 
 
 
TREATMENT-EMERGENT / TREATMENT-RELATED NCI CTCAE Grade 5 ADVERSE 
EVENTS 
 
Single-agent Ganetespib (N=402): 
Treatment emergent fatal AEs occurred in 10.9% of patients. The majority of which were due 
to disease progression (6.7%). Only the single events of cardia arrest (<1%) and acute renal 
failure (<1%) were considered to be related to Ganetespib treatment. 
 


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Ganetespib+ Docetaxel combination (N=222) from Studies 9090-07 (phase I) and 9090-08 
(phase II)  
17% of patients treated with Ganetespib in combination with docetaxel had experienced a 
Grade 5 event (death) during the treatment phase and within 30 days of last dose. This 
percentage is similar to that experienced in the docetaxel-alone arm (13%).  
The most common Grade 5 event was neoplasm progression (5% G+D, 5% D). All other Grade 
5 events in the combination arm occurred in less than 1% of patients with the exception of 
pulmonary embolism, pneumonia, and superior vena cava syndrome (1%). In the docetaxel- 
alone arm, 2% of patients experienced a Grade 5 event of pulmonary embolism, and 1% of 
patients experienced Grade 5 events of sudden cardiac death and sudden death.  
 
Ganetespib+ Docetaxel combination (N=338) from Studies 9090-14 (phase III)  
10% patients had a treatment-emergent AE that resulted in death: 12% in the combination 
treatment group and 9% in the docetaxel-alone group. Such events were assessed as 
treatment-related in 4 patients in each treatment group. The most frequent SAE resulting in 
death was neoplasm progression in both groups: 11 (3%) patients in the combination group 
and 10 (3%) patients in the docetaxel-alone group. All other Grade 5 events in the combination 
arm and the docetaxel-alone arm occurred in less than 1% of patients with the exception of 
“death” in the docetaxel-alone arm (1.2%).  
 
 
DOSE-LIMITING TOXICITY OF GANETESPIB AND CLASS EFFECTS  
 
Diarrhoea is the most frequent AE associated with the use of Ganetespib and also the well-
known dose limiting toxicity of Ganetespib (please see topic 8.3.4.3. “events of special interest 
with respect to Ganetespib treatment”, subtopic “diarrhoea” for detailed information on 
Ganetespib-induced diarrhoea).  
Of importance for the current EUDARIO trial, the combination of Carboplatin and Ganetespib 
(and Pemtrexed as a third drug) was well tolerated in patients with malignant pleural 
mesothelioma in the MESO-2 trial. In the combination arm of Carboplatin with Ganetespib two 
DLTs occurred at the identified MTD of Ganetespib (i.e. 200mg/m2), which was nausea grade 
3 lasting for more than 48 hours and one infusion related reaction, respectively. 
 
Events that may be class effect of HSP inhibitor (besides the already mentioned  
diarrhoea) include ocular toxicities and elevations in liver enzymes. Importantly, Ganetespib 
administered as a single agent was devoid of liver toxicities and visual impairment 
associated with other HSP90 inhibitors across all studies.  
In patients treated with the HSP90 inhibitors 17-DMAG or AUY922 who experience visual 
disturbances, the mechanism of visual disturbances is linked to induction of apoptosis in cells 
in the outer nuclear layer of the retina (17, 18). In contrast, Ganetespib did not elicit induction 
of apoptosis in preclinical studies using rodent models, consistent with the very low number of 
reported visual disturbance cases in the clinic.  
Liver toxicity in the 1st generation geldanamycin-derivative HSP90 inhibitors is an off-target 
effect. According to a study by Cysyk (19) the presence of benzoquinone moiety in the 
molecule is the suspected cause of liver toxicity. Ganetespib does not contain the 
benzoquinone moiety and, therefore, clinically significant liver toxicity is not expected. This is 
consistent with the safety information collected to date.  
 


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In addition, in single-agent Ganetespib studies there was no evidence of myelosuppressive 
effect (essentially no documented decrease in neutrophil count associated with Ganetespib 
administration). 
 
 Adverse Events with Ganetespib in combination with Paclitaxel in 
ovarian cancer patients (GANNET53 trial) 
 
Phase I dose escalation/de-escalation GANNET53 trial 
The most common adverse events (AEs) related to Ganetespib were transient grade 1/2 
diarrhea (n=70). The most frequent grade 1/2 AEs were diarrhea (n=70), QT corrected interval 
prolonged (n=11), neutropenia (n=10), headache (n=7), nausea (n=6), abdominal pain (n=5), 
constipation (n=5), pain (n=4), fatigue (n=3), dyspnoea (n=3), anemia (n=3), and anorexia 
(n=3). AEs ≥ grade 3 were diarrhoea (n=5), ascites (n=4), anemia (n=3), neutropenia (n=2), 
subileus (n=2), acute cardiac failure (n=1), asthenia (n=1), pain (n=1), placement of Tenkhoff-
catheter (n=1), polyneuropathy (n=1), syncope (n=1), and vomiting (n=1). There was 1 death 
on study (after DLT period) due to digestive tract hemorrhage from duodenal ulcer. Three 
patients discontinued due to SAEs (digestive hemorrhage n=1, cardiac failure n=1, anemia 
n=1), 5 due to progressive disease, one due to physicians decision. Two patients are still in 
follow-up. Detailed information on AEs which occurred in more than 1 patient (<10%) in the 
Phase I GANNET53 trial are summarised in Table 1. 
Summary: The combination of Ganetespib 150 mg/m² with Paclitaxel 80 mg/m² once weekly 
for 3 out of 4 weeks was generally well tolerated with no DLTs, and therefore chosen for the 
ongoing randomised phase II trial. Comparison of all occurred AEs which were indicated as 
related (possibly, probably, definitely) to Ganetespib revealed a similar toxicity profile as it was 
described in the IB: 
 
Table 1: Summary of Adverse events (AEs) (NCI CTCAE v4.03) which occurred in >1 patients in the 
Phase I dose escalation/de-escalation study (Total number of patients N=10)  
Grade 1-2 AEs 
Grade 3-4 AEs 
Reported 
Term 
number 
of 
patients 
(n=10) 
number 
of events 
(n) 
Relatedness* 
to G per 
patient (n) 
Reported Term 
number 
of 
patients 
(n=10) 
number 
of events 
(n) 
Relatedness* 
to G per 
patient (n) 
Diarrhoea 
8 
70 
related (8/10) 
Anemia 
3 
3 
related (1/10) 
unrelated (2/10) 
QT corrected 
interval 
prolonged 
6 
11 
related (5) 
unrelated (1) 
Diarrhoea 
3 
5 
related (3/10) 
Nausea 
6 
6 
related (3/10) 
unrelated 
(3/10) 
Ascites 
2 
4 
unrelated (2/10) 
 
Headache 
5 
7 
related (3/10) 
unrelated 
(2/10) 
Neutropenia 
2 
2 
related (2/10) 
Abdominal 
pain 
5 
5 
related (1/10) 
unrelated 
(4/10) 
Acute cardiac 
insufficiency 
stage IV; loss of 
systolic LV-
function 
1 
1 
related (1/10) 
Neutropenia 
3 
10 
related (3/10) 
Asthenia 
1 
1 
related (1/10) 


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Fatigue 
3 
3 
related (3/10) 
Pain 
1 
1 
unrelated (1/10) 
Dyspnoea 
3 
3 
related (3/10) 
Placement of 
Tenckhoff 
catheter 
1 
1 
unrelated (1/10) 
Pain 
3 
4 
unrelated 
(3/10)  
Polyneuropathy 
1 
1 
unrelated (1/10) 
Anemia 
3 
3 
related (3/10) 
Subileus 
2 
2 
unrelated (2/10) 
Anorexia 
3 
3 
related (2/10) 
unrelated 
(1/10) 
Syncope 
1 
1 
related (1/10) 
Asthenia 
2 
2 
unrelated 
(2/10) 
Vomiting 
1 
1 
unrelated (1/10) 
Constipation 
2 
5 
unrelated 
(2/10) 
 
Alopecia 
2 
2 
related (1/10) 
unrelated 
(1/10) 
Dysgeusia 
2 
2 
related (1/10) 
unrelated 
(1/10) 
Oedema 
peripheral 
2 
2 
related (2/10) 
Pruritus 
2 
2 
unrelated 
(2/10) 
Peripheral 
neuropathy 
2 
2 
related (2/10) 
Subileus 
2 
2 
unrelated 
(2/10) 
Weight loss 
2 
2 
related (2) 
 
 
* relatedness as evaluated by local PI; AEs categorised as related to study treatment included possibly, probably or definitely related  
G…Ganetespib 
 
Randomised, open label, multicentre Phase II GANNET53 trial 
Final safety data are not available yet, as the trial is ongoing. A summary of AEs in the first 86 
patients are given in Table 2 and Table 3. Two cases of gastrointestinal perforation (GIP) 
occurred in the randomised Phase II trial leading to a substantial protocol amendment 
excluding patients with pre-existing risk factors for GIP from study participation (see 8.3.4.3. 
for more information). This newly identified toxicity has been included into the IB. Besides GIP, 
comparison of occurred AEs which were indicated as related (possibly, probably, definitely) to 
Ganetespib revealed a similar toxicity profile as it was described in the IB. In general, good 
tolerability of Ganetespib in combination with Paclitaxel was seen in the randomised Phase II 
GANNET53 trial.  
Table 2: Summary of preliminary results (as of 23.08.2017) of related Adverse events (AEs) Grade 1-2 
(NCI CTCAE v4.03) which occurred in >10 % of patients in the Phase II study; included were all patients 
who received at least one dose of study medication in the experimental arm P+G. (Total number of 
patients N=86) 
Event 
Grade 1-2 
Arm P+G 
Number of 
patients 
n (%) 
(N=86) 
Number of 
events 
Relatedness to G 
per patient* 
n1 (%) 
(N1=n) 
Relatedness to P 
per patient* 
n2 (%) 
(N2=n) 
Diarrhoea 
75 (87,2) 
376 
75 (100,0) 
37 (49,3) 
Anemia 
42 (48,8) 
65 
32 (76,2) 
42 (100,0) 
Nausea 
37 (43,0) 
90 
36 (97,3) 
34 (91,9) 


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Alopecia 
36 (41,9) 
37 
11 (30,6) 
34 (94,4) 
Neuropathy peripheral 
32 (37,2) 
40 
11 (34,4) 
31 (96,9) 
Vomiting 
23 (26,7) 
37 
22 (95,7) 
19 (82,6) 
Fatigue 
22 (25,6) 
27 
21 (95,5) 
21 (95,5) 
Abdominal pain 
20 (23,3) 
24 
18 (90,0) 
14 (70,0) 
Neutrophil count decreased 
18 (20,9) 
26 
12 (66,7) 
18 (100,0) 
White blood cell decreased 
15 (17,4) 
24 
10 (66,7) 
15 (100,0) 
Asthenia 
13 (15,1) 
22 
12 (92,3) 
12 (92,3) 
Insomnia 
12 (14,0) 
12 
12 (100,0) 
10 (83,3) 
Constipation 
11 (12,8) 
19 
9 (81,8) 
9 (81,8) 
Electrocardiogram QT corrected interval 
prolonged 
11 (12,8) 
26 
11 (100,0) 
4 (36,4) 
Anorexia 
10 (11,6) 
17 
9 (90,0) 
9 (90,0) 
Headache 
9 (10,5) 
10 
9 (100,0) 
7 (77,8) 
* relatedness as evaluated by local PI; AEs categorised as related to study treatment included possibly, probably or definitely related  
G…Ganetespib 
P…Paclitaxel 
 
Table 3: Summary of preliminary results (as of 23.08.2017) of realated Adverse events (AEs) Grade 3 
– 5 (NCI CTCAE v4.03); included were all patients who received at least one dose of study medication 
in the experimental arm P+G (Total number of patients N=86). 
Event 
Grade 3-5 
Arm P+G 
Number of 
patients 
n (%) 
(N=86) 
Number of 
events 
Relatedness to G 
per patient* 
n1 (%) 
(N1=n) 
Relatedness to P 
per patient* 
n2 (%) 
(N2=n) 
Neutrophil count decreased 
11 (12,8) 
16 
7 (63,6) 
11 (100,0) 
Diarrhoea 
10 (11,6) 
14 
10 (100,0) 
0 (0,0) 
Anemia 
6 (7,0) 
6 
5 (83,3) 
6 (100,0) 
Asthenia 
3 (3,5) 
3 
3 (100,0) 
3 (100,0) 
Fatigue 
2 (2,3) 
2 
2 (100,0) 
1 (50,0) 
Febrile neutropenia 
2 (2,3) 
2 
1 (50,0) 
2 (100,0) 
Lymphocyte count decreased 
2 (2,3) 
2 
1 (50,0) 
2 (100,0) 
Nausea 
2 (2,3) 
2 
2 (100,0) 
1 (50,0) 
Sepsis 
2 (2,3) 
2 
2 (100,0) 
1 (50,0) 
Vomiting 
2 (2,3) 
2 
2 (100,0) 
2 (100,0) 
White blood cell decreased 
2 (2,3) 
3 
1 (50,0) 
2 (100,0) 
Alkaline phosphatase increased 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Allergic reaction 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Anal hemorrhage 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Anorexia 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Ascites 
1 (1,2) 
3 
1 (100,0) 
1 (100,0) 
Dyspnoea 
1 (1,2) 
2 
1 (100,0) 
1 (100,0) 
Esophagitis 
1 (1,2) 
1 
1 (100,0) 
0 (0,0) 
Gastritis 
1 (1,2) 
1 
1 (100,0) 
0 (0,0) 
General physical health deterioration 
1 (1,2) 
1 
1 (100,0) 
0 (0,0) 
Hypertension 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Hypertransaminasemia 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Icterus 
1 (1,2) 
1 
1 (100,0) 
0 (0,0) 


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Insomnia 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Intestinal perforation 
1 (1,2) 
1 
1 (100,0) 
0 (0,0) 
Melaena 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Rectal ulcer 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Small intestinal obstruction 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Small intestinal perforation 
1 (1,2) 
1 
1 (100,0) 
0 (0,0) 
Transaminases increased 
1 (1,2) 
1 
1 (100,0) 
1 (100,0) 
Visual acuity reduced 
1 (1,2) 
1 
1 (100,0) 
0 (0,0) 
* relatedness as evaluated by local PI; AEs categorised as related to study treatment included possibly, probably or definitely related  
G…Ganetespib 
P…Paclitaxel 
 
 Adverse Events with Ganetespib in Pemetrexed/Carboplatin in 
malignant pleural mesothelioma (MESO-02 trial) 
 
In general, the Ganetespib combination with Platin/Pemetrexed was well tolerated at a 
Ganetespib combination dose level of 150mg/m2 (to be used in the present trial) in patients 
included into the MESO-2 trial. A summary of toxicities are given in the text and Table 4, Table 
5, Table 6 and Table 7 below, which were kindly provided in personal communication with the 
studies PI, Sponsor and responsible trial statistician. 
Adverse events in treatment cycles 1 and 2 only 
Table 4 and Table 5 show the maximum grade (NCI CTCAE v4.0) per adverse event (AE) per 
patient observed in the MESO-02 trial (on treatment (Ganetespib, pemetrexed and 
cisplatin/Carboplatin), cycles 1 and 2 only). All patients (N=27) had at least one grade 1 or 
grade 2 AE [Table 4]. Common AEs include fatigue (n = 17), anemia (n=16), nausea (n=14), 
anorexia (n=10), constipation (n=10) and dyspnea (n=10). Eleven patients had at least one AE 
with maximum grade 3 (8 pts) or grade 4 (3 pts) [Table 5]. They included: one patient with 
hearing impairment (grade 4); two patients with neutrophil count decrease (grade 4); one 
patient with diarrhea, hyperkalemia, nausea, neutrophil count decrease and platelet count 
decrease (all grade 3); and one patient with ascites, pleural effusion and upper respiratory 
infection (all grade 3). 
 
Table 4: Number of patients experiencing AEs of maximum grade 2 (NCI CTCAE v4.0) in treatment 
cycles 1 and 2 
Results given by Organ Class (AE shown if 5 or more patients experience G1 or G2 AE) 
Organ Class 
Adverse Event (if 5 or more 
patients affected) 
Total 
Blood and lymphatic system 
16 
  
Anemia 
16 
Cardiac 
  
2 
Ear and labyrinth 
  
3 
Eye 
  
4 
Gastrointestinal 
19 
Abdominal pain 
6 
Constipation 
10 
Diarrhea 
8 


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Nausea 
14 
Vomiting 
9 
  
Weight loss 
5 
General disorders and administration site conditions 
21 
  
Fatigue 
17 
Infections and infestations 
  
9 
Investigations 
  
5 
Metabolism and nutrition 
10 
  
Anorexia 
10 
Musculoskeletal and connective tissues 
8 
  
Back pain 
6 
Nervous system 
  
2 
Other (non CTCAE term) 
  
2 
Psychiatric 
  
4 
Renal and urinary 
  
2 
Respiratory, thoracic and mediastinal 
14 
Cough 
7 
  
Dyspnea 
10 
Skin and subcutaneous tissue 
  
8 
Vascular 
  
3 
Total patients experiencing at least one G1 or G2 AE   
27 
 
Table 5: Number of patients experiencing AEs of maximum grade 3 or 4 (NCI CTCAE v4.0) in treatment 
cycles 1 and 2 
All Adverse Events shown 
Organ Class 
Adverse Event 
CTCAE 
Grade 
3 
4 
Ear and labyrinth 
Hearing impaired 
0 
1 
Gastrointestinal 
Ascites 
1 
0 
Diarrhea 
1 
0 
Nausea 
3 
0 
  
Vomiting 
1 
0 
Infections and infestations 
Infections and infestations - Other 
1 
0 
  
Upper respiratory infection 
1 
0 
Investigations 
Neutrophil count decreased 
1 
2 
  
Platelet count decreased 
2 
0 
Metabolism and nutrition 
Hyperkalemia 
1 
0 
Respiratory, thoracic and mediastinal 
Dyspnea 
1 
0 
Pleural effusion 
1 
0 
  
Sleep apnea 
1 
0 
Total patients with at least one Grade 3 or 4 AE  (Total = 11) 
8 
3 
 
Adverse events at any time 


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Table 6 and Table 7 show the maximum grade (NCI CTCAE v4.0) per adverse event (AE) per 
patient observed in the MESO-02 trial (reported at any time on study). All patients (N=27) had 
at least one grade 1 or grade 2 AE [Table 6]. Common AEs include fatigue (n = 20), dyspnea 
(n=15), nausea (n=15), anemia (n=13), diarrhea (n=13), anorexia (n=12), constipation (n=12) 
and vomiting (n=12). Eighteen patients had at least one AE with maximum grade 3 (17 pts) or 
grade 4 (5 pts) [Table 7]. These included: one patient with hearing impairment (grade 4); one 
patient with neutrophil count decrease (grade 4) and anemia (grade 3); one patient with 
neutrophil count decrease (grade 4), syncope and upper respiratory infection (all grade 3); one 
patient with sepsis (all grade 4) and anxiety (grade 3); and one patient with platelet count 
decrease (grade 4), anemia, hypokalemia and hyponatremia (all grade 3). 
 
Dose Limiting Toxicity (DLT) summary (copied from Scientific Milestone Report – 
10/03/2016) 
 
“The 3 proposed dose cohorts of Ganetespib + Pemetrexed/Cisplatin have been 
completed with the top dose of Ganetespib (200 mg/m2) confirmed as the MTD. One 
DLT was observed in the 200 mg/m2 cisplatin cohort (nausea, grade 3 lasting longer 
than 48 hours).” 
 
“The 100 and 150 mg/m2 cohorts for Carboplatin were completed without evidence of 
any DLTs. As per the dose escalation design, the next 3 patients were recruited to the 
200 mg/m2 cohort (1 DLT observed: infusion-related reaction), and expanded to recruit 
a further 3 patients. Two patients from the expansion group experienced infusion 
related reactions in cycle 2 (not classified as ‘formal DLTs’ as observed in cycle 2. DLT 
assessments in the Carboplatin cohort are assessed in cycle 1 only). The Trial 
Management Group (TMG) agreed the 3 occurrences of infusion-related reactions 
warranted further investigation, and it was agreed the 200 mg/m2 cohort would be 
further expanded to include an additional 3 patients. Cohort 3 is now closed to 
recruitment (including the additional 3 patients as advised by the TMG). One patient 
from this final expansion group experienced a DLT during cycle 1 (nausea, grade 3 
lasting longer than 48 hours). This completes phase I recruitment into the trial.” 
 
“A DLT review meeting carried out for the last dose cohort of Ganetespib + 
pemetrexed/Carboplatin on 29th February 2016 confirmed that the MTD is 200mg/m2.” 
 
Table 6: Number of patients experiencing AEs of maximum grade 2 (NCI CTCAE v4.0) at any time 
Results given by Organ Class (AE specified if at least 5 patients experience G1 or G2 AE) 
Organ Class 
Adverse Event (if 5 or more 
patients affected) 
Total 
Blood and lymphatic system 
13 
  
Anemia 
13 
Cardiac 
  
2 
Ear and labyrinth 
  
4 
Eye 
  
4 
Gastrointestinal 
21 
Abdominal pain 
9 
Constipation 
12 
Diarrhea 
13 
Dyspepsia 
5 


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Nausea 
15 
Vomiting 
12 
  
Weight loss 
8 
General disorders and administration site conditions 
23 
Fatigue 
20 
Non-cardiac chest pain 
9 
  
Pain 
6 
Infections and infestations 
9 
Infections and infestations - Other 
5 
  
Upper respiratory infection 
7 
Investigations 
  
7 
Metabolism and nutrition 
13 
  
Anorexia 
12 
Musculoskeletal and connective tissue 
10 
  
Back pain 
8 
Nervous system 
11 
  
Peripheral sensory neuropathy 
5 
Other (non CTCAE term) 
5 
  
Other (non CTCAE term) 
5 
Psychiatric 
6 
  
Insomnia 
6 
Renal and urinary 
  
2 
Respiratory, thoracic and mediastinal 
18 
Cough 
8 
  
Dyspnea 
15 
Skin and subcutaneous tissue 
  
11 
Vascular 
  
4 
Total patients experiencing at least one G1 or G2 AE 
  
27 
 
Table 7: Number of patients experiencing AEs of maximum grade 3 or 4 (NCI CTCAE v4.0) at any time 
All Adverse Events shown 
Organ Class 
Adverse Event 
CTCAE Grade 
3 
4 
Blood and lymphatic system 
Anemia 
6 
0 
Ear and labyrinth 
Hearing impaired 
0 
1 
Eye 
Glaucoma 
1 
0 
Gastrointestinal 
Ascites 
1 
0 
Diarrhea 
2 
0 
Nausea 
4 
0 
  
Vomiting 
2 
0 
Infections and infestations 
Infections and infestations - Other 
1 
0 
Lung infection 
1 
0 
Sepsis 
0 
1 
Upper respiratory infection 
2 
0 


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Wound infection 
2 
0 
Investigations 
Neutrophil count decreased 
3 
2 
  
Platelet count decreased 
2 
1 
Metabolism and nutrition 
Hyperglycemia 
1 
0 
Hyperkalemia 
1 
0 
Hypokalemia 
1 
0 
  
Hyponatremia 
1 
0 
Nervous system 
Syncope 
1 
0 
Psychiatric 
Anxiety 
1 
0 
Respiratory, thoracic and mediastinal 
Apnea 
1 
0 
Dyspnea 
1 
0 
Pleural effusion 
1 
0 
  
Sleep apnea 
1 
0 
Vascular 
Vasculitis 
1 
0 
Total patients with at least one AE of Grade 3 or 4 
(Total  = 18) 
17 
5 
 
 Events of special interest with respect to Ganetespib treatment 
Diarrhoea 
Diarrhoea is the most frequent adverse event associated with the use of Ganetespib and the 
well-known dose limiting toxicity of Ganetespib.  
The postulated mechanism of action for Ganetespib - induced diarrhoea is inhibition of EGFR 
in cells that line the gastrointestinal tract, leading to a transient secretory diarrhoea, typically 
limited to 24 to 48 hours following Ganetespib infusion. This AE is manageable with 
Loperamide. Prophylactic use of loperamide can reduce the occurrence of diarrhoea from 
>80% to approximately 40%.  
As expected, diarrhoea seen in the Phase I GANNET53 dose escalation/de - escalation study 
patients was always transient and always, but once, mild or moderate in grade. Only one grade 
3 diarrhoea was seen in a patient who was not compliant with respect to Loperamide intake. 
This led to an aggravation of the grade 2 diarrhoea to a grade 3 diarrhoea.  
Also, in the Phase II GANNET53 trial (first 100 patients evaluated) diarrhoea was typically 
transient and self-limited and mild or moderate in grade.  
ECG QT prolonged 
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.  
Also, in the Phase I GANNET53 dose escalation/de-escalation study a thorough evaluation 
and review of QT times in all patients was performed. QT prolongations were seen in 6/10 


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patients. Importantly, all QT prolongations were grade 1. Of note, 5/6 patients already showed 
a grade 1 QT prolongation prior to the first dosing of ganetetspib. In 1/6 patients a new grade 
1 QT prolongation occurred in an ECG 24-hours after Ganetespib dosing. In this patient with 
a new 24-hours post dose QT prolongation, QT time normalized after switch of Paclitaxel 
premedication from Odansetron to Granisetron during repeated treatment. Odansetron (in 
contrast to Granisetron) is known to cause QT prolongation and should not be combined with 
Ganetespib. In 3/10 patients QT prolongation were evaluated as related (possibly or probably) 
to Ganetespib by the sponsor. Among these 3 patients, only one patient showed a grade 1 QT 
prolongation solely in the 24h post Ganetespib dose ECG, probably relating this QT 
prolongation to the Ganetespib. 
Gastrointestinal perforation (GIP) 
Gastrointestinal perforation (GIP) has been added as new important identified risk to the IB 
Edition 11 of 13-November-2015 since two SUSARs of GIP occurred in the randomised Phase 
II GANNET53 trial. Within the safety database of Synta Pharmaceuticals a total of 6 perforation 
cases were identified in 1,524 patients (as of 21-September-2015) resulting in a reporting rate 
of 0.39%. However, within the GANNET53 trial a total of 133 ovarian cancer patients have 
been included into the randomised Phase II GANNET53 trial, of which 86 were treated with 
Ganetespib by 26-July-2017 (90 patients were randomised into the Ganetespib combination 
arm, but 4 never received a single dose of Ganetespib). Two patients with GIP were identified 
resulting in a reporting rate of 2.33%. Of note, both of these two patients had pre-existing risk 
factors for GIP (prior to inclusion into the GANNET53 trial). 
 
As a response to the two GIP cases occuring in the GANNET53 phase II trial (first GIP case 
on 19-July-2015, second GIP case on 26-August-2015), a substantial amendment has been 
implemented with new in- and exclusion criteria excluding pre-existing risk factors for GIP. With 
this measure, patient safety with respect to GIP was significantly increased. No case of GIP 
occurred since the implementation of the adjusted in- and exclusion criteria.  
Importantly, these adjusted in- and exclusion criteria are implemented in the current protocol 
in platinum-sensitive ovarian cancer patients in order to exclude patients with a risk profile for 
GIP from study participation. 
 
 Potential overlapping toxicities of the combination of Ganetespib and 
Niraparib 
 
Potential overlapping toxicities of the Ganetespib/Niraparib combination were estimated based 
on the available safety data 1) of single-agent Ganetespib in the Investigator`s Brochure (IB 
edition 13, release date: 07 November 2018), 2) on the combination of Ganetespib with 
Paclitaxel in platinum-resistant ovarian cancer (randomised Phase II GANNET53 trial, 
NCT02012192, preliminary safety data in 86 patients have been included into the protocol 
under the topic 8.3.4.1, for the estimate of overlapping toxicities the final unpublished data in 
133 patients have been used herein) and 3) on Niraparib as single-agent maintenance therapy 
in platinum-sensitive, recurrent ovarian cancer (randomised, placebo controlled Phase III 
ENGOT-OV16/NOVA trial, NCT01847274; the safety profile has been included into the 
protocol under topic 9.3.2 and is also published in Mirza et al, NEJM 2016; a total of 553 
patients were enrolled). 
 


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The most frequent and well-known AE associated with the use of Ganetespib is diarrhoea 
which is typically low grade and transient, lasting 24-48 hours after Ganetespib administration 
(postulated mechanism of action is inhibition of EGFR in enterocyte cells that line the GI tract, 
leading to a transient secretory diarrhoea). Single-agent Ganetespib studies showed no 
evidence of a myelosuppressive effect. Treatment-related SAEs (Expected Serious Adverse 
Reactions) occurring in ≥ 1% of patients treated with single-agent Ganetespib (n=402) are 
diarrhoea (1,7%), vomiting (1%), and asthenia (1%) according to the IB.  
 
In platinum-resistant ovarian cancer patients treated with a Ganetespib/Paclitaxel combination 
(Phase II GANNET53 trial) transient grade 1/2 diarrhoea occurred in 78.9% of patients and 
11.1% of patients experienced ≥ grade 3 diarrhoea (as compared to 25.6% and 4.7% in the 
Paclitaxel only arm, respectively). In patients treated with the Ganetespib/Paclitaxel 
combination, nausea  ≥ grade 3 was present in 2.2% of and also vomiting ≥ grade 3 occurred 
in 2.2% of patients (while both were not reported in the Paclitaxel only arm). 
 
Neutrophil count decrease ≥ grade 3 was seen in 12.0% of ovarian cancer patients treated 
with the Ganetespib/Paclitaxel combination (as compared to 9.3% in the control arm with 
Paclitaxel alone). Febrile neutropenia occurred in 2.2% of patients treated with the 
Ganetespib/Paclitaxel combination while no febrile neutropenia was seen in the single agent 
Paclitaxel arm. Anemia ≥ grade 3 was seen in 7.8% of patients treated with the 
Ganetespib/Paclitaxel combination (as compared to 9.3% in the Paclitaxel only arm). Of note, 
no ≥ grade 3 thrombocytopenia occurred, neither in the Ganetespib/Paclitaxel arm nor in the 
Paclitaxel only arm. Grade 1/2 thrombocytopenia occurred in 6% of patients treated with the 
Ganetespib/Paclitaxel combination and was not present in the Paclitaxel only arm.  
Fatigue grade 1/2 occurred in 23.3% of patients treated with the Ganetespib/Paclitaxel 
combination and grade ≥ 3 fatigue was seen in 2.2% (as compared to 16.3% and 0% in the 
Paclitaxel only arm, respectively). 
 
The most relevant AE of Niraparib single agent maintenance treatment in platinum-sensitive 
ovarian cancer patients (ENGOT-OV16/NOVA trial, (4) is thrombocytopenia, occurring at any 
grade in 61.3% of patients with 33.8% of patients experiencing grade 3/4 thrombocytopenia 
(in comparison to 5.6% and 0.6% on the placebo group, respectively). Neutropenia of any 
grade occurred in 30.2% of patients and 19.6% of patients experienced grade 3/4 neutropenia 
(in comparison to 6.1% and 1.7% in the placebo group, respectively; no grade 5 events were 
observed in this ENGOT-OV16 study). The rate of febrile neutropenia was not reported in a 
table listing all AEs of any grade in at least 10% of patients. Anemia of any grade occurred in 
50.1% of patients and at grade 3/4 in 25.3% (in comparison to 6.7% and 0% the placebo 
group).  
Fatigue of any grade occurred in 59 and 0.6% in the placebo arm, respectively). 
Diarrhoea of any grade occurred in 19.1% of patients and was grade 3/4 in 0.3% of patients 
(as compared to 20.7% and 1.1% in the placebo group, respectively). Nausea of any grade 
occurred in 73.6% of patients with 3% experiencing grade 3/4 nausea (compared to 35.2% 
and 1.1% in the placebo group, respectively). 34% of patient experienced any grade vomiting 
and 1.9% of patients had grade 3/4 vomiting (as compared to 16.2% and 0.6% in the placebo 
group, respectively). 
Of note, after dose adjustment on the basis of an individual adverse event profile, the incidence 
of grade 3/4 neutropenia, thrombocytopenia, or fatigue was infrequent beyond cycle 3 of 
treatment. Thrombocytopenia was transient and platelet levels stabilised beyond cycle 3. 


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In summary, while single agent Ganetespib has not shown evidence for a myelosuppressive 
effect, potential overlapping toxicities of Ganetespib and Niraparib are of hematologic nature.  
Particularly febrile neutropenia is a potential important risk for combination treatment in ovarian 
cancer patients. Thrombocytopenia and anemia are important risks in the maintenance 
treatment of platinum-sensitive ovarian cancer patients with single agent Niraparib. However, 
the addition of Ganetespib to Paclitaxel has to date not shown to aggravate thrombocytopenia 
or anemia in platinum-resistant ovarian cancer patients. However, we cannot exclude 
Ganetespib to aggravate these AEs in combination with Niraparib in platinum-sensitive ovarian 
cancer patients.  
Overlapping toxicities of Ganetespib and Niraparib might also include fatigue and gastro-
intestinal adverse events such as diarrhoea, vomiting and nausea. 
 
 Potential overlapping toxicities of the combination of Ganetespib and 
Carboplatin 
 
By now, first safety data on the combination of Ganetespib 150mg/m2 with Carboplatin 
AUC5 are available in platinum-sensitive ovarian cancer patients treated in the 
EUDARIO trial. A first IDMC evaluation took place on 2 July 2019 after the first 6 patients 
were treated with this combination (pre-planned according to protocol) and IDMC 
concluded that there are no objections to continuation of the study. 
 
The safety data of the first 6 patients is available (Safety data on Carboplatin/Ganetespib 
combination in the first 6 patients treated within the EUDARIO trial for IDMC evaluation). 
Meanwhile 
11 
patients 
(status 
24 
July 
2019) 
have 
been 
treated 
with 
the 
Ganetespib/Carboplatin combination in the EUDARIO trial without any unexpected safety 
signal or safety concern. 
 
Further evaluation of potential overlapping toxicities of Ganetespib in combination with 
Carboplatin by the Sponsor and the Coordinating Investigator are provided herein 
based on  
1) The well-known safety profile of Carboplatin, demonstrating a cornerstone of 
ovarian cancer treatment (condensed in the Summary of Product Characteristics of 
Carboplatin (ANNEX III).  
2) Ganetespib safety data provided in the Investigator`s Brochure (IB edition 13, 
release date: 07 November 2018), 
 
The most frequent and relevant AEs and SAEs associated with the use of Ganetespib have 
already been pointed out above (under the topic of potential overlapping toxicities with 
Niraparib).  
Thus, we focus in the following on Carboplatin and potential overlapping toxicities of both 
drugs. 
 
Myelosupression is the well-known dose limiting toxicity of Carboplatin and belongs to the very 
common (>=1/10) carboplatin side-effects. While single agent Ganetespib has not shown 
evidence for a myelosuppressive effect, potential overlapping toxicities of Ganetespib and 
Carboplatin are of hematologic nature. Particular febrile neutropenia is a potential important 


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risk for carboplatin-based combination treatment in ovarian cancer patients. Neutropenia with 
granulocyte counts below 1000/mm3 is seen in 18% of patients treated with Carboplatin. Febrile 
neutropenia is a rare (>=1/10000, <1/1000) adverse event reported with the use of Carboplatin. 
In patients with normal baseline values, thrombocytopenia with platelet counts below 
50.000/m3 occurs in 25% of patients. Anemia with hemoglobin values of less than 9,5 
mg/100ml occurs in about 48% of patients treated with Carboplatin. We cannot exclude 
Ganetespib to aggravate these AEs in combination with Carboplatin in the ovarian cancer 
patient population treated in the EUDARIO trial. 
 
Overlapping toxicities of Ganetespib and Carboplatin might also occur with respect to gastro-
intestinal adverse events such as diarrhoea, vomiting and nausea. In patients treated with 
Carboplatin vomiting occurs in 65% of patients (very common), in one-third of whom it is 
severe. Nausea occurred in an additional 15% (very common), diarrhoea in about 6% 
(common) and constipation in about 5% (common). Treatment-related SAEs (Expected 
Serious Adverse Reactions) in patients treated with single-agent Ganetespib include diarrhoea 
(1,7%), vomiting (1%), and nausea (0.7%) according to the IB edition 13. Of note, nausea 
grade 3 lasting for more than 48 hours demonstrated a DLT event in the MESO-2 trial when 
combining Carboplatin with a Ganetespib at the MTD dose of 200mg/m2 (in a triple combination 
also involving Pemtrexed). Thus, there is a risk for overlapping toxicity with respect to 
gastrointestinal adverse events when combining Carboplatin and Ganetespib. 
 
Hepatotoxicity is common in patients treated with Carboplatin. About one third of patients with 
normal liver function tests show elevated values after treatment with Carboplatin (including 
elevation of total bilirubin in 5%, SGOT in 15%, and alkaline phosphatase in 24% of patients). 
However, these modifications are generally mild and reversible in about one half of the 
patients. Clinically significant liver toxicity in not expected in patients treated with single-agent 
Ganetespib. Importantly, liver toxicity seen in the 1st generation geldanamycin-derivative 
HSP90 inhibitor is an off-target effect. The presence of a benzoquinone moiety in the molecule 
is suspected to have caused liver toxicity. Ganetespib does not contain such a benzoquinone 
moiety. This is consistent with the safety information collected to date that hepatotoxicity 
reported as a related serious adverse events in patients treated with single agent Ganetespib 
occurred in only 0.2% of patients. 
 
Other typical and common (>=1/100, <1/10) adverse events associated with the use of 
Carboplatin include peripheral neuropathy (in about 6% of patients after treatment with 
Carboplatin), clinical ototoxicity (about 1% of patients, usually manifestation as tinnitus), 
lowering of renal function (common AE, defined as decrease in creatinine clearance below 
60ml/min) and alopecia. None of these are expected to worsen in a combination treatment with 
Ganetespib considering the single agent safety profile of Ganetespib.  
 
 Clinical Pharmacokinetics 
The PK of Ganetespib, administered at various doses on a weekly or twice weekly schedule, 
is under investigation in three Phase I trials. Preliminary data and calculated parameters are 
available from these trials in patients with solid and haematologic tumours and normal healthy 
male subjects, and are summarised below. 


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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 haematologic 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, 
respectively, resulting in the classification of STA-12-0671 as a “major” metabolite according 
to the Metabolites in Safety Testing (MIST) guidance. 
 
 


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9 INFORMATION 
ON 
THE 
INVESTIGATIONAL 
MEDICINAL 
PRODUCTS (IMPS) NIRAPARIB 
 Name and Chemical Information 
Niraparib (formerly MK-4827), or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 
4-methylbenzenesulfonate hydrate (1:1:1), is an orally available, potent, highly selective poly 
(adenosine diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor. The crystalline 
tosylate monohydrate salt of Niraparib is being developed as a monotherapy agent for tumours 
with defects in the homologous recombination deoxyribonucleic acid (DNA) repair pathway, as 
a sensitizing agent in combination with cytotoxic agents and radiotherapy, and in combination 
with immune-oncology biologics. The Niraparib drug product is formulated as a dry-filled 
capsule (100 mg) for oral administration. 
 Preclinical experience 
Nonclinical data on Niraparib are discussed in detail in the Niraparib Investigator’s Brochure 
(IB). Briefly, in nonclinical models, Niraparib has been observed to inhibit normal DNA repair 
mechanisms and induce synthetic lethality when administered to cells with homologous 
recombination defects. In a BRCA1-mutant xenograft study, Niraparib dosed orally caused 
tumour regression, which was mirrored by a >90 % reduction in tumour weight compared with 
control. In a BRCA2-mutant xenograft study, Niraparib-dosed mice showed 55 % to 60 % 
growth inhibition, both by tumour volume and weight. 
Niraparib displayed strong antitumour activity in in vivo studies with BRCA1-mutant breast 
cancer (MDA-MB-436), BRCA2-mutant pancreatic cancer (CAPAN-1), and with patient-
derived Ewing sarcoma mice models. Utilizing patient-derived ovarian and breast cancer 
xenograft models, Niraparib demonstrated response in both BRCAmut and BRCA wild-type 
tumours. 
 Clinical experience 
 Phase III NOVA trial in relapsed platinum-sensitive ovarian cancer patients 
(EudraCT No.: 2013-000685-11) 
The primary efficacy and safety data of Niraparib as maintenance treatment in patients 
with platinum-sensitive recurrent ovarian cancer are derived from a Phase III study 
(NOVA), which included a total of 367 Niraparib-treated patients at the time of data cut. 
Niraparib, as a daily oral treatment, prolonged the effect of platinum-based chemotherapy, 
improved progression-free survival (PFS), and reduced the risk of recurrence or death in 
a broad population of patients.  
Within the germline BRCA mutation (gBRCAmut) cohort, the median PFS was 21.0 months in 
patients on Niraparib versus 5.5 months on placebo (hazard ratio [HR], 0.27; p < 0.0001). PFS 
was also significantly longer with Niraparib in the homologous recombination deficient-positive 
(HRDpos) group of the non-gBRCAmut (without germline BRCA mutation) cohort (median, 
12.9 months versus 3.8 months; HR, 0.38; p < 0.0001) and in the overall non-gBRCAmut 
cohort (median, 9.3 months versus 3.9 months; HR, 0.45; p < 0.0001).  


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Secondary endpoints, including chemotherapy-free interval (CFI), time to first subsequent 
treatment (TFST), and progression-free survival 2 (PFS2), confirmed the PFS benefit of 
Niraparib treatment in both cohorts, provided evidence that niraparib does not diminish 
responsiveness to subsequent therapy, and demonstrates a persistent treatment effect of 
Niraparib. There was no evidence of a detrimental impact of Niraparib treatment on overall 
survival (OS). Dose reductions had no impact on PFS.  
Patient-reported outcomes data were similar for patients in the Niraparib and placebo 
treatment arms. Data from the Functional Assessment of Cancer Therapy – Ovarian Symptom 
Index (FOSI) and European Quality of Life Scale, 5-Dimensions (EQ-5D-5L) questionnaires 
showed equivalent outcomes for Niraparib versus placebo for both generic and disease-
specific outcomes in the gBRCAmut and the overall non-gBRCAmut cohorts.  
The non-gBRCAmut cohort represents patients with diverse tumour biology. Exploratory 
analyses were conducted to identify any potential drivers of Niraparib treatment effect in these 
biomarker subgroups (HRDpos/somatic BRCA mutation [sBRCAmut], HRDpos/BRCA wild 
type [BRCAwt], and HRD negative [HRDneg]). The benefit of Niraparib treatment within the 
HRDpos group as a whole was not due to patients with somatic BRCA mutations. In the 
HRDpos primary efficacy population, the median PFS for Niraparib was similar to that seen in 
HRDpos/BRCAwt patients. The treatment effect observed in the gBRCAmut cohort was 
comparable to the results observed in HRDpos/sBRCAmut subgroup. Review of data for 
patients with BRCA mutations (germline or somatic) combined across both the gBRCAmut and 
non-gBRCAmut cohorts also showed a significant treatment effect.  
The overall population of the non-gBRCAmut cohort included patients with tumours that were 
HRDneg, and exploratory analyses demonstrated that this population experienced a benefit 
from Niraparib treatment. At 18 months, more than twice as many Niraparib-treated patients 
than placebo-treated patients were considered progression-free. 
 
 
Niraparib Safety Profile 
Niraparib was evaluated in a series of Phase I clinical trials in patients with solid tumours. 
144 patients have been treated with Niraparib at doses up to 400 mg once daily (QD) in 
Phase I studies. The dose-limiting toxicity (DLT) at this dose was thrombocytopenia; the 
recommended Phase II dose (RP2D) was determined to be 300 mg QD. 
Overall, Niraparib appears to have a predictable adverse event (AE) profile that is readily 
managed through routine laboratory testing (ie, complete blood count [CBC]) and clinical 
surveillance (ie, blood pressure monitoring) and adherence to the recommended dose 
modifications. The most commonly observed non-haematologic treatment-emergent 
adverse events (TEAEs) (any grades) were nausea, fatigue, constipation, and vomiting; 
the majority of the non-haematological TEAEs were mild to moderate in severity. The most 
commonly observed haematologic TEAEs (any grades) were anemia, thrombocytopenia, 
and neutropenia. The incidence of myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) in patients who received Niraparib was similar to that in patients who 
received placebo. Although Grade 3/4 haematologic laboratory events were common at the 
initiation of treatment, no severe clinical sequelae were observed and relatively few patients 


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discontinued due to these AEs. Dose adjustment based on individual tolerability during the 
first 3 cycles substantially reduced the incidence of these events beyond Cycle 3. 
Baseline Platelet Count and Weight as Predictors of Thrombocytopenia. 
An analysis was conducted using the data collected in ENGOT-OV16/NOVA and the initial 
phase I study, PN001. This analysis determined that only baseline platelets had an impact on 
platelet nadir; lower baseline platelets (<180 109/L) were associated with an increased 
frequency of thrombocytopenia Grade ≥1 (76 %) or Grade ≥ 3 (45 %) compared to patients 
with higher baseline platelet counts. Further, an exploratory analysis of clinical data versus 
baseline body weight from ENGOT-OV16/NOVA was conducted.  For this analysis, the weight 
categories were based on quartiles with the lowest quartile (patients with a body weight less 
than 58 kg at baseline) compared to the highest quartile (patients with a body weight greater 
than or equal to 77 kg at baseline).  While TEAEs occurred in most patients regardless of body 
weight, Grade ≥3 TEAEs, SAEs, and TEAEs leading to dose modification or treatment 
discontinuation occurred more commonly in the weight <58 kg cohort than in the ≥77 kg cohort. 
In the cohort of patients with a body weight <58 kg, approximately 80 % of patients had a dose 
reduction compared to 59 % of patients with a weight greater than or equal to 77 kg. Treatment 
discontinuations were increased in the subjects with lower body weight (24 %) compared to 
patients in the highest quartile (10 %). 
The potential relationship between body weight and TEAEs was further explored in an analysis 
to evaluate the correlation of grade 3 or 4 thrombocytopenia and baseline body weight.  The 
lowest platelet count in the first 30 days was plotted versus baseline body weight to determine 
if low body weight identified a subgroup of patients with higher levels of thrombocytopenia 
during Cycle 1.  In the first 30 days of treatment, a baseline body weight >77 kg is associated 
with a lower incidence of grade 3 or 4 thrombocytopenia (14 %) relative to the group with body 
weight <58 kg (43 %).  
Finally, a classification tree approach was used to refine the best cut-off points for predicting 
the likelihood of a patient developing ≥Grade 3 thrombocytopenia within 30 days after the first 
dose of Niraparib. The results of the model show that the subgroup of patients with a baseline 
body weight <77 kg or baseline platelet count <150,000 µL had a grade 3/4 thrombocytopenia 
rate in the first 30 days of 35.4 % compared to 11.5 % in the group of patients with a body 
weight >77 kg and a platelet count >150,000 µL. Further, the average daily dose was 258 mg 
through the first two cycles for patients with a body weight >77 kg and platelet count >150,000 
µL, and was only 206 mg for patients with body weight < 77 kg or platelet count <150,000 µL. 
Thus, the actual delivered dose approximated a starting dose of 200 mg despite the intended 
delivery of a starting dose of 300 mg. These observations are to be confirmed in the present 
study with the inclusion of study treatment dosed at 200 mg (2 capsules of Niraparib or 
placebo) in patients whose baseline weight is <77 kg or baseline platelet count is <150,000 
µL. 
 
Influence of Moderate Hepatic Impairment at Baseline 
 
Niraparib dose adjustment is recommended for patients with moderate hepatic impairment.  
For patients with moderate hepatic impairment, reduce the starting dose of niraparib to 200 
mg once daily.  The pharmacokinetics of niraparib have been assessed in patients with 


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moderate hepatic impairment (see Section 9.4.1 Absorption), but have not been assessed in 
patients with severe hepatic impairment. 
 Clinical Pharmacokinetics 
 Absorption 
Following a single-dose administration of 300 mg Niraparib under fasting conditions, Niraparib 
was measurable in plasma within 30 minutes and the mean peak plasma concentration (Cmax) 
for Niraparib was reached in about 3 hours [804 ng/mL (%CV:50.2 %)]. Following multiple oral 
doses of Niraparib from 30 mg to 400 mg once daily, accumulation of Niraparib was 
approximately 2 fold. 
 
The systemic exposures (Cmax and AUC) to Niraparib increased in a dose proportional manner 
when the dose of Niraparib increased from 30 mg to 400 mg. The absolute bioavailability of 
Niraparib is approximately 73 %, indicating minimal first-pass effect. 
 
Concomitant administration of a high fat meal did not significantly affect the PK of Niraparib 
after administration of 300 mg of Niraparib. 
 
In a recently completed clinical study of cancer patients using NCI-ODWG criteria to classify 
the degree of hepatic impairment, niraparib AUCinf in patients with moderate hepatic 
impairment was 1.56 (90% CI: 1.06 to 1.30) times the niraparib AUCinf in patients with normal 
hepatic function following administration of a single 300 mg dose.  
 
 Distribution 
Niraparib was moderately protein bound to human plasma (83.0 %). The apparent Vd/F was 
1220 L, indicating extensive tissue distribution of Niraparib. In a population PK analysis, the 
Vd/F of Niraparib was 1074 L in cancer patients. 
 
 Metabolism 
Niraparib is metabolized primarily by CEs to form a major inactive metabolite, M1. In a mass 
balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the major 
circulating metabolites. The mean half-life of M1 was 88 hours. The exposure ratio of M1 to 
Niraparib was approximately 1.3-2.2 fold in plasma. 
 
 Elimination 
Following a single oral 300-mg dose of Niraparib, the mean terminal half-life of Niraparib 
ranged from 48 to 51 hours (approximately 2 days). In a population PK analysis, the apparent 
total clearance of Niraparib was 16.2 L/h in cancer patients. 
 
Niraparib is eliminated primarily through the hepatobiliary and renal routes. Following 
administration of a single oral 300 mg dose of [14C]-Niraparib, on average 86.2 % (range 71 
% to 91 %) of the dose was recovered in urine and feces over 21 days. Radioactive recovery 
in the urine accounted for 47.5 % (range 33.4 % to 60.2 %) and the feces for 38.8 % (range 
28.3 % to 47.0 %) of the dose. In pooled samples collected over 6 days, 36.7 % of the dose 


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was recovered in the urine primarily as metabolites and 21.1 % of the dose was recovered in 
the feces primarily as unchanged Niraparib. 
 
 Specific Populations 
Geriatric Patients: Population PK analyses indicated that age had no significant impact on 
the PK of Niraparib. 
 
Pediatric Patients: No studies have been conducted to investigate the PK of Niraparib in 
pediatric patients. 
 
Racial or Ethnic Groups: Population PK analyses indicated that race had no significant 
impact on the PK of Niraparib. 
 
10 INFORMATION ON THE COMPARATOR PRODUCTS (NON-IMP) 
Study treatment with Ganetespib will be compared to two different options of standard 
treatment which are combined with Carboplatin in arm A. Therefore these products are 
investigational products, however treatment with these will be performed according to the local 
standard of care of the hospital. 
 Gemcitabine 
Commercially available Gemcitabine will be utilized in this study, all available products are 
allowed. See the Gemcitabine SmPC, for more details. 
 Paclitaxel 
Commercially available Paclitaxel will be utilized in this study, all available products are 
allowed. See the Paclitaxel SmPC, for more details. 
 
11 INFORMATION ON THE NON-INVESTIGATIONAL PRODUCT 
(NON-IMP) 
 Carboplatin 
Commercially available Carboplatin will be utilized in this study, all available products are 
allowed. Carboplatin will be administered according to the directions of the prescribing 
information. Dose will be calculated according to Calvert's formula to obtain an AUC5 or AUC4 
regarding on the combination drug. For more details see the Carboplatin SmPC. 
 
 


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12 STUDY DESIGN 
 Description of study 
This is a multicentre, international, open-label, three-arm, randomised (1:1:1) Phase II study. 
The study design is depicted in Figure 4: Study design. 
 
TREATMENT ARMS: 
 
ARM A (standard arm): 
Choice of two regimens, based on investigator decision: Carboplatin (AUC4; d1, q3w) + 
Gemcitabine (1000 mg/m²; d1 + d8, q3w) or Carboplatin (AUC5; d1, q3w) + Paclitaxel (175 
mg/m²; d1, q3w); followed by maintenance treatment with Niraparib (200 mg/ 300 mg oral daily, 
q4w) 
 
ARM B (first experimental arm): 
Carboplatin (AUC5, d1, q3w) + Ganetespib (150 mg/m²; d1, q3w);  
followed by maintenance treatment with Niraparib (200 mg/ 300 mg oral daily, q4w) 
 
ARM C (second experimental arm): 
Carboplatin (AUC5, d1, q3w) + Ganetespib (150 mg/m², d1, q3w);  
followed by maintenance treatment with Niraparib (200 mg oral daily, q4w) + Ganetespib (100 
mg/m²; d1, d8, d15, d22, iv q4w) 
 
 
Figure 4: Study design 
 
 


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 Subject population 
The study target population consists of female patients with high-grade serous, high–grade 
endometrioid, undifferentiated epithelial ovarian cancer, carcinosarcoma, fallopian tube or 
primary peritoneal cancer. By definition, patients will have experienced progressive disease > 
6 months after previous platinum based treatment. There are no limits in number of prior 
treatment lines. 
 
 Subject eligibility 
Before any study-specific procedure, the appropriate written informed consent must be 
obtained. 
 
1. Inclusion criteria  
Patients must meet the following criteria to be eligible for study entry: 
 
Signed and dated written informed consent prior to admission to the study in accordance 
with ICH-GCP guidelines and with the local legislation. 
 
Female patients ≥ 18 year of age 
 
High-grade serous, high grade endometrioid, undifferentiated epithelial ovarian, or 
carcinosarcoma, fallopian tube or primary peritoneal cancer  
 
Platinum-sensitive relapse > 6 months after previous platinum-based treatment (calculated 
from the first day of the last cycle of the last platinum based chemotherapy until the date 
of progression confirmed according to RECIST 1.1 on imaging) 
 
No limits in number of prior treatment lines 
 
Measurable or evaluable disease according to RECIST 1.1 
 
ECOG performance status 0-1 
 
Adequate functions of the bone marrow:  
o Platelets ≥ 100 x 109/L  
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
o Hemoglobin ≥8.5 g/dl (patients may not receive a transfusion within 4 weeks prior 
to initiating study treatment) 
 
Adequate function of the organs: 
o Creatinine ≥ 30ml/min, as calculated using the Cockroft-Gault equation 
o Total bilirubin ≤ 1.5 x upper limit of normal (≤ 2.0 in patients with known Gilberts 
syndrome) OR direct bilirubin ≤ 1 x ULN  
o SGOT/SGPT (AST/ALT) ≤ 2.5 x upper limit of normal unless liver metastases are 
present, in which case they must be ≤ 5 x ULN   
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 parameter: 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). 


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 
Participant receiving corticosteroids (dose < 10 mg/day methylprednisolone equivalent), 
including inhaled steroids, may continue as long as their dose is stable for at least 4 weeks 
prior to initiating protocol therapy.  
 
Participant must agree to not donate blood during the study or for 90 days after the last 
dose of study treatment. 
 
Female participant has a negative serum pregnancy test within 7 days prior to taking study 
treatment if of childbearing potential and agrees to abstain from activities that could result 
in pregnancy from screening through 180 days after the last dose of study treatment, or is 
of nonchildbearing potential. Nonchildbearing potential is defined as follows (by other than 
medical reasons): 
o ≥ 45 years of age and has not had menses for >1 year 
o Patients who have been amenorrhoeic for < 2 years without history of a 
hysterectomy and oophorectomy must have a follicle stimulating hormone value in 
the postmenopausal range upon screening evaluation 
o Post-hysterectomy, 
post-bilateral 
oophorectomy, 
or 
post-tubal 
ligation. 
Documented hysterectomy or oophorectomy must be confirmed with medical 
records of the actual procedure or confirmed by imaging. Tubal ligation must be 
confirmed with medical records of the actual procedure, otherwise the patient must 
be willing to use 2 adequate barrier methods throughout the study, starting with the 
screening visit through 180 days after the last dose of study treatment. See below 
for a list of acceptable birth control methods. Information must be captured 
appropriately within the site’s source documents. Note: Abstinence is acceptable if 
this is the established and preferred contraception for the patient. 
o Birth Control: Participants of childbearing potential who are sexually active and their 
partners must agree to the use of a highly effective form of contraception throughout 
their participation beginning with time of consent, during the study treatment and 
for 180 days after last dose of study treatment(s): 
 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
 
Oral route 
 
Intravaginal route 
 
Transdermal route 
 
Progestogen-only hormonal contraception associated with inhibition 
of ovulation  
 
Oral 
 
Injectable 
 
Implantable 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Sexual abstinence, if the preferred and usual lifestyle of the subject 
 
Participant must agree to not breastfeed (or store breast milk for use) during the study or 
for 180 days after the last dose of study treatment. 
 
Able to take oral medications  


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 
Availability of archival ovarian cancer tissue from primary diagnosis (delivery of FFPE block 
or slides is prerequisite for randomisation)  
 
 
 
2. Exclusion criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
 
Ovarian tumours with low malignant potential (i.e. borderline tumours) 
 
Any prior radiotherapy to the pelvis or abdomen, or any radiotherapy encompassing > 20 % 
of the bone marrow within 2 weeks, or any radiotherapy within 1 week prior to Day 1 of 
protocol therapy. 
 
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 
 
Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). 
 
Any serious, uncontrolled medical disorder, non-malignant systemic disease, or active, 
uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular 
arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary 
disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior 
vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent. 
 
Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment 
with aspirin (> 325 mg/day). 
 
Patients with a history of diagnosis, detection or treatment of any prior malignancies ≤ 2 
years prior to initiating protocol therapy, except: basal or squamous cell carcinoma of the 
skin and cervical cancer that has been definitively treated.  
 
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 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 or leptomeningeal metastases (patients who are 
asyptomatic since treatment of brain or leptomeningeal metastases, eg after irradiation, 
are eligible) 
 
Left ventricular ejection fraction (LVEF) 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 Yourk Heart Assiciation (NYHA) Class 3 or 4; myocardial 
infarction within the past 6 months; unstable angina; coronary angioplasty or coronary 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 


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 
Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a 
Class Ia antiarrhythmic drug (e.g. sotalol, amiodarone, dofetilide). Use of other 
antiarrhythmic drugs is permitted 
 
Second- or third-degree atrioventricular (AV) block, except: treated with a permanent 
pacemaker 
 
Complete left bundle branch block (LBBB) 
 
Concomitant use of drugs which prolong QTc interval and have a known risk to cause 
Torsade de Pointes (see appendix F for a non-exhaustive list) 
 
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. 
 
Participation in another clinical study with experimental therapy within 28 days or five half-
lives (whichever is shorter) of experimental therapy before start of treatment. 
 
Participant must not be simultaneously enrolled in any interventional clinical trial. 
 
Women who are pregnant or are lactating 
 
Patients unable to be regularly followed for any reason (geographic, familiar, social, 
psychologic, housed in an institution eg. prison because of a court agreement or 
administrative order) 
 
Subjects that are dependent on the sponsor/CRO or investigational site as well as on the 
investigator. 
 
History of known hypersensibility against any medication used in the study 
 
Intolerance / Hypersensitivity reactions to components and exipients of study drugs  
 
Peripheral neuropathy of grade >2 per NCI CTCAE, version 5, within 4 weeks prior to 
randomization 
 
Administration of a live, attenuated vaccine within 30 days prior to Cycle1 Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study. Examples 
of live vaccines incluse but are not limited to: measles, mumps, rubella, varicella zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), typhoid and intranasal 
influenza vaccines (eg. Flumist®). Inactivated influenza vaccinations can be administered 
during the flu season. 
 
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 
 
3. Conditions for the start of maintenance therapy with Niraparib and/or Ganetespib 
 
Before start of the maintenance therapy patients must have following lab values: 
        Absolute neutrophil count ≥ 1,500/µL 
        Platelets ≥ 100,000/µL 
        Hemoglobin ≥ 9 g/dL 
        Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥  
       30 mL/min using the Cockcroft-Gault equation 
        Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR direct  
       bilirubin ≤ 1 x ULN 
        Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver  
       metastases are present, in which case they must be ≤ 5 x ULN 
 
 


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 Study duration 
First patient in (FPI): Nov 2018 
Last patient in (LPI): Feb 2020 
Last patient last treatment (LPLT) with Ganetespib: May 2021 
Estimated End of study (EOS) (evaluation of the secondary endpoint overall survival): Aug 
2022 
 
 End of study 
The Eudario clinical trial is suggested to end in January 2022  (evaluation of secondary 
endpoint overall survival). 
 
 Premature termination of the study 
The trial must be terminated prematurely by the sponsor or the IDMC 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 
 
For other medical, scientific, operational or administrative reasons. 
In that case the Independent Ethics Committee (IEC) and the competent regulatory authority 
must be informed within 15 days of early termination.  
 
In the event of a premature termination of the trial the TESARO and Aldeyra Therapeutics will 
continue to provide study treatment(s), in accordance with the procedures in the protocol, for 
patients until it is no longer a viable clinical option, in the event the Investigator believes, after 
discussion with the Sponsor, that some patients are continuing to receive clinical benefit that 
would otherwise be out of reach.  
 
 Study site discontinuation 
The Sponsor must terminate this study or discontinue a site participating in this trial at any time 
for reasons including, but 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 IDMC) 
 
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. 
 Withdrawal and replacement of subjects 
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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 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. 
 
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.  
 Discontinuation from IMP or non-IMP 
The investigator should permanently discontinue a subjects’ treatment with the study drugs in 
the event of: 
- 
Unequivocal disease progression 
- 
Intolerable Adverse Events (CTCAE 5) that cannot be managed by dose reduction 
- 
Withdrawal of informed consent 
- 
Change in the patient’s status creating an unfavourable risk/benefit in favour to stop 
study treatment 
- 
Eligibility criteria are violated and represent a safety issue for patient 


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Further dose reductions considered necessary but not allowed according to the protocol. More 
detailed information on IMP and non-IMP modifications and discontinuation is found in section 
18. 
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.  
 
 Study objectives 
The primary aim of this study is to determine the efficacy of ganetespib in combination with 3 
weekly carboplatin followed by maintenance therapy with Niraparib (+/-Ganetespib) compared 
to platinum-based combination therapy (according to physicans choice) followed by Niraparib. 
 
Seconary aims of this study are determination of tollerabilty and evaluation of quality of life of 
patients treated with ganetespib in combination with 3 weekly carboplatin followed by 
maintenance therapy with Niraparib (+/-Ganetespib) compared to platinum-based combination 
therapy (according to physicans choice) followed by Niraparib. 
 
Primary endpoint: 
Progression-free survival (PFS) by RECIST 1.1 
PFS is defined as the days between randomisation and the date of documented progression 
or death of any cause whatever comes first. 
 
 
Secondary endpoints: 
- 
Post-progression PFS (PFS2) by RECIST 1.1 
PFS2 is defined as time from randomisation in this trial to objective tumour progression 
by RECIST 1.1 on next-line treatment or death from any cause. 
- 
Time to First Subsequent Therapy (TFST) 
TFST is defined as the days between randomisation and start date of the first 
subsequent (post-progression) anticancer therapy or death. 
- 
Time to Second Subsequent Therapy (TSST) 
TSST is defined as the days between randomisation and start date of the second 
subsequent (post-progression) anticancer therapy or death. 
- 
Overall survival (OS): 
OS is defined as the days between randomisation and the date of documented death 
from any cause. 
- 
Safety: Adverse events (AEs), measure according to NCI CTCAE, version 5, laboratory 
parameters, ECOG PS, vital signs  
- 
Objective response rate (ORR): best ORR; confirmed ORR 
ORR is defined as 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 


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following efficacy assessment, no less than four weeks later. Response is measured 
by RECIST 1.1.  
- 
Patient-reported outcome (PRO):  
measured by EORTC QLQ-C30, EORTC QLQ-OV28; responders are defined as 
improvement of >10 points on the PRO scales 
 
Predefined Subgroup analyses: 
PFS will be analysed according to the following pre-defined subgroups: 
- 
BRCA mutation status: yes versus no or unknown 
- 
1 prior line of chemotherapy versus >1 prior chemotherapy line 
- 
prior PARPi treatment: yes versus no 
 
Experimental endpoints: 
Biomarker analysis on DNA, RNA and protein level (e.g. free circulating tumour DNA, 
circulating tumour cells etc.) 
 
 
 Randomisation and stratification  
Randomisation will be performed in a 1:1:1 ratio to the treatment arms. 
 
Stratification factors: 
- 
BRCA mutation (germline or somatic): yes versus no or unknown 
- 
1 prior line of chemotherapy versus >1 prior chemotherapy line 
- 
prior PARPi treatment: yes versus no 
 
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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13 STATISTICAL ANALYSIS 
 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.  
 
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.  
 
Per-protocol population 
The per-protocol (PP) population will include all patients who received at least one cycle of 
study treatment without major protocol deviations. Major protocol deviations will be determined 
and documented prior to database lock. 
 Sample size calculation 
A randomised, open-label, three-arm study will be performed. Group allocation ratio will be 
1:1:1. Twice as many patients will be on the Carboplatin-combination therapy with Ganetespib 
(arms B and C) as are in the standard chemotherapy treatment group (arm A). 
The primary aim of this study is to determine the efficacy of the new agent regarding 
progression-free survival (PFS). The main analysis will combine the two study arms with 
Ganetespib (arms B and C) and compare it against the standard arm (arm A). 
With a minimum of 78 PFS events, the study provides 80 % power to detect a PFS hazard 
ratio (HR) of 0.60 with 2-sided α=0.2, assuming a median PFS of 10 months with standard 
chemotherapy (arm A) and 16.7 months with Ganetespib combination arms (arms B+C), and 
a randomisation ratio of 2:1 between arms B+C vs arm A. With a total sample size of 120 (arm 
B+C=80; arm A=40), this study has 15 months accural, and 15 months additional follow up. 
 
 Efficacy analysis 
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 0.2. 
 
Progression-free survival (PFS) serves as the primary endpoint of the study. PFS is defined 
as the days between randomisation and the date of documented progression or death of any 
cause whatever comes first. 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. 
 
Regarding PFS Hypothesis testing between the two treatment arms (A vs. B+C) will be 
performed using a log-rank test. For each treatment arm the median time to progression will 


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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 the end of the study (approximately 15 months after the last 
patient was randomised). In addition, Cox proportional hazards regression analysis adjusting 
for the stratification factors will be applied. The same procedure will be applied to exploratively 
compare the different treatment arm (A vs. B, A vs. C, B vs. C) 
 
Secondary endpoints with respect to efficacy are post progression PFS (PFS2), time to first 
subsequent therapy (TFST), time to second subsequent therapy (TSST), overall survival (OS), 
and objective response rate (ORR: best and confirmed ORR).  
 
Post progression PFS (PFS2) is defined as time from randomisation in this trial to objective 
tumour progression on next-line treatment or death from any cause. 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. 
Regarding PFS2, comparisons will be performed pooling arms B and C and comparing them 
jointly against arm A (A vs. B+C) and also separately between study arms (A vs. B, A vs. C, B 
vs. C).  
 
Time to First Subsequent Therapy (TFST) is defined as the days between randomisation and 
start date of the first subsequent (post-progression) anticancer therapy or death. Any patient 
with unknown subsequent therapy or death status will be censored at the last documented 
time-point to have not received subsequent anticancer therapy. Regarding TFST, comparisons 
will be performed pooling arms B and C and comparing them jointly against arm A (A vs. B+C) 
and also separately between study arms (A vs. B, A vs. C, B vs. C). 
 
Time to Second Subsequent Therapy (TSST) is defined as the days between randomisation 
and start date of the second subsequent (post-progression) anticancer therapy or death. Any 
patient with unknown second subsequent therapy or death status will be censored at the last 
documented time-point to have not received second subsequent anticancer therapy. 
Regarding TSST, comparisons will be performed pooling arms B and C and comparing them 
jointly against arm A (A vs. B+C) and also separately between study arms (A vs. B, A vs. C, B 
vs. C). 
 
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. Regarding OS, comparisons will be 
performed pooling arms B and C and comparing them jointly against arm A (A vs. B+C) and 
also separately between study arms (A vs. B, A vs. C, B vs. C). 
 
Statistical analyses for all time-to-event variables (PFS2, TFST, TSST, OS) will be carried out 
in the same way as described for PFS with the Kaplan-Meier method and Cox proportional 
hazards regression. 
 
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 


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ORR). ORR is considered confirmed when the result is repeated in the following efficacy 
assessment, no less than four weeks later. Hypothesis testing regarding ORR testing between 
the two treatment arms will be performed using a Mantel-Haenszel test and a logistic 
regression analysis adjusting for the stratification factors. The odds ratio and 95% confidence 
interval of the odds ratio will be presented. Regarding ORR, comparisons will be performed 
pooling arms B and C and comparing them jointly against arm A (A vs. B+C) and also 
separately between study arms (A vs. B, A vs. C, B vs. C).  
 
Patient-reported outcome (PRO) is also a secondary study endpoint. 
 
PRO will be assessed using validated questionnaires (the EORTC QLQ-C30 and the EORTC 
QLQ-OV28) (see section 16.2.1 and appendix B). Statistical analysis of PROs 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, the group-by-time interaction effect, a random 
intercept on patient level and a first-order autoregressive covariance matrix. Main PRO 
endpoints will be gastrointestinal symptoms measured by the EORTC QLQ-OV28 
Gastrointestinal Scale and overall quality of life as measured by the EORTC QLQ-C30 
Summary Score (19). These scales will be tested for non-inferiority of the two treatment arms 
(group B and C) compared to the control arm (group A). Based on descriptive statistics for the 
QLQ-C30 Summary Score in the literature we estimated the standard deviation (SD) of the 
score to be 20 points in the EUDARIO trial (taking into account that patients in the EUDARIO 
trial are on treatment and in an advanced disease stage). Based on this estimate we defined 
the minimal important difference (MID) to be 10 points (i.e. 0.5 SD). The MID will be used as 
non-inferiority margin (δ) in our analysis. For the individual domains of the EORTC QLQ-C30 
and QLQ-OV28 (in particular the Gastrointestinal scale) the MID is considered to be 10 points 
as well. Additional analyses will be done for frequencies of responders (improvement of >10 
points on the PRO scales) and for time until definitive deterioration (20). Sensitivity analyses 
will be done using different methods for data imputation, to investigate robustness of results. 
Regarding PRO analysis, comparisons will be performed pooling arms B and C and comparing 
them jointly against arm A (A vs. B+C) and also separately between study arms (A vs. B, A vs. 
C, B vs. C). 
 
Predifined subgroup analyses: 
PFS in the following predefined subgroups of patients will be analysed: 
- 
BRCA mutation status: yes versus no or unknown 
- 
1 prior line of chemotherapy versus >1 prior chemotherapy line 
- 
prior PARPi treatment: yes versus no 
The same statistical methods as outlined for the overall study population will be applied 
regarding these subgroup analyses with the exception of adjusted analyses in respect to the 
concerned subgroup. 
 
 


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 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. 
 
 Subgroup analysis 
Efficacy analyses will be done for the following predefined subgroups of patients: 
 
- 
BRCA mutation status: yes versus no or unknown 
- 
1 prior line of chemotherapy versus >1 prior chemotherapy line 
- 
prior PARPi treatment: yes versus no 
 
 
 Comparability of treatment arms 
The three 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. 
 
 Interim analysis 
No interim analysis will be performed. 
 
 


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14 RISK-BENEFIT CONSIDERATIONS 
The aim of EUDARIO is to improve survival and wellbeing of platinum-sensitive ovarian cancer 
patients by combining standard platinum-based chemotherapy and PARPi-maintenance 
therapy with the HSP90 inhibitor Ganetespib.  
Our EU-project consortium has produced solid basic research findings strongly supporting 
synergy of these drug combinations. The suggested mechanism of action is broad DNA repair 
inhibition after induction of DNA damage by Carboplatin to achieve maximum cancer cell 
death. With this clinical trial we aim to translate robust research findings into patient benefit 
therewith prolonging survival and wellbeing of ovarian cancer patients. 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). 
 
Epithelial Ovarian Cancer is the most lethal among gynaecological malignancies. Despite high 
initial response rates to primary therapy, the vast majority of patients will inevitably relapse 
within a short period of time and ultimately die of the disease. There is a pressing need for 
innovative new treatment strategies to prolong progression-free survival and overall survival in 
EOC patient. This risk for disease relapse and death is opposed by the risk to harm patients 
with the experimental treatment applied in the current clinical trial. 
 
All patients in this trial receive platinum-based chemotherapy, which is the standard treatment 
in relapsed, platinum-sensitive EOC patients. Maintenance treatment with PARPi is approved 
for BRAC1/2 mutated, relapsed platinum-sensitive OC in Europe. The recent NOVA trial has 
shown clear benefit also for relapsed, platinum-sensitive OC patients without BRCA1/2 
mutations. In March 2017 Niraparib was approved by the FDA for maintenance treatment of 
relapsed platinum-sensitive ovarian cancer independent of BRCA status. EMA approval 
process is ongoing. Within this clinical trial all platinum-sensitive patients have access to 
proven efficaceous PARPi treatment.  
 
The clinical partners participating in this trial have gained extensive experience with the IMP 
Ganetespib in the ongoing GANNET53 trial in platinum-resistant ovarian cancer. In general, 
the applied Ganetespib Paclitaxel combination was well tolerated in these heavily pre-treated 
ovarian cancer patients. One new toxicity signal was identified during the randomised Phase 
II GANNET53 trial which was considered possibly related to Ganetespib, i.e. gastrointestinal 
perforation. As a consequence, in-/exclusion criteria have been adapted in a substantial 
amendment to exclude ovarian cancer patients with a pre-existing risk profile for GIP from 
participation in the GANNET53 trial. Since adaptation of in-/exclusion criteria no further GIP 
cases occurred. In general, Ganetespib has been applied in 1,611 patients of various different 
malignant diseases without major safety concerns. 
In the present trial we implemented these strict in-/exclusion criteria excluding patients at risk 
of GIP right from the start in order to minimise patients risk. 
In the present trial Ganetespib is applied in two different combinations, together with 
Carboplatin on one hand and together with Niraparib on the other hand. 
The risk to harm patients with the experimental treatment of both Ganetespib combinations is 
minimised via 1) safety run-ins for both applied Ganetespib combinations with repeated IDMC 
evaluations, 2) thorough choice of dose levels of combination treatment, 3) careful 
determination of dose-reduction steps in the trial protocol in response to potential side-effects 


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and 4) re-assuring safety data on the Carboplatin/Ganetespib combination from a previous trial 
(MESO-02) in mesothelioma. 
 
Carboplatin/Ganetespib combination (arms B and C): Safety will be evaluated by IDMC 4 
weeks after first 6 and 12 patients have been included.  
Prior to this current trial, the combination of Ganetespib with Carboplatin AUC5, q3w 
(corresponds to the Carboplatin schedule in the present study) has been tested and was 
established as being well tolerated. A dose- escalation trial aiming to determine MTD has been 
performed at the University College London, UK, (PI Prof. Dean A Fennell) in 27 patients with 
malignant pleural mesothelioma (MESO-02 trial). The PI confidentially reported good 
tolerability and has confidentially shared with us re-assuring safety data (which are included in 
this protocol). In the MESO-02 trial Ganetespib was escalated up to > 200 mg/m2. No safety 
concerns arose even in a triplicate combination including Carboplatin AUC5, 3qw. In the 
present trial we will apply Ganetespib at a dose level of 150 mg/m2 in combination with 
Carboplatin (AUC5, 3qw). This is a lower Ganetspib dose to be used in a dual combination 
than found to be well tolerated in a triple combination in the MESO-02 trial. Furthermore, 
Ganetespib 150 mg/m2 is the recommended general combination dose of Ganetespib based 
on previous trials. We expect a favourable safety profile of this combination. 
 
Niraparib/Ganetespib combination (maintenance treatment in arm C): Two safety evaluations 
by IDMC are planned 4 weeks after the start of maintenance therapy of 6 and 12 patients, 
respectively. Thus a total of 12 patients will be evaluated by the IDMC. To minimise risk to 
patients receiving this new combination, a stop of entering maintenance treatment will be 
performed until recommendations of the IDMC are available.  Only in case of positive 
evaluation of the safety profile of the Niraparib/Ganetespib combination by the IDMC after 6 
and 12 patients, respectively, subsequent patients in arm C will start maintenance treatment 
with this drug combination. In case of negative evaluation of safety by the IDMC, patients in 
arm C will proceed with Niraparib single agent maintenance treatment. In addition, we have 
thoroughly chosen the dose levels of both drugs. The standard single agent Niraparib dose in 
maintenance treatment is 200-300 mg orally per day. In the present trial we apply a starting 
dose of 200 mg Niraparib in combination with Ganetespib. From the NOVA trial data we expect 
no negative impact on efficacy but less toxicity using this lower Niraparib combination dose 
level. Furthermore, we will use a lower Ganetespib dose in the combination with Niraparib, 
namely 100 mg/m2, than the established Ganetespib combination dose of 150 mg/m2. Close 
monitoring of patients on this new drug combination have been implemented in this trial 
protocol with weekly laboratory evaluation. This is of particular importance, as the main side-
effects expected are of haematologic nature. Close monitoring will allow us to guide potentially 
necessary dose-reduction steps and to individualise dosing levels of both Ganetespib and 
Niraparib in this combination treatment. With these safety measures we will minimise patients 
risk receiving this treatment combination. 
 
There is a risk in the EUDARIO 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 disease control derived from this 
new innovative therapeutic approach. An IDMC consistent of 4 independent experts in the field 
of gynaecologic oncology and statistics will closely and continuously monitor patient safety and 


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trial development. The IDMC can, if required, propose a protocol amendment and in case the 
risk to the patients outweighs the potential benefit, propose termination of the study. 
 
15 STUDY PROCEDURES 
 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 
to one of the three treatment arms. Only subjects who meet 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. Furthermore, a screen failure log must be maintained by the 
investigator. 
Within 4 weeks (28 days) prior to randomisation:  
 
Obtain signed and dated informed consent 
 
Register the patient in the eCRF 
 
Record current and past medical history, significant diseases and medical procedures 
(at Investigator’s discretion) and concurrent illnesses 
 
Record ovarian cancer history and all previous anticancer treatments 
 
Platinum-free interval (PFI) for the most recent platinum-based therapy must be 
calculated  
 
Record all surgical interventions performed for ovarian cancer 
 
Demographic data (date of birth, ethnicity, marital status, highest level of education, 
current employment status) 
 
Tumour assessment which is not older than 28 days at the time of randomisation: chest, 
abdomen and pelvis CT scan or MRI abdomen/pelvis 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 (see section 16.1). 
 
Archival tissue samples from primary diagnosis sent to central histopathological review 
(for confirmation of high-grade serous, high-grade endometrioid, or undifferentiated 
epithelial ovarian cancer, carcinosarcoma of the ovary, fallopian tube or primary 
peritoneal carcinoma (see section 16.7). 
 
Whenever technically feasible CT- or sonographically-guided biopsy samples of the 
actual relapse should be performed after informed consent has been obtained but prior 
to the first study drug administration. Alternatively tissue of the actual relapse which 
was sampled during debulking surgery in the relapsed situation can be provided (see 
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 
Concomitant medications: Document all medications (other than previous anticancer 
treatment) and significant non-drug therapies (see section 16.3). 
 
Adverse Events (AEs): report any serious adverse events (SAEs) considered to be 
related to a protocol-mandated intervention (see section 19.1). 
 
Within 2 weeks (14 days) prior to randomisation: 
 
Urine/serum pregnancy test in WOCBP (for definition see section 6)  
 
Electrocardiogram (ECG; average of triplicate ECG recording) (see section 16.5) 
 
Assess left ventricular ejection fraction (LVEF) by ECHO (see section 16.5) 
 
Physical examination including vital signs and measured body height and weight (see 
section 16.4) 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments: Haematology, Biochemistry panel, Coagulation and 
urinanalysis (see section 16.6  
 
Perform measurement of CA-125 at least once during the screening period. (see 
section 16.1). 
 
Completion of PRO questionnaires [EORTC QLQ-C30, EORTC QLQ-OV28 (Appendix 
C)] (see section 16.2) 
Randomisation: 
 
Verification of inclusion and exclusion criteria 
 
All eCRF Screening pages need to completed 
 
Patient must receive the first dose of study treatment within 7 days of randomisation 
 
Table 8: Screening Schedule of Events 
Procedures / Assessments 
Screening 
Randomisation 
Week number prior to randomisation 
- 4 
- 2 
Days prior to randomisation 
- 28 to -1 
-14 to -1 
Informed consent 
X 
 
Registration in the eCRF 
X 
 
Medical historya 
X 
 
Ovarian Cancer History and Previous anticancer 
treatments 
X 
 
Confirmation of PFI 
X 
 
Past Surgical Interventions for Ovarian Cancer 
X 
 
Demographic data 
X 
 
CT/MRIb 
X 
 
Archival tissue sample from primary diagnosisc 
X 
 
Biopsy of the actual relapsed 
X 
 
Pregnancy teste 
 
X 


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ECGf 
X 
LVEFg 
X 
Height 
X 
Physical examination incl. vital signsh (BP, HR, T ) 
X 
Body weight 
X 
ECOG Performance status 
X 
Haematologyi 
 
X 
Biochemistry Panelj 
 
X 
Coagulationk 
 
X 
Urinanalysisl 
 
X 
CA-125m 
 
X 
PRO questionnairen 
 
X 
Adverse eventso 
X (if applicable) 
 
Concomitant medication 
X (if applicable) 
 
Verify all Inclusion / Exclusion criteria 
 
 
X 
Randomise Patient via eCRFp 
X 
a Record current and past medical history, significant diseases and medical procedures (at Investigator’s discretion) 
and concurrent illnesses 
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. 
c Archival tissue samples from primary diagnosis 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. 
d CT- or sonographically-guided biopsy samples of the actual relapse (after informed consent has been obtained, 
but prior to the first study drug administration) should be performed whenever technically feasible after informed 
consent has been obtained but prior to the first study drug administration. Alternatively tissue of the actual relapse 
which was sampled during debulking surgery in the relapsed situation can be provided. 
e Urine/serum pregnancy testing is not required in patients after surgical sterilisation or bilateral ovarectomy or 
hysterectomy; > 12 months amenorrhea, age > 60 years. 
f 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. 
g Assess left ventricular ejection fraction (LVEF) by ECHO 
h Blood pressure and heart rate will be measured after patient was in a sitting position for at least 10 minutes. 
i Haematology laboratory tests include assessment of:  
§ Hemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†,platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
j Biochemistry panel laboratory tests include assessment of: 
 
§ Sodium, potassium, calcium 
 
§ Serum albumin, serum urea 
 
§ ALT, AST, LDH, AP, total bilirubin 
 
§ Creatinine 
k Coagulation parameter tests include assessment of aPTT or INR 
l Urinanalysis or urine dipstick for proteinuria 
m Measured at least once during the screening period. Measurement needs to be within 2 weeks of treatment start. 
n Questionnaires EORTC QLQ-C30, EORTC QLQ-OV28. 


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o 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 
p Patients must receive their first dose of study treatment within 7 days of randomisation. 
 
 Treatment period 
The trial treatment will start after archival tissue from primary diagnosis has been sent (for later 
histopathological review and companion diagnostics) and the patient has been randomised 
into one of the three treatment arms. 
Treatment should begin within 7 days of randomisation.  
A total of six cycles of platinum-based combination therapy (Gemcitabine or Paclitaxel or 
Ganetespib) are planned to be administered to all patients (arms A, B and C). Platinum-based 
combination therapy is followed by maintenance treatment if the patient has experienced a 
stable disease (SD), partial response (PR), or complete response (CR) after completion of 
platinum-based therapy. 
 
Platinum-based chemotherapy: One treatment cycle lasts 3 weeks, q3w. Each patient will 
receive 6 cycles of platinum-based chemotherapy. Patients in the standard chemotherapy arm 
A will receive Carboplatin plus Gemcitabine or Carboplatin plus Paclitaxel (investigators 
choice). In the two experimental treatment arms B and C Carboplatin will be combined with 
Ganetespib. 
 
Maintenance treatment: Platinum-based chemotherapy is followed by maintenance 
treatment if the patient has experienced stable disease (SD), partial response (PR), or 
complete response (CR), by CT measurement, after completion of 6 cycles of a platinum-
based therapy. Furthermore, specific laboratory findings have to be fulfilled to enter 
maintenance treatment (please see respective sections 15.2.4 and 15.2.5). Patients must not 
have received transfusions and colony stimulating factors ≤ 4 weeks before Niraparib 
maintenance therapy, and must have a negative pregnancy test 7 days before start of the 
therapy. Any known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior 
chemotherapy that persisted > 4 weeks would also be detriminal for maintenance therapy. 
Niraparib will either be given alone (arms A and B) or in combination with Ganetespib (arm C). 
In arm C the combination of Niraparib and Ganetespib will be given for 9 months, thereafter 
Ganetespib treatment will be stopped and Niraparib maintenance therapy will be continued as 
single agent.  
Maintenance treatment is not allowed to start prior to 6 weeks after last platinum-based 
treatment. Maintenance treatment should preferentially start between 6 and 9 weeks, but will 
be allowed until up to 12 weeks after last platinum-based treatment. Exception: Patients in Arm 
C whos maintenance treatment start is delayed due to necessary IDMC evaluation after 6 and 
12 patients are allowed to start maintenance treatment beyond the 12 weeks. 
 
 Chemotherapy Arm A: Carboplatin and Gemcitabine (Standard platinum-based 
chemotherapy, investigators choice)  
 
Day 1 of treatment cycles, Carboplatin and Gemcitabine 


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Only applicable for day 1 cycle 1 (which is the first day of dosing): If performed at Screening 
within 3 days prior to start of dosing, physical examination including vital signs, measurement 
of body weight and height, determination of ECOG PS, pregnancy test, blood collection for 
haematology, biochemistry panel and urinanalysis as well as CA-125 evaluation, do not have 
to be repeated. 
The following tests and procedures should be performed on day 1 of treatment cycles. 
 
Day 1 of cycles 1, 3 and 5: Completion of PRO questionnaires (see section 15.2) 
 
Physical examination including vital signs and measurement of body weight (see 
section 16.4 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments; Haematology and Biochemistry panel (see section 16.6) 
 
Evaluation of tumour marker CA-125 
 
Urine/serum pregnancy test in WOCBP (for definition see section 6). 
 
Day 1 of cycles 1 and 4: Blood sampling for biomarker analysis prior to administration 
of study drug (please see section 16.7) 
 
Administration of premedication for Carboplatin Gemcitabine treatment according to 
institutional standards (please see section 17.1) 
 
Administration of Gemcitabine as an i.v. infusion, provided that there are no significant 
findings at the Day 1 visit (e.g. physical examination, ECOG PS, laboratory 
assessments or pregnancy test) prior to administration (see section 17.1). 
 
Administration of Carboplatin as an i.v. infusion, provided that there are no significant 
findings at the Day 1 visit (e.g. physical examination, ECOG PS, laboratory 
assessments or pregnancy test) prior to administration (see section 17.1). 
 
Record concomitant medications (see section 16.3) 
 
Evaluate and document adverse events (AEs) (see section 19.1 and Appendix B)  
 
Day 8 Carboplatin and Gemcitabine 
 
Physical examination including vital signs and measurement of body weight (see 
section 16.4 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments; Haematology (see section16.6) 
 
Administration of premedication according to institutional standards (please see 
section 17.1) 
 
Administration of Gemcitabine as an i.v. infusion, provided that there are no significant 
findings at the Day 8 visit (e.g. physical examination, ECOG PS, laboratory 
assessments or pregnancy test) prior to administration (see section 17.1). 
 
Record concomitant medications (see section 16.3) 
 
Evaluate and document adverse events (AEs) (see section 19.1 and Appendix B) 
 
After completion of chemotherapy treatment, Carboplatin and Gemcitabine 
 
Tumour assessment has to be done after completion of last cycle of chemotherapy 
treatment to confirm SD, PR or CR in order to evaluate if patient is eligible to continue 
with maintenance therapy. 
 


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Table 9: Carboplatin Gemcitabine Schedule of Events (arm A, Investigator`s choice) 
Procedures / Assessments 
TREATMENT (-1/+2 days) 
Cycle 1 
Cycle 2-6 
Week number 
1 
2 
3 
4 
5 
6 
Cycle day 
1 
8 
15 
1 
8 
15 
Physical 
examination 
incl. 
vital 
signsa (BP, HR, T ) 
X 
X 
No treatment 
X 
X 
No treatment 
Body height and weightb 
X 
X 
X 
X 
ECOG Performance status 
X 
X 
X 
X 
Haematologyc 
X 
X 
X 
X 
Biochemistry Paneld 
X 
 
X 
 
Pregnancy teste 
X 
 
X 
 
PRO questionnairef 
X 
 
(X) 
 
Administration of Carboplatin  
X 
 
X 
 
Administration of Gemcitabine 
X 
X 
X 
X 
CA-125 
X 
 
X 
 
CT/MRIg 
 
 
(X) 
 
Blood 
sample 
collection 
for 
biomarker analysish 
X 
 
(X) 
 
Biopsy of the actual relapsei 
 
X 
 
 
 
 
Adverse eventsj 
Continuously 
Concomitant medication 
Continuously 
a Blood pressure and heart rate will be measured after patient was in a sitting position for at least 10 minutes 
b Body height is only to be measured at C1D1 
c Haematology laboratory tests include assessment of:  
§ Hemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†,platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
d Biochemistry panel laboratory tests include assessment of: 
 
§ Sodium, potassium, calcium 
 
§ Serum albumin, serum urea 
 
§ ALT, AST, LDH, AP, total bilirubin 
 
§ Creatinine 
e Urine/serum pregnancy testing is not required in patients after surgical sterilisation or bilateral ovarectomy or 
hysterectomy; > 12 months amenorrhea, age > 60 years. 
f Questionnaires EORTC QLQ-C30, EORTC QLQ-OV28 on day 1 of cycles 1, 3 and 5.  
g Tumour assessments will be made every 12 weeks and after completion of chemotherapy and 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. After completion of 6 chemotherapy 
cycles, tumour assessment has to be done to confirm SD, PR or CR in order to evaluate if patient is eligible to 
continue with maintenance therapy. 
h Blood collection for biomarker analysis will be performed before the administration of study drug on day 1 of cycle 
1 and thereafter on day 1 of cycle 1 and cycle 4, prior to administration of study drug. An additional blood sample 
for biomarker analysis will be taken at disease progression (first visit after diagnosis of progression). 
i. An additional biopsy 24h (+/-2h) after the first study treatment will be taken in a subset of ~10 patients enrolled at 
participating sites. This biopsy will only be done if technically feasible and for subjects that had an uncomplicated 
fresh biopsy procedure for this trial during the screening period. 


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j 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 
 
 Chemotherapy Arm A: Carboplatin and Paclitaxel (standard platinum-
chemotherapy, investigators choice) 
Day 1 of treatment cycle: Carboplatin and Paclitaxel  
Only applicable for day 1 cycle 1: The following tests and procedures should be performed on 
Cycle 1 Day 1 (which is the first day of dosing). The physical examination including vital signs, 
measurement of body weight and height, determination of ECOG PS, pregnancy test, blood 
collection for haematology, biochemistry panel and urinanalysis as well as CA-125 evaluation 
do not have to be repeated if performed at Screening within 3 days prior to start of dosing. 
 
Day 1 of cycles 1, 3 and 5: Completion of PRO questionnaires (see section 15.2) 
 
Physical examination including vital signs and measurement of body weight (see 
section 16.4 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments; Haematology and Biochemistry panel (see section 16.6) 
 
Evaluation of Tumour marker CA-125 
 
Urine/serum pregnancy test in WOCBP (for definition see section 6). 
 
Day 1 of cycles 1 and 4: Blood sampling for biomarker analysis prior to administration 
of study drug (please see section 16.7) 
 
Administration of premedication for Carboplatin and Paclitaxel treatment according to 
institutional standards. (please see section 17.1) 
 
Administration of Paclitaxel as an i.v. infusion, provided that there are no significant 
findings at the Day 1 visit (e.g. physical examination, ECOG PS, laboratory 
assessments or pregnancy test) prior to administration (see section 17.1). 
 
Administration of Carboplatin as an i.v. infusion, provided that there are no significant 
findings at the Day 1 visit (e.g. physical examination, ECOG PS, laboratory 
assessments or pregnancy test) prior to administration (see section 17.1). 
 
Record concomitant medications (see section 16.3) 
 
Evaluate and document adverse events (AEs) (see section 19.1 and Appendix B) 
 
 


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After completion of chemotherapy treatment, Carboplatin and Paclitaxel 
 
Tumour assessment has to be done after completion of 6 cycles of platinum-based 
chemotherapy treatment to confirm SD, PR or CR in order to evaluate if patient is 
eligible to continue with maintenance therapy. 
 
Table 10: Carboplatin Paclitaxel Schedule of Events (arm A, investigators choice) 
Procedures / Assessments 
TREATMENT (-1/+2 days) 
Cycle 1 
Cycle 2-6 
Week number 
1 
2 
3 
4 
5 
6 
Cycle day 
1 
8 
15 
1 
8 
15 
Physical 
examination 
incl. 
vital 
signsa (BP, HR, T ) 
X 
Nio treatment 
No treatment 
X 
No treatment 
No treatment 
Body height and weightb 
X 
X 
ECOG Performance status 
X 
X 
Haematologyc 
X 
X 
Biochemistry Paneld 
X 
X 
Pregnancy teste 
X 
X 
PRO questionnairef 
X 
(X) 
Administration of Carboplatin  
X 
X 
Administration of Paclitaxel 
X 
X 
CA-125 
X 
X 
CT/MRIg 
 
(X) 
Blood 
sample 
collection 
for 
biomarker analysish 
X 
(X) 
Biopsy of the actual relapsei 
 
X 
 
 
 
 
Adverse eventsj 
Continuously 
Concomitant medication 
Continuously 
a Blood pressure and heart rate will be measured after patient was in a sitting position for at least 10 minutes 
b Body height is only to be measured at C1D1 
c Haematology laboratory tests include assessment of:  
§ Hemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†,platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
d Biochemistry panel laboratory tests include assessment of: 
 
§ Sodium, potassium, calcium 
 
§ Serum albumin, serum urea 
 
§ ALT, AST, LDH, AP, total bilirubin 
 
§ Creatinine 
e Urine/serum pregnancy testing is not required in patients after surgical sterilisation or bilateral ovarectomy or 
hysterectomy; > 12 months amenorrhea, age > 60 years. 
f Questionnaires EORTC QLQ-C30, EORTC QLQ-OV28.on day 1 of cycles 1, 3 and 5. 
g Tumour assessments will be made every 12 weeks and after completion of chemotherapy and 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. After completion of 6 platinum-based 


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chemotherapy cycles, tumour assessment has to be done to confirm SD, PR or CR in order to evaluate if patient is 
eligible to continue with maintenance therapy. 
h Blood collection for biomarker analysis will be performed before the administration of study drug on day 1 of cycle 
1 and cycle 4, prior to administration of study drug. An additional blood sample for biomarker analysis will be taken 
at disease progression (first visit after diagnosis of progression). 
i. An additional biopsy 24h (+/-2h) after the first study treatment will be taken in a subset of ~10 patients enrolledat 
participating sites. This biopsy will only be done if technically feasible and for subjects that had an uncomplicated 
fresh biopsy procedure for this trial during the screening period. 
j 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 
 
 Chemotherapy based treatment Arms B and C: Carboplatin and Ganetespib 
(experimental platinum-combination) 
 
Day 1 of treatment cycle: Carboplatin and Ganetespib 
Only applicable for day 1 cycle 1: The following tests and procedures should be performed on 
Cycle 1 Day 1 (which is the first day of dosing). The physical examination including vital signs, 
measurement of body weight and height, determination of ECOG PS, pregnancy test, blood 
collection for haematology, biochemistry panel and urinanalysis as well as for CA-125 
evaluation, do not have to be repeated if performed at Screening within 3 days prior to start of 
dosing. 
 
 
Day 1 of cycles 1, 3 and 5: Completion of PRO questionnaires (see section 15.2) 
 
Physical examination including vital signs and measurement of body weight (see 
section 16.4 
 
Determine ECOG PS (see Appendix A) 
 
Day 1 of each cycle: Electrocardiogram (ECG) (see section 16.5) 
 
Laboratory assessments; Haematology and Biochemistry panel (see section 16.6) 
 
Evaluation of Tumour marker CA-125 
 
Urine/serum pregnancy test in WOCBP (for definition see section 6). 
 
Day 1 of cycles 1 and 4: Blood sampling for biomarker analysis prior to administration 
of study drug (please see section 16.7) 
 
Administration of premedication as described unter 17.1  
 
Administration of Carboplatin as an i.v. infusion, provided that there are no significant 
findings at the Day 1 visit (e.g. physical examination, ECOG PS, laboratory 
assessments or pregnancy test) prior to administration (see section 17.1). 
 
Administration of Ganetespib (150 mg/m2) as an i.v. infusion, provided that there are 
no significant findings at the Day 1 visit (e.g. physical examination, ECOG PS, 
laboratory assessments or pregnancy test) prior to administration (see section 17.1). 
 
Record concomitant medications (see section 16.3) 
 
Evaluate and document adverse events (AEs) (see section 19.1 and Appendix B) 
 
 
 


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After completion of chemotherapy based treatment, Carboplatin and Ganetespib 
 
Tumour assessment has to be done after completion of 6 cycles of platinum-based 
chemotherapy treatment to confirm SD, PR or CR in order to evaluate if patient is 
eligible to continue with maintenance therapy. 
 
Table 11: Carboplatin Ganetespib Schedule of Events (Arm B and C)  
Procedures / Assessments 
TREATMENT (-1/+2 days) 
Cycle 1 
Cycle 2-6 
Week number 
1 
2 
3 
4 
5 
6 
Cycle day 
1 
2 
8 
15 
1 
8 
15 
Physical examination incl. vital 
signsa (BP, HR, T ) 
X 
 
No treatment 
No treatment 
X 
No treatment 
No treatment 
Body height and weightb 
X 
 
X 
ECOG Performance status 
X 
 
X 
ECGc 
X 
X 
X 
Haematologyd 
X 
 
X 
Biochemistry Panele 
X 
 
X 
Pregnancy testf 
X 
 
X 
PRO questionnaireg 
X 
 
(X) 
Administration of Carboplatin 
X 
 
X 
Administration of Ganetespib 
X 
 
X 
CA-125 
X 
 
X 
CT/MRIh 
 
 
(X) 
Blood sample collection for 
biomarker analysisi 
X 
 
(X) 
Biopsy of the actual relapsej 
 
X 
 
 
 
 
 
Adverse eventsk 
Continuously 
Concomitant medication 
Continuously 
a Blood pressure and heart rate will be measured after patient was in a sitting position for at least 10 minutes 
b Body height is only to be measured at C1D1 
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. 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 2 of cycle 1. In case of QTc prolongation (pre- or post-dose), further intensified 
ECG monitoring will be performed at the next dosing of Ganetespib. At a minimum pre-dose ECGs will be performed 
on days 1 of each cycle of Ganetepib treatment.  
d Haematology laboratory tests include assessment of:  
§ Hemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†,platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
e Biochemistry panel laboratory tests include assessment of: 
 
§ Sodium, potassium, calcium 
 
§ Serum albumin, serum urea 
 
§ ALT, AST, LDH, AP, total bilirubin 
 
§ Creatinine 


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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 on day 1 of  cycles 1, 3 and 5. 
h. Tumour assessments will be made every 12 weeks and after completion of chemotherapy and 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. After completion of platinum-based 
chemotherapy cycles, tumour assessment has to be done to confirm SD, PR and CR in order to evaluate if patient 
is eligible to continue with maintenance therapy. 
i Blood collection for biomarker analysis will be performed before the administration of study drug on day 1 of cycle 
1 and 4, prior to administration of study drug. An additional blood sample for biomarker analysis will be taken at 
disease progression (first visit after diagnosis of progression). 
j. An additional biopsy 24h (+/-2h) after the first study treatment will be taken in a subset of 10 patients ~enrolled at 
participating sites. This biopsy will only be done if technically feasible and for subjects that had an uncomplicated 
fresh biopsy procedure for this trial during the screening period. 
k 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 
 
  Maintenance treatment in arms A and B: Niraparib single agent 
Criteria to assess eligibility to start with Niraparib maintenance therapy (Arm A and B)  
 CT scan after completion of 6 cycles of platinum-based treatment showing SD, PR or CR 
(confirmed by tumour assessment according to RECIST 1.1) 
 Patients must have received 6 cycles of platinum-based treatment to start maintenance 
treatment  
 With respect to laboratory findings:  
 
o Absolute neutrophil count ≥ 1,500/µL 
o Platelets ≥ 100,000/µL 
o Hemoglobin ≥ 9 g/dL 
o Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance 
≥ 30 mL/min using the Cockcroft-Gault equation 
o Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR direct  
bilirubin ≤ 1 x ULN 
o Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver  
metastases are present, in which case they must be ≤ 5 x ULN 
 
Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks 
prior to start of Niraparib.  
 
Participant must not have received colony-stimulating factors (eg. granulocyte colony-
stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant 
erythropoietin) ≤ 4 weeks prior to start of Niraparib. 
 
Participant must have a negative pregnancy test within 7 days prior to start of Niraparib. 
 
Any known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior 
chemotherapy that persisted > 4 weeks and was related to the induction chemotherapy 
part of this study. 
 


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Maintenance treatment is not allowed to start prior to 6 weeks after last platinum-based 
treatment. Maintenance treatment should preferentially start between 6 and 9 weeks, but will 
be allowed until up to 12 weeks after last platinum-based treatment. Exception: Patients in Arm 
C who’s maintenance treatment start is delayed due to necessary IDMC evaluation after 6 and 
12 patients are allowed to start maintenance treatment beyond the 12 weeks. 
 
Please refer to section 16.1 to determine the starting dose of Niraparib for maintenance 
treatment.. 
 
Maintenance visits will be performed in a 4-weeks cycle, q4w. 
 
Day 1 of all treatment cycles Niraparib single agent 
 
Day 1 of cycle 1 and than on day 1 of every other cycle, i.e. cycles 3, 5, 7 etc : 
Completion of PRO questionnaires (see section 16.2) 
 
Physical examination including vital signs and measurement of body weight and 
height (height only at Day 1 of cycle 1) (see section 16.4) 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments; Haematology and Biochemistry panel (see section 16.6) 
 
Evaluation of tumour marker CA-125 
 
Urine/serum pregnancy test in WOCBP (for definition see section 6). 
 
Day 1 of cycle 1 and than on day 1 of every third cylcle, i.e. cycles 4, 7, 10 etc.: Blood 
sampling for biomarker analysis prior administration of study drug (please see section 
16.7)  
 
Day 1 of cycle 1: Niraparib capsules dispensed; first dose administered at site 
 
Day 1 of all other cycles: Niraparib capsules dispensed / collected* 
 
Record concomitant medications (see section 16.3) 
 
Evaluate and document adverse events (AEs) (see Appendix B) 
* Please note: In case not all capsules were used, please count the remaining capsules first 
and instruct the patient afterwards to use up the remaining capsules before starting the new 
bottle. 
 
Weekly in the first 2 cycles of maintenance treatment  
 
Laboratory assessments: Haematology (see section 16.6) 
 
Every 12 Weeks starting from day 1 cycle 1 of maintenance treatment 
 
Tumour assessments through CT/MRI (see section 16.1) 
 
 


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Table 12: Niraparib single agent Maintenance Schedule of Events (Arm A and B) 
Procedures / Assessments 
Cycle 1+2 
Cycle 3 
 
Follow 
schedule 
cycle 3 for all 
subsequent 
cycles until 
progression 
Cycle day 
1 
8 
15 
22 
1 
8 
15 
22 
Physical examination incl. vital 
signsa (BP, HR, T ) 
X 
 
 
 
X 
No tstudy center visit 
No tstudy center visit 
No tstudy center visit 
Body height and weightb 
X 
 
 
 
X 
ECOG Performance status 
X 
 
 
 
X 
Haematologyc 
X 
X 
X 
X 
X 
Biochemistry Paneld 
X 
 
 
 
X 
Pregnancy teste 
X 
 
 
 
X 
PRO questionnairef 
X 
 
 
 
(X) 
Niraparib dispensed / collected 
X 
 
 
 
Xj 
CA-125 
X 
 
 
 
X 
CT/MRIg 
X 
 
 
 
(X) 
Blood 
sample 
collection 
for 
biomarker analysish 
X 
 
 
 
(X) 
Urinalysis 
x 
 
 
 
x 
 
 
 
 
Adverse eventsi 
Continuously 
Concomitant medication 
Continuously 
Bone Marrow Aspirate and Biopsy 
At any time of MDS or AML diagnosis 
a Vital signs include weight, temperature, systolic and diastolic blood pressure (BP) and heart rate (HR); BP and HR 
will be measured after patient was in a sitting position for at least 10 minutes 
b Body height is only to be measured at C1D1c Haematology laboratory tests include assessment of :  
§ Hemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†,platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
and needs to be done weekly in the first two cycles.   
d Biochemistry panel laboratory tests include assessment of: 
 
§ Sodium, potassium, calcium 
 
§ Serum albumin, serum urea 
 
§ ALT, AST, LDH, AP, total bilirubin 
 
§ Creatinine 
e Urine/serum pregnancy testing is not required in patients after surgical sterilisation or bilateral ovarectomy or 
hysterectomy; > 12 months amenorrhea, age > 60 years. 
f Questionnaires EORTC QLQ-C30, EORTC QLQ-OV28, on day 1 of cycle 1 and than on day 1 of every other 
cycle , i.e. cycles 3, 5, 7 etc. 
g Tumour assessments every 12 weeks 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. Tumour assessment has to be done before start of 
maintenance therapy to confirm SD, PR or CR. 
h Blood collection for biomarker analysis will be performed before the administration of study drug on day 1 of cycle 
1 and thereafter on day 1 of every third cycle, cycles 4, 7, 10 etc prior to administration of study drug. An additional 
blood sample for biomarker analysis will be taken at disease progression (first visit after diagnosis of progression). 
i 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 
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j In case not all capsules were used, please count the remaining capsules first and instruct the patient afterwards to 
use up the remaining capsules before starting the new bottle 
 
 Maintenance Treatment Arm C: combination maintenance treatment Niraparib 
and Ganetespib 
Criteria to assess eligibility to start with Niraparib + Ganetespib combination 
maintenance therapy (arm C) 
 CT scan after completion of 6 cycles of platinum-based treatment showing SD, PR or CR. 
 Patients must have received 6 cycles of platinum-based treatment to start maintenance 
treamtment  
 With respect to laboratory findings:  
 
o Absolute neutrophil count ≥ 1,500/µL 
o Platelets ≥ 100,000/µL 
o Hemoglobin ≥ 9 g/dL 
o Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance 
≥ 30 mL/min using the Cockcroft-Gault equation 
o Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR direct  
bilirubin ≤ 1 x ULN 
o Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver  
metastases are present, in which case they must be ≤ 5 x ULN 
 
 
Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks 
prior to start of Niraparib. 
 
Participant must not have received colony-stimulating factors (eg. granulocyte colony-
stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant 
erythropoietin) ≤ 4 weeks prior to start of Niraparib. 
 
Participant must have a negative pregnancy test within 7 days prior to start of Niraparib. 
 
Any known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior 
chemotherapy that persisted > 4 weeks and was related to induction chemotherapy part in 
this study. 
 
Maintenance treatment is not allowed to start prior to 6 weeks after last platinum-based 
treatment. Maintenance treatment should preferentially start between 6 and 9 weeks, but will 
be allowed until up to 12 weeks after last platinum-based treatment. Exception: Patients in Arm 
C whos maintenance treatment start is delayed due to necessary IDMC evaluation after 6 and 
12 patients are allowed to start maintenance treatment beyond the 12 weeks.  
 
Please refer to section 16.1 to determine the starting dose of Niraparib for maintenance 
treatment. 
 
Of note, in case of negative safety evaluation of the Niraparib and Ganetespib combination by 
the IDMC, patients in arm C will proceed with Niraparib single agent maintenance treatment. 
Maintenance visits will be performed in a 4-weeks cycle, q4w. 
 
 


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Day 1 all treatment cycles Niraparib and Ganetespib 
 
Day 1 cycle 1 and than on day 1 of every other cycle, i.e. cylces 3, 5, 7 etc: 
Completion of PRO questionnaires (see section 15.2) 
 
Physical examination including vital signs and measurement of body weight and 
height (height only at Day 1 of cycle 1) (see section 16.4) 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments; Haematology and Biochemistry panel (see section 16.6) 
 
Evaluation of tumour marker CA-125 
 
Urine/serum pregnancy test in WOCBP (for definition see section 6). 
 
Day 1 of cycle 1 and than on day 1 of every third cylcle, i.e. cycles 4, 7, 10 etc.: Blood 
sampling for biomarker analysis prior to administration of study drug (please see 
section 16.7) 
 
Day 1 of each cycle: Electrocardiogram (ECG) (see section 16.5) 
 
Day 1 of cycle 1: Niraparib capsules dispensed; first dose administered at site 
 
Day 1 of all other cycles: Niraparib capsules dispensed / collected* 
 
Administration of Ganetespib (100 mg/m2) as an i.v. infusion 
 
Record concomitant medications (see section 16.3) 
 
Evaluate and document adverse events (AEs) (see Appendix B) 
* Please note: In case not all capsules were used, please count the remaining capsules first 
and instruct the patient afterwards to use up the remaining capsules before starting the new 
bottle 
 
Day 8, 15, 22 all cycles Niraparib + Ganetespib 
 
Physical examination including vital signs and measurement of body weight (see 
section 16.4) 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments; Haematology panel (see section 16.6) 
 
Administration of Ganetespib as an i.v. infusion, provided that there are no significant 
findings at the Day of administration (e.g. physical examination, ECOG PS, laboratory 
assessments or pregnancy test, see section 16) 
 
 Every 12 Weeks starting from day 1 cycle 1 of maintenance treatment 
 
Tumour assessments through CT/MRI (see section 16.1) 
 
 


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Table 13: Niraparib + Ganetespib Maintenance Schedule of Events (Arm C) 
Procedures / Assessments 
Cycle 1 and 2 
Cycle 3 and beyond 
Follow schedule of 
cycle 2 for all 
subsequent cycles 
until progression.  
The combination of 
Niraparib and 
Ganetespib will be 
given for 9 months. 
Thereafter 
Ganetespib 
treatment will be 
stopped and 
Niraparib 
maintenance 
therapy will be 
continued as 
single agent until 
disease 
progression.   
Cycle day 
1 
2 
8 
15 
22 
1 
8 
15 
22 
Physical examination incl. vital 
signsa (BP, HR, T ) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Body height and weightb 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance status 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECGc 
X 
X 
(X) 
(X) 
(X) 
X 
(X) 
(X) 
(X) 
Haematologyd 
X 
 
X 
X 
X 
X 
X 
X 
X 
Biochemistry panele 
X 
 
 
 
 
X 
 
 
 
Pregnancy testf 
X 
 
 
 
 
X 
 
 
 
PRO questionnaireg 
X 
 
 
 
 
(X) 
 
 
 
Administration of Ganetespib 
X 
 
X 
X 
X 
X 
X 
X 
X 
Niraparib dispensed / collectedk 
X 
 
 
 
 
X 
 
 
 
CA-125 
X 
 
 
 
 
X 
 
 
 
CT/MRIh 
X 
 
 
 
 
(X) 
 
 
 
Blood 
sample 
collection 
for 
biomarker analysisi 
X 
 
 
 
 
(X) 
 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
Adverse eventsj 
Continuously 
Concomitant medication 
Continuously 
Bone Marrow Aspirate and Biopsy 
At any time of MDS or AML diagnosis 
a Vital signs include weight, temperature, systolic and diastolic blood pressure (BP) and heart rate (HR); BP and HR 
will be measured after patient was in a sitting position for at least 10 minutes 
b Body height is only to be measured at C1D1 
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. 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 2 of cycle 1. In case of QTc prolongation (pre- or post-dose), further intensified 
ECG monitoring will be performed at the next dosing of Ganetespib. At a minimum pre-dose ECGs will be performed 
on days 1 of each cycle of Ganetepib treatment.  
d Haematology laboratory tests include assessment of:  
§ Hemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†,platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
e Biochemistry panel laboratory tests include assessment of: 
 
§ Sodium, potassium, calcium 
 
§ Serum albumin, serum urea 
 
§ ALT, AST, LDH, AP, total bilirubin 
 
§ Creatinine 
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, on day 1 of cycle 1 and than on day 1 of every other 
cycle, i.e. cycles 3, 5, 7 etc. 


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h Tumour assessments every 12 weeks 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. Tumour assessment has to be done before start of 
maintenance therapy to confirm SD, PR or CR. 
i Blood collection for biomarker analysis will be performed before the administration of study drug on day 1 of cycle 
1 and thereafter on day 1 of every third cycle, i.e. 4, 7, 10 prior to administration of study drug. An additional blood 
sample for biomarker analysis will be taken at disease progression (first visit after diagnosis of progression). 
j 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 
k In case not all capsules were used, please count the remaining capsules first and instruct the patient afterwards 
to use up the remaining capsules before starting the new bottle 
 
 End of treatment / Safety Follow-up 
All patients will receive a safety follow-up 28 days (+/- 7 days) after the last dose of Ganetespib 
(maximum of 9 months maintenance treatment) as well as after the last dose of Niraparib 
(treatment until progression) or prior to initiation of a new anti-cancer treatment, whichever 
occurs earlier.  
 
Safety follow-up includes the following (see Table 14): 
 
Completion of PRO questionnaires (see section 15.2) 
 
Physical examination including vital signs and measurement of body weight (see 
section 16.4) 
 
Determine ECOG PS (see Appendix A) 
 
Laboratory assessments; Haematology and Biochemistry panel (see section 16.6) 
 
Blood sampling for biomarker analysis (this blood sample at progression can be taken 
at the visit following diagnosis of progressive disease or the latest at safety follow-up) 
 
Evaluation of Tumour marker CA-125 
 
Electrocardiogram (ECG) (see section 16.5) 
 
Assess left ventricular ejection fraction (LVEF) by ECHO (see section 16.5) 
 
Urine/serum pregnancy test in WOCBP (for definition see section 6). 
 
Record concomitant medications (see section 16.3) 
 
Evaluate and document adverse events (AEs) (see section 19.1 and Appendix B) 
 
 Longterm FU prior to progression 
Patients who discontinue study treatment without having developed progressive disease will 
first continue to be followed monthly (+/- 7 days) as listed below until progression and will then 
continue with long-term follow-up after progression as described below under 15.5. 
 
Completion of PRO questionnaires every 8 weeks (see section 16.2) 
 
Tumour assessments through CT/MRI every 12 weeks (see section 16.1) 


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 
Evaluation of Tumour marker CA-125 every 4 weeks 
 
Additional cancer therapy  
 
Date of progression 
 
Evaluate any deaths, serious adverse events (SAEs), or other adverse events (AEs) 
of concern that are believed to be related to prior treatment with the study drug (see 
section 19.1 and Appendix C) 
 
 Longterm FU after progression 
In all patients a long-term follow-up period will be performed after the safety follow-up visits 
(arm A, B and C, see Table 14).  
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. 
 
Additional cancer therapy 
 
Date of next progression, following the subsequent cancer therapy  
 
Evaluate any deaths, serious adverse events (SAEs), or other adverse events (AEs) 
of concern that are believed to be related to prior treatment with the study drug (see 
section 19.1 and Appendix B) 
 
Table 14: Longterm follow-up Schedule of Events 
Procedures / Assessments 
Safety FU 
Follow-up  
PRIOR to progression: 
every month 
Follow-up  
AFTER progression: 
every 3 months 
Physical examination incl. vital signsa (BP, 
HR, T ) 
X 
 
 
Body weight 
X 
 
 
ECOG Performance status 
X 
 
 
ECGb 
X 
 
 
LVEF 
X 
 
 
Haematologyc 
X 
 
 
Biochemistry Paneld 
X 
 
 
Pregnancy teste 
X 
 
 
PRO questionnairef 
X 
(X) 
 
CA-125 
X 
X 
 
CT/MRIg 
 
(X) 
 
Survival status, MDS/AML monitoring (for 
5 years), additional cancer therapy, date 
of subsequent progression  
 
X 
X 
Adverse eventsh 
Continuously 
 
a Blood pressure and heart rate will be measured after patient was in a sitting position for at least 10 minutes 
b 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.  
c Haematology laboratory tests include assessment of:  


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§ Hemoglobin, haematocrit, RBC, WBC, absolute neutrophil count, differential (%)†,platelets 
† Neutrophils, eosinophils, basophils, lymphocytes, monocytes 
d Biochemistry panel laboratory tests include assessment of: 
 
§ Sodium, potassium, calcium 
 
§ Serum albumin, serum urea 
 
§ ALT, AST, LDH, AP, total bilirubin 
 
§ Creatinine 
e Urine/serum pregnancy testing is not required in patients after surgical sterilisation or bilateral ovarectomy or 
hysterectomy; > 12 months amenorrhea, age > 60 years. 
f Questionnaires EORTC QLQ-C30, EORTC QLQ-OV28 every 8 weeks prior to progression. . 
g Tumour assessments every 12 weeks 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. 
h 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. 
 
16 STUDY ASSESSMENTS 
Details of the timing of assessments are presented in the Schedule of Assessments (see 
details in section 15).  
 
 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 D). Evidence of progressive disease is considered clear radiological 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 or at 
the next scheduled tumour assessment if it is to occur more than 4 weeks after the initial 
response. 
 
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. 


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Already existing CT scan can be used as screening CTs, if not older than 28 days at the time 
of randomisation.  
 
Post-baseline tumour assessments are to be performed every 12 weeks  during platinum-
based therapy and after completion of platinum-based therapy (independent of any treatment 
interruptions using the same imaging technique as used during screening). Patients evaluated 
with SD, PR, or CR after completion of platinum-based therapy will start with maintenance 
treatment. During maintenance treatment tumour assessment will be performed every 12 
weeks (+/- 1 week) starting from day 1 cycle 1 of maintenance treatment until disease 
progression (independent of any treatment interruptions using the same imaging technique as 
used during screening)  
If there is suspicion of disease progression based on clinical or laboratory findings before the 
next scheduled assessment, an unscheduled assessment should be performed. 
 
 Patient-reported outcome (PRO) 
 PRO instruments 
The following PRO questionnaires will be used in all study arms of this study: EORTC QLQ-
C30, EORTC QLQ-OV28 (Appendix C). 
 
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. 
 
All scales are scored according to EORTC guidelines resulting in a score range from 0 to 100 
points. 
 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, event-driven on day 1 of every second cycle (d1c1, d1c3, d1c5) during platinum-
based therapy. During maintenance treatment PRO questionnaires will be filled in event-driven 
on day 1 of every second cycle (d1c1, d1c3, d1c5, d1c7…). Patients who discontinue study 
treatment without having developed progressive disease will complete PRO questionnaires 
every 8 weeks until progression. In the long-term follow-up after progression no further PRO 
evaluations will take place. 
 
15.2.3 PRO assessment procedure 


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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 
questionnaire completion. The study nurse or investigator will be available for any questions 
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. 
 
 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. 
 
 Physical examination 
Physical examinations will be performed by trained medical personnel. 
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 sitting position for 
10 minutes. 
 
 Electrocardiography (ECG) and Left ventricular ejection fraction (LVEF) 
ECG: 
A standard 12-lead ECG assessment will be performed at screening and at EOT/safety follow-
up. 
 
Each patient receiving 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). This applies to both, all 
treatment cycles during platinum-based combination (arms B and C) and all treatment cycles 
of Niraparib combination (arm C). In addition, a 24-hours post-Ganetespib-dose ECG (+/- 4 
hours) will be performed on day 2 of cycle 1. This also applies to both, the first cycle of 
platinum-based combination therapy and the first cycle of Niraparib combination treatment. 
 
The investigator will evaluate ECG findings in the first cycle of Ganetespib combination 
treatments (this applies again to both the Carboplatin Ganetespib combination as well as to 
the Niraparib Ganetespib combination) and will decide on an individualized risk-adjusted 
continued ECG monitoring schedule. At a minimum pre-dose ECGs will be performed on 
days 1 of each cycle of Ganetepib treatment.  
 
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. 


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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, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG 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 
Screening and at EOT/Safety Follow up (time points specified in section 15, schedule of 
assessments).  
 
 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. 
 
 Biomarker analysis  
Blood samples for analysis of biomarkers (including cell free tumour DNA and CTCs analyses) 
will be taken before and during study treatment in all patients (arm A, B and C) on days 1 of 
every third treatment cycle during platinum-based therapy (d1c1, d1c4) as well as on days 
1 of every third treatment cycle during maintenance treatment (d1c1, d1c4, d1c7, d1c10 
etc.) as outlined in section 15. 
 
The following biosamples will be collected to determine potential prognostic or predictive 
biomarkers (such as but not exclusively p53 status and other HSP90 clients) and to confirm 
high-grade serous, high-grade endometrioid, undifferentiated ovarian cancer, carcinosarcoma, 
fallopian tube or primary peritoneal cancer in all patients treated in this trial: 
 
 
Mandatory archival tumour tissue from primary diagnosis (formalin-fixed paraffin-
embedded tissue, FFPE). Chemo-naive tumour tissues (instead of tissue after neo-
adjuvant chemotherapy) will preferentially be collected. 
 
Mandatory blood collection before and during experimental therapy on days 1 of every 
third treatment cycle (during both platinum-based therapy and maintenance 
treatment) 
 
Whenever technically feasible, it is recommended to collect tissue of the actual 
platinum-sensitive relapse. This can be obtained by CT- or sonography guided biopsy 
of the actual relapse after informed consent has been obtained but prior to the first 


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study drug application or during routine debulking surgery in the actual relapsed 
situation. Both, FFPE and/or fresh frozen tissue samples (preferred) can be collected 
and provided to the consortium for biomarker analysis. 
In a subset of ~10 patients who are treated at participating sites, a second biopsy will 
be collected 24 hours (+/- 2 hours) after the first application of study treatment (Cycle 
1 Day 2) if technically feasible. These paired biopsies will be used to analyse the 
underlying “mechanism of action” of the study treatment (i.e. DNA damage response). 
It is aimed that this subset of 10 patients consists of 3 patients in the control arm A and 
7 patients in the experimental arms B + C (in line with the ratio 2:1 of randomisation). 
 
Prospectively collected biomaterials for biomarker analysis 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 of collected biomaterials 
are given separately in the Sample Handling Manual and Logistics Manual. 
 
Determination of p53 status and other biomarkers in collected biomaterials  
Archival tissues (FFPE) and tissues of of the actual relapse (FFPE and/or fresh-frozen tissues) 
will be collected in this trial. DNA, RNA and/or protein will be extracted from collected tissues. 
The p53 status and other biomarkers (including e.g. analysis of the p53-homologues p73 and 
p63, or other HSP90 clients) will be analysed. No germline BRCA testing will be performed, 
only retrospective somatic testing in the tumour tissues together with other relevant biomarkers 
e.g. involved in DNA repair. 
Blood samples for biomarker analysis (including e.g. circulating tumour cells and cell free 
tumour DNA) will be taken before and during study treatment in all patients. 
17 STUDY MEDICATION 
 Dosage and Administration 
 
An expected number of 120 patients will be treated with: 
 
Treatment arms:  
 
Standard arm A: 
6 cycles of standard platinum-based chemotherapy, q3w  
One of the two listed regimens, according to investigator decision:  
- Carboplatin (AUC4, d1, iv) and Gemcitabine (1000 mg/m²; d1+d8, iv) or  
- Carboplatin (AUC5, d1,iv) and Paclitaxel (175 mg/m²; d1, iv) and  
   followed by maintenance treatment with Niraparib continuous oral daily (q4w) until    
   progression, as below: 
 
Niraparib dosing according to body weight and thrombocyte values: 
Baseline Criteria  
Starting Dose  
≥77 kg and ≥150,000 µL 
300 mg (3 X 100 mg capsules) daily  
<77 kg or <150,000 µL 
200 mg (2 X 100 mg capsules) daily 


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Table 15 Niraparib dosing for arm A and arm B 
 
First experimental arm B: 
6 cycles of Carboplatin (AUC5; d1,iv) + Ganetespib (150 mg/m²; d1, iv), q3w 
Carboplatin infusion needs to be given first, followed by Ganetespib infusion. 
6 cycles of Carboplatin Ganetespib treatment are followed by maintenance treatment with 
Niraparib continuous oral daily (q4w) until progression, according to the Niraparib dosing table 
above. 
 
Second experimental arm C: 
6 cycles of Carboplatin (AUC5; d1, iv) + Ganetespib (150 mg/m², d1,iv), q3w 
Carboplatin infusion needs to be given first, followed by Ganetespib infusion. 
6 cycles of Carboplatin Ganetespib treatment are followed by maintenance treatment with 
Niraparib 200 mg oral daily (q4w) until progression + Ganetespib 100 mg/m² weekly (d1, d8, 
d15, d22, q4w) for 9 months. After 9 months Ganetespib treatment will be stopped and 
Niraparib maintenance therapy will be continued as single agent treatment.  
 
Ganetespib administration in general: 
Ganetespib is given as infusion intravenously over 1 hour. 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.  
The use of vascular access devices (VADs) such as ports and peripherally-inserted central 
catheters (PICCS) containing silicone for Ganetespib 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.  
 
Premedications: 
Ganetespib: Prophylactic medication with Loperamide 2 mg is strongly recommended in all 
patients who receive Ganetespib (this applies for both combinations, ie. Ganetespib in 
combination with Carboplatin and Ganetespib in combination with Niraparib) 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. This applies for both Ganetespib 
combination in this trial, i.e. the Ganetespib Carboplatin and the Ganetspib Niraparib 
combination. 
 
Carboplatin 
Paclitaxel 
and 
Carboplatin 
Gemcitabine 
(standard 
platinum-based 
chemotherapy): Local pre-medication standard at clinical site can be used.  
 
Carboplatin Ganetespib: Local pre-medication standard at clinical site can be used for 
Carboplatin. With respect to Ganetespib, prophylactic medication with Loperamide 2 mg is 
strongly recommended 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. Of note, Carboplatin infusion needs to be given first, followed by Ganetespib infusion. 
 


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Ganetespib Niraparib: With respect to Ganetespib, prophylactic medication with Loperamide 2 
mg is strongly recommended 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. 
 
18 DOSING SELECTION/ DOSE MODIFICATION/ DELAYS  
 Dose modifications for Carboplatin and Gemcitabine (Arm A) 
The following dose modifications for standard chemotherapy Carboplatin/Gemcitabine are 
recommended: 
 
Dose reduction levels for Gemcitabine and Carboplatin are given in Table 16: Dose levels for 
Gemcitabine and Carboplatin. 
Table 16: Dose levels for Gemcitabine and Carboplatin 
Drug 
Protocol Starting  
Dose 
Protocol 
Dose  
Level -1 
Protocol 
Dose  
Level -2 
Indication 
for further 
dose 
reductions 
Gemcitabine 1000 mg/m2 
800 mg/m2 
- 
Discontinue study 
medication 
Carboplatin 
AUC4 
AUC3 
- 
Discontinue study 
medication 
 
 Haematologic toxicity 
Treatment should be delayed if either of the following occurs within 24 hours prior to the 
administration of therapy: 
 Absolute neutrophile count (ANC) < 1.5 x 109/L (or < 1.0 x 109/L if the patient is 
planned to receive G-CSF) 
 Platelet (PLT) count  < 100 x 109/L 
Complete blood cell count (CBC) should be repeated, at least weekly, until haematologic 
recovery has occurred (ANC ≥ 1.5 x 109/L or > 1.0 x 109/L if the patient is planned to receive 
G-CSF and PLT ≥ 100 x 109/L). If haematologic recovery occurs within 7 days, no dose 
modification is mandated and any dose modification is left to the discretion of the individual 
investigator. If haematologic recovery occurs beyond 7 days doses of Carboplatin/ 
Gemcitabine should be modified according to the blood count. G-CSF should be used as 
stipulated by the ASCO guidelines or according to local practice guidelines. 
 
Patients who fail to recover adequate counts after a delay of 2 weeks or more, or who have 
consecutive dose-limiting toxicities, are not likely to be able to tolerate standard chemotherapy 
treatment. Significant modifications to the chemotherapy dose may be required. Such extreme 


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modifications are likely to be rare and should therefore be discussed on a case by case basis 
with the Sponsor.  
Table 17 gives recommendations for dose modifications for Gemcitabine on day 8.  
 
 
Table 17: Recommendations for Gemcitabine dose adjustments on day 8 for haematologic toxicities 
Finding 
Modification 
ANC (x 109/L) 
 
Platelets (x 109/L) 
 
≥ 1.5 
and 
≥ 100 
100 % 
≥1.0 to 1.4 
and/or 
75 – 99 
50 % 
< 1.0 
and/or 
< 75 
Omit dose 
 
Patients may receive erythropoietin (EPO), iron supplements and/or blood transfusions as 
clinically indicated for the management of their anemia.  
Dose adjustment for Gemcitabine in combination with Carboplatin for subsequent cycles is 
based on toxicity observed during the preceding cycle. The dose of Gemcitabine should be 
permanently reduced on day 1 and day 8 in case of any of the following haematological 
toxicities: 
 
Absolute Neutrophil Count < 500 x 106/L for more than 5 days 
 
Absolute Neutrophile Count < 300 x 106/L for more than 3 days 
 
Febrile Neutropenia 
 
Platelets < 25 x 109/L 
 
cycle delay of more than one week due to toxicity 
If any of the above toxicities recur after the initial dose reduction for the subsequent cycles, 
Gemcitabine and Carboplatin should be reduced according to Table 16. Gemcitabine should 
be given only on day 1 (omit Gemcitabine on day 8).  
 
 Non-haematologic toxicity 
Renal toxicity 
The combination of Gemcitabine and Carboplatin is not directly expected to cause renal 
toxicity. Therefore, no specific dose modifications are recommended for renal toxicity. Any 
concerns should be discussed with the Sponsor.   
However, the administered dose of Carboplatin must be recalculated, based on a recalculated 
or remeasured GFR, for  
 
renal toxicity (CTC Grade 2, serum creatinine > 1.5 x ULN) 
 
changes in serum creatinine of ≥ 10% 
 
each dose modification of Carboplatin 
 
cycle 2 if there has been significant doubt about the true GFR at cycle 1 (e.g. due to 
significant ascites). 
 


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Hepatic toxicity  
If Gemcitabine will be administered to patients with liver metastases or hepatitis in their history 
a deterioration of the existing liver insuffiency is possible. Transaminases should be checked 
on a regular basis.  
 
 
Other  
There are no dose modifications planned for alopecia, nausea, diarrhea or constipation. These 
side effects should be treated with supportive medical measures. Non-steroidal anti-
inflammatory agents can be used prophylactically or symptomatically, as per local practice.   
Any CTC grade 4 non-haematologic AE (except nausea or vomiting) will require the patient to 
be taken off treatment. For any grade 3 non-haematologic toxicity (except nausea or vomiting) 
the drugs should be withheld until symptoms resolve to ≤ grade 1. If the grade 3 event persists 
for ≥ 3 weeks, or recurs, then discussion with the Sponsor is recommended. 
 
 Hypersensitivity to Carboplatin (regardless of combination) 
If there is a hypersensitivity reaction to Carboplatin this should be managed as per local 
institutional protocols. Cisplatin can be substituted for Carboplatin at the discretion of the 
treating physician. Cisplatin (75 mg/m2) would be administered i.v. over 30 minutes every 3 
weeks. For patients who experience dose-limiting toxicity with Cisplatin, the dose can be 
reduced to 60 mg/m2 and subsequently to 50 mg/m2 if further dose-limiting toxicity occurs.  
 
 Dose modifications for Carboplatin/Paclitaxel (Arm A) 
 
The following dose modifications for standard chemotherapy Carboplatin/Paclitaxel are 
recommended: 
Dose reduction levels for Carboplatin and Paclitaxel are given in Table 18. 
Table 18: Dose reduction levels for Paclitaxel and Carboplatin 
Drug 
Protocol Starting  
Dose 
Protocol 
Dose  
Level -1 
Protocol 
Dose  
Level -2 
Indication 
for further 
dose 
reductions 
Paclitaxel 
175 mg/m2 
135 mg/m2 
110 mg/m2 
Discontinue study 
medication 
Carboplatin 
AUC5 
AUC4 
AUC3 
Discontinue study 
medication 
 Dose levels are adjusted individually for each drug. 
 Up to 2 dose-reductions are acceptable for Paclitaxel and Carboplatin in cases of severe 
haematologic toxicity. 
 No dose re-escalations are permitted following dose-reduction for toxicity. 
 
 


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 Haematologic toxicity 
Treatment should be delayed if either of the following occurs within 24 hours prior to the 
administration of therapy: 
 
Absolute neutrophil count (ANC) < 1.5 x 109/L (or < 1.0 x 109/L if the patient is planned 
to receive G-CSF) 
 
Platelet (PLT) count < 100 x 109/L. 
 
CBC should be repeated, at least weekly, until haematologic recovery has occurred (ANC ≥ 
1.5 x 109/L or > 1.0 x 109/L if the patient is planned to receive G-CSF and PLT ≥100 x 109/L). 
If haematologic recovery occurs within 7 days, no dose modification is mandated and any dose 
modification is left to the discretion of the individual investigator. If haematologic recovery 
occurs beyond 7 days, doses of Carboplatin and Paclitaxel should be modified according to 
the day 22 blood count (or subsequent CBC if lower).  
G-CSF should be used as stipulated by the ASCO guidelines, or according to local practice 
guidelines. In particular, to prevent severe infections linked to febrile neutropenia prophylactic 
G-CSF should be initiated according to the ASCO guidelines, or according to local practice 
guidelines such as the INCa recommendations in France.  
 
Patients who fail to recover adequate counts after a delay of 2 weeks or more, or who have 
consecutive dose-limiting toxicities, are not likely to be able to tolerate standard chemotherapy 
treatment. Significant modifications to the chemotherapy dose may be required. Such extreme 
modifications are likely to be rare and should therefore be discussed on a case by case basis 
with the Sponsor. 
Haematologic dose-limiting toxicities and permitted dose modifications are described in Table 
19. Patients developing any other dose-limiting toxicity require dose modification 
independently of the ANC and platelets on day 22. 
Patients may receive erythropoietin (EPO), iron supplements and/or blood transfusions as 
clinically indicated for the management of their anemia. 
 
Table 19: Guidelines for Paclitaxel and Carboplatin dose modification for delayed haematologic recovery 
according to the blood test on day 22 
Delayed ANC recovery (> 7 days) 
Results on day 22 
ANC ≥ 1.5 x 109/L 
(> 1.0x109/L if G-CSF 
is planned to be given) 
ANC < 1.5 x 109/L  
(< 1.0x109/L if G-CSF is 
planned to be given) 
Delayed PLT 
Recovery (>7 
days) 
PLT ≥ 100 x 109/L 
Paclitaxel: 
No modification 
Paclitaxel: 
Either: 
Use G-CSF and 
continue current dose 
Or 
Reduce by 1 dose level 
Carboplatin: No 
modification 
Carboplatin: No 
modification 


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PLT  < 100 x 109/L 
Paclitaxel: 
No modification 
Paclitaxel: 
Either: 
Use G-CSF and 
continue current dose 
Or 
Reduce by 1 dose level 
Carboplatin: 
Reduce by 1 AUC unit 
Carboplatin:  
Reduce by 1 AUC unit 
 
Table 20: Guidelines for Paclitaxel and Carboplatin dose modification due to dose-limiting toxicity 
Dose-Limiting Toxicity: ANC1 
Dose-Limiting 
Toxicity: PLT2 
No 
Yes 
No 
Paclitaxel: 
No modification 
Paclitaxel: Either: 
Use G-CSF and continue 
current dose 
or 
Reduce by 1 dose level 
Carboplatin: No modification 
Carboplatin: No modification 
Yes 
Paclitaxel: 
No modification 
Paclitaxel: Either: 
Use G-CSF and continue current 
dose 
or 
Reduce by 1 dose level 
Carboplatin: 
Reduce by 1 AUC unit 
Carboplatin: 
Reduce by 1 AUC unit 
 
1 This is defined by the occurrence of either, or both, of 
 
febrile neutropenia (defined as fever with or without clinically or microbiologically documented 
infection with an ANC less than 1 x 109/L and fever ≥ 38.5°C [CTCAEv5]) or 
 
prolonged grade 4 neutropenia (defined as ANC < 0.5 x 109/L) persisting ≥ 7 days 
There are no planned dose modifications for uncomplicated grade 4 neutropenia lasting less than 7 
days. 
2 This is defined by the occurrence of either, or both, of 
 
grade 4 thrombocytopenia (defined as PLT < 25 x 109/L) or 
 
bleeding associated with grade 3 thrombocytopenia (PLT 25 – 50 x 109/L) There 
are no modifications planned for uncomplicated grade 3  thrombocytopenia. 
 
 
 


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 Non-haematologic Toxicity 
Renal toxicity 
The combination of Carboplatin and Paclitaxel is not directly expected to cause renal toxicity. 
Therefore, no specific dose modifications are recommended for renal toxicity. Any concerns 
should be discussed with the Sponsor. 
However, the administered dose of Carboplatin must be recalculated, based on a 
recalculated or remeasured GFR, for 
 
renal toxicity (CTC Grade 2, serum creatinine >1.5 x ULN) 
 
changes in serum creatinine of ≥10% 
 
each dose modification of Carboplatin 
 
Cycle 2, if there has been significant doubt about the true GFR at Cycle 1 
(e.g. due to significant ascites). 
 
Hepatic toxicity (elevated transaminases) 
If hepatic toxicity occurs and the transaminases are < 2.5 x ULN then treatment can be 
continued as per the protocol without any dose modifications or delays. If the transaminases 
become elevated to 2.5 – 5 x ULN, then treatment can still be continued at the discretion of 
the treating investigator. Dose reductions of Paclitaxel can be performed according to local 
practice. If the transaminases are elevated to > 5 x ULN (grade 3 CTCAE v5.0) then treatment 
with all drugs should be withheld until resolution≤ to grade 1. 
Neuropathy 
Grade 2 sensory or motor neuropathy requires Paclitaxel treatment to be interrupted until 
neuropathy has resolved to grade 1. On recovery, Paclitaxel should be reduced by 1 dose 
level. If this requires a delay of more than three weeks then the Paclitaxel should be omitted 
from subsequent cycles and treatment continued with single-agent Carboplatin at the same 
AUC used in combination with Paclitaxel. Alternatively to stop of Paclitaxel, a switch to 
Docetaxel combination is allowed. 
Grade ≥ 3 sensory or motor neuropathy requires Paclitaxel to be omitted from subsequent 
cycles, and treatment continued either with single-agent Carboplatin at the same dose as 
previously used. 
Mucositis 
For mucositis grade ≥ 3, chemotherapy should be delayed until the mucositis has resolved 
to grade ≤ 1. Paclitaxel can be reduced by one dose level in subsequent cycles at the 
discretion of the treating physician. If the mucositis persists at grade ≥ 3 for more than  three 
weeks, or recurs, then chemotherapy dose modifications should be discussed with the 
Sponsor. 
Hypersensitivity to Paclitaxel 
Prior to Paclitaxel administration, hypersensitivity prophylaxis should be implemented 
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A hypersensitivity reaction to Paclitaxel is not a dose-limiting toxicity. The acute management 
should occur as per local practice. 
If a hypersensitivity reaction occurs then patients may be retreated with Paclitaxel at full dose, 
according to local protocols. This is likely to require increased prophylactic medications and/or 
a slowing of the initial infusion rate. The infusion rate can be gradually increased in the 
absence of further hypersensitivity reactions. 
Emergency resuscitation equipment and personnel should be available during the period of 
re-challenge. If the re-challenge occurs within 72 hours of the original intended dose and a 
negligible quantity, i.e. 50 ml or less, of the original dose was administered, re- administer the 
full dose. If a substantial proportion has been given then the balance of the full original dose 
should be administered. 
If the re-challenge is being considered more than 72 hours after the original intended dose 
then a full blood count should be taken to check suitability. 
The Paclitaxel can be deceased at the discretion of the treating physician, i.e. the patient can 
continue on treatment with single agent Carboplatin and remain on study. Alternatively to stop 
of Paclitaxel, a switch to Docetaxel combination is allowed. 
Hypersensitivity to Carboplatin 
See section 18.1.3 (Hypersensitivity to Carboplatin (regardless of combination)) 
 
Other 
A patient in whom enterocolitis is suspected should be urgently addressed for specialized 
advice in connection with the oncology team who should inform about the enterocolitis risk 
due to taxanes and specify the details of treatment and administered dose schedule as well 
as the date of last treatment. A permanent discontinuation of treatment by Paclitaxel is 
recommended in case of any suspected enterocolitis. The patient should be re-disussed 
during Multidisciplinary Team meeting and the Sponor needs to be informed. 
There are no dose modifications planned for alopecia, nausea, diarrhoea or constipation. 
These side effects should be treated with supportive medical measures. Non-steroidal anti-
inflammatory agents can be used prophylactically or symptomatically, as per local practice. 
Any CTC grade 4 non-haematologic AE (except nausea or vomiting) will require the patient 
to be taken off study. For any grade 3 non-haematologic toxicity (except nausea or vomiting) 
the drugs should be withheld until symptoms resolve to ≤ grade 1. If the grade 3 event persists 
for ≥ 3 weeks, or reoccurs, then discussion with the Sponsor. 
 
Expected toxicities of Paclitaxel and Carboplatin 
A list of expected AEs (based on the current SPCs) associated with Paclitaxel and Carboplatin 
is given in the Investigator File. This list should be used to assist the treating physician in the 
classification of SAEs. The SPC should be referred to for specific guidance. 
 
 


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 Dose modification for Carboplatin/Ganetespib combination 
Dose reduction levels for Ganetespib and Carboplatin are given in Table 21. 
 
Table 21: Dose reduction levels for Ganetespib and Carboplatin given in combination 
* if Ganetespib dose needs to be reduced below 75 mg/m², then discontinue Ganetespib. 
 
Drug 
Protocol 
Starting 
Dose 
Protocol 
Dose  
Level -1 
Protocol 
Dose  
Level -2 
Protocol 
Dose  
Level -3 
Indication 
for further 
dose 
reductions 
Ganetespib 
150 mg/m2 
125 mg/m2 
100 mg/m2 
75 mg/m2 
Discontinue 
study 
medication 
Carboplatin AUC5 
AUC4 
AUC3 
- 
Discontinue 
study 
medication 
 
In addition to the specific toxicities presented in the tables in section 18.3.1 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. 
 
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 15.3. 
 
For Ganetespib no dose reduction is necessary due to a body surface area (BSA) above 2.0. 
 
 Haematologic Toxicity  
Table 22: Dose modifications for the combination therapy of Carboplatin and Ganetespib on day 21 
(q3w) 
Finding 
Modification 
Platelet count <100 x 109 /L 
Carboplatin and Ganetespib must be interrupted until 
platelet counts are ≥ 100 x 109 /L with weekly blood counts 
for CBC monitored until recovery. Carboplatin and 
Ganetespib shall than be resumed at the same dose 
level, i.e. Carboplatin AUC5 and Ganetespib 150mg/m2. 
2nd (or more) occurrence of 
platelet count <100 x 109 /L or 
Carboplatin and Ganetespib must be interrupted until 
platelet counts are ≥ 100 x 109 /L with weekly blood counts 


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prolonged 
platelet 
count 
<100.000/µl until day 35 (2 
weeks from the last planned 
Ganetespib administration) 
for CBC monitored until recovery. Carboplatin shall than 
be resumed at a reduced dose level, while remaining the 
Ganetespib dose level. If Carboplatin is already reduced to 
the lowest dose level than reduce dose level of Ganetespib. 
Neutrophils < 1 x 109 /L  
Carboplatin and Ganetespib must be interrupted until 
neutrophil counts are ≥ 1 x 109 /L with weekly blood counts 
for CBC monitored until recovery.  
If prophylaxis with G-CSF is not considered feasible, 
Ganetespib shall be resumed at a reduced dose level, 
while remaining the Carboplatin dose level.  
If prophylaxis can be given, Carboplatin and Ganetespib 
are resumed at the same dose level. 
prolonged neutrophils count < 
1 x 109 /L until day 35 (2 weeks 
from 
the 
last 
planned 
Ganetespib administration) or 
grade 4 neutropenia 
Carboplatin and Ganetespib must be interrupted until 
neutrophil counts are ≥ 1 x 109 /L with weekly blood counts 
for CBC monitored until recovery.  
If prophylaxis with G-CSF is not considered feasible, 
Ganetespib and Carboplatin shall both be resumed at a 
reduced dose level, respectively.  
If prophylaxis can be given, Carboplatin and Ganetespib 
are resumed at the same dose level. 
2nd occurrence of neutrophils 
count < 1 x 109 /L 
Carboplatin and Ganetespib must be interrupted until 
neutrophil counts are ≥ 1 x 109 /L with weekly blood counts 
for CBC monitored until recovery.  
Carboplatin shall be resumed at reduced dose level, 
while remaining the Ganetespib dose level  
3nd occurrence of neutrophils 
count < 1 x 109 /L 
Carboplatin and Ganetespib must be interrupted until 
neutrophil counts are ≥ 1 x 109 /L with weekly blood counts 
for CBC monitored until recovery.  
Ganetespib shall be resumed at a reduced dose level, 
while remaining the Carboplatin dose level.  
4th occurrence of neutrophils 
count < 1 x 109 /L 
Carboplatin and Ganetespib must be interrupted until 
neutrophil counts are ≥ 1 x 109 /L with weekly blood counts 
for CBC monitored until recovery.  
Carboplatin shall be resumed at reduced dose level, 
while remaining the Ganetespib dose level 
5th occurrence of neutrophils 
count < 1 x 109 /L 
Carboplatin and Ganetespib must be interrupted until 
neutrophil counts are ≥ 1 x 109 /L with weekly blood counts 
for CBC monitored until recovery.  
Ganetespib shall be resumed at a reduced dose level, 
while remaining the Carboplatin dose level. 
6th occurrence of neutrophils 
count < 1 x 109 /L 
Discontinue Carboplatin and Ganetespib treatment 
 


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 Non-haematologic Toxicity 
Renal toxicity 
The combination of Carboplatin and Ganetespib is not directly expected to cause renal 
toxicity. Therefore, no specific dose modifications are recommended for renal toxicity. Any 
concerns should be discussed with the Sponsor. 
However, the administered dose of Carboplatin must be recalculated, based on a 
recalculated or remeasured GFR, for: 
 
renal toxicity (CTC Grade 2, serum creatinine >1.5 x ULN) 
 
changes in serum creatinine of ≥10% 
 
each dose modification of Carboplatin 
 
Cycle 2, if there has been significant doubt about the true GFR at Cycle 1 
(e.g. due to significant ascites). 
 
 Dose Modification for Niraparib single agent in maintenance treatment (Arm 
A and B) 
 Dose modification of Niraparib for non-haematologic parameters 
 
Dose reduction levels for Niraparib are given in Table 23. 
Dose interruption and/or reduction may be implemented at any time for any grade toxicity 
considered intolerable by the patient.For patients whose initial dose is 3 capsules daily (300 
mg/day), dose reductions to 2 capsules daily (200 mg/day) and subsequently to 1 capsule daily 
(100 mg/day) will be allowed. No further dose reduction will be allowed.  
For patients whose initial dose is 2 capsules (200 mg/day), dose reduction to 1 capsule once 
daily (100 mg/day) will be allowed. No further dose reduction will be allowed. 
 
Table 23: Dose reduction levels of Niraparib  
Recommended Niraparib Dose Modifications for Adverse Reactions 
Dose level 
Initial Dose: 3 capsules per day 
Initial Dose: 2 capsules per day 
Starting dose 
3 capsules once daily (300 mg/day)  2 capsules once daily (200 mg/day)  
First dose 
reduction 
2 capsules once daily (200 mg/day)  1 capsule once daily (100 mg/day) 
Second dose 
reduction 
1 capsule once daily (100 mg/day) 
NA 
 
Treatment must be interrupted for any non-haematologic, non-hepatic National Cancer 
Institute (NCI)-CTCAE (v.5) Grade 3 or 4 AE which the Investigator considers to be related to 
administration of Niraparib. If toxicity is appropriately resolved to baseline or grade 1 or less 
within 28 days, the patient may restart treatment with Niraparib, but with a dose level reduction 
according to Table 23 if prophylaxis is not considered feasible. If the event recurs at similar or 
worse grade, treatment should be interrupted again and, upon resolution, a further dose 


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reduction must be made. No more than 2 dose reductions will be permitted during single agent 
Niraparib maintenance treamtent (arms A and B).  
 
If the toxicity requiring dose interruption has not resolved completely or to NCI-CTCAE Grade 
1 during the maximum 4 week (28 day) dose interruption period, and/or the patient has already 
undergone a maximum of 2 dose reductions (to a minimum dose of 100 mg QD), the patient 
must permanently discontinue treatment with Niraparib.  
Dose interruption, reduction or permanent discontinuation may be implemented at any time 
depending on laboratory and/or clinical evidence of hepatic toxicity. 
 
 
Dose modification for Other Non-haematologic Adverse Reactions for Niraparib single 
agent treatment in maintenance (arms A and B) 
Table 24 Niraparib Dose modification for Other Non-haematologic Adverse Reactions 
Abnormality 
Intervention 
Non-haematologic CTCAE ≥ 
Grade 3 adverse reaction where 
prophylaxis is not considered 
feasible or adverse reaction 
persists despite treatment 
Withhold Niraparib for a maximum of 28 days or until resolution of 
adverse reaction. 
Resume Niraparib at a reduced dose level.  
CTCAE ≥ Grade 3 treatment-
related adverse reaction lasting 
more than 28 days while patient 
is administered Niraparib 100 
mg/day 
Discontinue Niraparib. 
 
Hepatic toxicity  
Dose modification for liver function abnormalities are given in Table 28. 
Table 25: Dose modification for hypertransaminasaemia (AST/ALT) 
Finding 
Modification 
Grade 2* 
AST/ALT 
Monitor liver enzymes and direct bilirubin initially within 24 
hours and then at least weekly until abnormalities resolve to 
Grade ≤ 1. No interruption is necessary, unless ALT and/or 
AST worsens to > 5 × ULN (or > 5 × baseline, if baseline 
abnormal), or symptoms of liver injury or hypersensitivity 
develop.  
Grade 3* 
AST/ALT 
(>5 x ULN, CTCAE v5.0) 
in the absence of other signs 
of liver dysfunction  
Niraparib must be interrupted (for a maximum of up to 28 days) 
and monitor liver enzymes and direct bilirubin initially within 24 
hours and then every 24 to 72 hours until clear signs of 
improvement, and then at least weekly until abnormalities 
resolve to Grade ≤ 1. 
1st occurrence: Niraparib shall be resumed at reduced dose 
level  
2nd 
occurrence: 
Niraparib 
shall 
be 
permanently 
discontinued. 


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Grade 4 
AST/ALT 
(>20 x ULN, CTCAE v5.0) 
Niraparib must be interrupted (for a maximum of up to 28 days) 
and monitor liver enzymes and direct bilirubin initially within 24 
hours and then every 24 to 72 hours until clear signs of 
improvement, and then at least weekly until abnormalities 
resolve to Grade ≤ 1. 
1st 
occurrence: 
Niraparib 
shall 
be 
permanently 
discontinued  
 
 
*In case of ALT or AST > 3 × ULN AND bilirubin > 2 × ULN (suspected DILI) Niraparib  
must be interrupted. The patient should be evaluated for the presence of confounding 
factors including malignant disease in the liver, coadministration of other suspect drugs, 
cholestasis, and viral or autoimmune hepatitis that could have caused the laboratory 
abnormalities. Other laboratory investigations of liver function such as international 
normalized ratio (INR) should be implemented as indicated. If no alternative cause is 
identified, Niraparib must be permanently discontinued. Patients should be followed until 
all abnormalities have returned to normal, returned to baseline levels, or an alternative 
cause is found to explain the combination of the increased transaminases and total 
bilirubin.” 
 
 Dose modifications for haematologic parameters for Niraparib single agent 
treatment in maintenance (arms A and B) 
The dose interruption/modification criteria for haematologic parameters will be based on blood 
counts and are outlined in Table 26. 
 
Table 26: Dose modification/reduction for Haematologic toxicitities of Niraparib on day 28 (q4w) 
Finding 
Modification 
Platelet count 75 -99.9 x 109 /L 
Niraparib must be interrupted (for up to a maximum of 
28 days) until platelet counts are ≥100.000/µl, with 
weekly blood counts for CBC monitored until recovery. 
Niraparib may then be resumed at same dose level or 
at a reduced dose level based on clinical judgement. 
2nd and 3rd occurrence of platelet 
count 75 -99.9 x 109 /L 
Niraparib must be interrupted (for up to a maximum of 
28 days) until platelet counts are ≥100.000/µl, with 
weekly blood counts for CBC monitored until recovery. 
Niraparib may then be resumed at a reduced dose 
level.  
Discontinue Niraparib if the platelet count has not 
returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient has already 
undergone dose reduction to 100mg QD. 
Platelet count < 75 x 109 /L 
Niraparib must be interrupted (for up to a maximum of 
28 days) until platelet counts are ≥100.000/µl, with 
weekly blood counts for CBC monitored until recovery. 


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Niraparib may then be resumed at a reduced dose 
level.  
Discontinue Niraparib if the platelet count has not 
returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient has already 
undergone dose reduction to 100 mg QD. 
Neutrophil < 1 x 109 /L 
Niraparib must be interrupted (for up to a maximum of 
28 days) until neutrophil counts ≥1.500/µl, with weekly 
blood counts for CBC monitored until recovery. 
Niraparib may then be resumed at a reduced dose 
level.  
Discontinue Niraparib if the neutrophil count has not 
returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient has already 
undergone dose reduction to 100 mg QD. 
Hemoglobin <8 g/dL 
Niraparib must be interrupted (for a maximum of up to 
28 days) until hemoglobin is ≥ 9 g/dL, with weekly blood 
counts for CBC monitored until recovery. Niraparib may 
be resumed at a reduced dose level. 
Discontinue Niraparib if the hemoglobin has not 
returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient has already 
undergone dose reduction to 100 mg QD. 
Iron substitution and erythropoiesis-stimulating agents 
are allowed according to standard of care. Also bloed 
transfusions are allowed if indicated during the 
treatment period. 
Haematologic adverse reaction 
requiring transfusion 
For patients with platelet count ≤10,000/μL, platelet 
transfusion should be considered. If there are other risk 
factors such as co-administration of anticoagulation or 
antiplatelet drugs, consider interrupting these drugs 
and/or transfusion at a higher platelet count, such as ≤ 
20.000/µl. 
 
Resume Niraparib at a reduced dose level. 
Discontinue Niraparib if the patient has already 
undergone dose reduction to 100 mg QD. 
Confirmed diagnosis of MDS or 
AML 
Permanently discontinue Niraparib. 
Abbreviation: CBC = complete cell count 
 
In the case of thrombocytopenia, following the first occurrence, resumption of therapy may 
occur at the same dose or 1 dose level lower when the haematologic toxicity has resolved. 
Subsequent occurrences should trigger dose reduction upon resumption of therapy. If the 


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platelet count has not reverted within 28 days of interruption to ≥ 100 x 109 /L, then study 
treatment should be discontinued. 
 
If dose interruption or modification is required at any point on study because of haematologic 
toxicity, to ensure safety of the new dose, weekly blood draws for complete blood cell count 
(CBC) will be required for an additional 4 weeks after the AE has been resolved to the specified 
levels, after which monitoring every 4 weeks may resume. Weekly blood draws for CBC can 
be collected either at study site or local laboratories. If the haematologic toxicity has not 
recovered to the specified levels within 4 weeks (28 days) of the dose interruption period, 
and/or the patient has already undergone a maximum of 2 dose reductions (to a minimum dose 
of 100 mg QD), the patient must permanently discontinue treatment with Niraparib.  
Any patient requiring transfusion of platelets or red blood cells (1 or more units) or 
hematopoietic growth factor support must undergo a dose reduction upon recovery if study 
treatment is resumed.  
The patient must be referred to a haematologist for further evaluation (1) if transfusions are 
required on more than 1 occasion or (2) if the treatment-related haematologic toxicities have 
not recovered to CTCAE grade 1 or less after 4 weeks. If a diagnosis of MDS/AML is confirmed 
by a haematologist, the patient must permanently discontinue study treatment.  
For major surgery while on treatment, up to 28 days of drug interruption is allowed.  
Once the dose of study treatment has been reduced, any re-escalation must be discussed with 
the Sponsor.  
All dose interruptions and reductions (including any missed doses), and the reasons for the 
reductions/interruptions, are to be recorded in the electronic case report from (eCRF). 
 
 Dose Modification for Niraparib and Ganetespib in maintainance treatment 
(arm C) 
 Dose modifications for Niraparib plus Ganetespib combination treatment in 
maintenance (arm C) 
Please consider, Niraparib starting dose is only 200 mg, Ganetespib starting dose is only 100 
mg/m2. Thus, only 1 dose reduction step of each of the two drugs is possible: If toxicity persists 
then one or both drugs should be discontinued, based on the toxicity observed (see Table 27). 
 
For dose reduction levels please see Table 23 for Niraparib and see Table 21 for Ganetespib. 
 
Dose modifications for haematologic toxicity with Niraparib and Ganetespib in maintenance 
treatment are given in Table 27. 
 
Of note, if Niraparib maintenance treatment is stopped in arm C for any reason, then 
Ganetespib will be continued as single agent until 9 months of total Ganetespib treatment 
(including the time of Niraparib and Ganetespib combination treatment).  
 
 
 
 


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Table 27: Dose modification for Niraparib and Ganetespib in maintenance treatment on day 28 (q4w) 
Finding 
Modification 
Platelet count 75-99.9 x 109 /L Ganetespib and Niraparib must be interrupted (for up to a 
maximum of 28 days) until platelet counts are > 100 x 109 
/L with weekly blood counts for CBC monitored until 
recovery.  
Niraparib and Ganetespib shall then be resumed at the 
same dose level, i.e. Niraparib 200mg QD and 
Ganetespib 100mg/m2.  
Exception: In case of prolonged platelet count <100 x 109 
/L over >2 weeks, Niraparib shall be resumed at 100mg 
QD, while retaining Ganetespib at 100mg/m2. 
2nd or 3rd occurrence of platelet 
count 75-99.9 x 109 /L 
Ganetespib and Niraparib must be interrupted (for up to a 
maximum of 28 days) until platelet counts are > 100 x 109 
/L with weekly blood counts for CBC monitored until 
recovery.  
Niraparib shall then be resumed at a 100mg QD, while 
retaining Ganetespib at 100mg/m2.  
Discontinue Niraparib if the platelet count has not returned 
to acceptable levels within 28 days of the dose interruption 
period, or if the patient has already undergone a dose 
reduction to 100mg QD. 
In case of discontinuation of Niraparib, then Ganetespib 
will be continued as single agent until 9 months of 
Ganetespib treatment 
Platelet count <75 x 109 /L 
Ganetespib and Nirarparib must be interrupted (for a 
maximum of up to 28 days) until platelet counts are > 100 
x 109 /L with weekly blood counts for CBC monitored until 
recovery.  
Niraparib shall then be resumed at a 100mg QD, while 
retaining Ganetespib at 100mg/m2.  
Discontinue Niraparib if the platelet count has not returned 
to acceptable levels within 28 days of the dose interruption 
period, or if the patient has already undergone a dose 
reduction to 100mg QD. 
In case of discontinuation of Niraparib, then Ganetespib 
will be continued as single agent until 9 months of 
Ganetespib treatment 
1th 
or 
2rd 
occurrence 
of 
neutrophils < 1 x 109 /L 
Ganetespib and Niraparib must be interrupted (for a 
maximum of up to 28 days) until neutrophil counts are  ≥ 
1,500 /μL with weekly blood counts for CBC monitored until 
recovery.  


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Niraparib shall then be resumed at 100mg QD and 
Ganetespib  at 75mg/m2. 
Discontinue Niraparib if the neutrophil count has not 
returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient has already undergone 
a dose reduction to 100mg QD. 
In case of discontinuation of Niraparib, then Ganetespib 
will be continued as single agent until 9 months of 
Ganetespib treatment. 
G-CSF treatment is allowed but cannot be used as 
prophylaxis ahead of any event. 
Hemoglobin < 8g/dL 
Ganetespib and Niraparib must be interrupted (for a 
maximum of up to 28 days) until hemoglobin ≥ 9 g/dL with 
weekly blood counts for CBC monitored until recovery.  
Resume Niraparib at 100mg QD, while retaining 
Ganetespib at 100mg/m2. 
Discontinue Niraparib if hemoglobin has not returned to 
acceptable levels within 28 days of the dose interruption 
period, or if the patient has already undergone a dose 
reduction to 100mg QD. 
In case of discontinuation of Niraparib, then Ganetespib 
will be continued as single agent until 9 months of 
Ganetespib treatment. 
Iron substitution and erythropoiesis-stimulating agents are 
allowed according to standard of care. Also bloed 
transfusions are allowed if indicated during the treatment 
period. 
Haematologic 
adverse 
reaction requiring transfusion 
For patients with platelet count ≤10,000/μL, platelet 
transfusion should be considered. If there are other risk 
factors such as co-administration of anticoagulation or 
antiplatelet drugs, consider interrupting these drugs and/or 
transfusion at a higher platelet count, such as ≤ 20.000/µl. 
 
Resume Niraparib at a reduced dose level. Discontinue 
Niraparib if the patient has already undergone dose 
reduction to 100 mg QD. 
Confirmed diagnosis of MDS 
or AML 
Permanently discontinue Niraparib. 
 
 
 
 
 
 
 


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Hepatic toxicity  
Dose modification for liver function abnormalities are given in Table 28. 
Table 28: Dose modification for hypertransaminasaemia (AST/ALT) 
Finding 
Modification 
Grade 2* 
AST/ALT 
Monitor liver enzymes and direct bilirubin initially within 24 
hours and then at least weekly until abnormalities resolve to 
Grade ≤ 1. No interruption is necessary, unless ALT and/or 
AST worsens to > 5 × ULN (or > 5 × baseline, if baseline 
abnormal), or symptoms of liver injury or hypersensitivity 
develop.  
Grade 3* 
AST/ALT 
(>5 x ULN, CTCAE v5.0) 
in the absence of other signs 
of liver dysfunction  
Niraparib and Ganetespib must be interrupted (for a maximum 
of up to 28 days) and monitor liver enzymes and direct bilirubin) 
initially within 24 hours and then every 24 to 72 hours until clear 
signs of improvement, and then at least weekly until 
abnormalities resolve to Grade ≤ 1. 
1st occurrence: Niraparib shall be resumed at reduced dose 
level, while remaining the Ganetespib dose level  
2nd 
occurrence: 
Niraparib 
shall 
be 
permanently 
discontinued. 
In case of discontinuation of Niraparib, then Ganetespib will 
be continued as single agent until 9 months of Ganetespib 
treatment  
Grade 4 
AST/ALT 
(>20 x ULN, CTCAE v5.0) 
Niraparib and Ganetespib must be interrupted (for a maximum 
of up to 28 days) and monitor liver enzymes and direct bilirubin 
initially within 24 hours and then every 24 to 72 hours until clear 
signs of improvement, and then at least weekly until 
abnormalities resolve to Grade ≤ 1. 
1st occurrence: Niraparib and Ganetespib shall be 
permanently discontinued  
 
 
 
*In case of ALT or AST > 3 × ULN AND bilirubin > 2 × ULN and/or direct bilrubin >35% 
(suspected DILI) Niraparib and Ganetespib must be interrupted. The patient should be 
evaluated for the presence of confounding factors including malignant disease in the 
liver, coadministration of other suspect drugs, cholestasis, and viral or autoimmune 
hepatitis that could have caused the laboratory abnormalities. Other laboratory 
investigations of liver function such as international normalized ratio (INR) should be 
implemented as indicated. If no alternative cause is identified, Niraparib and Ganetespib 
must be permanently discontinued. Patients should be followed until all abnormalities 
have returned to normal, returned to baseline levels, or an alternative cause is found to 
explain the combination of the increased transaminases and total bilirubin.” 
 
 
 
 


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Dose modification for hyperbilirubinaemia are given in Table 29. 
Table 29: Dose modification for hyperbilirubinaemia 
Finding 
Modification 
Grade 2* 
Hyperbilirubinaemie  
Niraparib and Ganetespib must be interrupted (for a maximum 
of up to 28 days) and monitor liver enzymes and direct bilirubin 
initially within 72 hours and then at least weekly until bilirubin 
resolves to Grade ≤ 1. No interruption is necessary, unless 
bilirubin elevation worsens to > 3 × ULN (or > 3 × baseline, if 
baseline abnormal) and/or ALT to > 3 × ULN (or > 3 × baseline, 
if baseline abnormal).  
For a first occurrence, Niraparib and Ganetspib shall be 
resumed at the same dose level when recovered to ≤ grade 1. 
For a second occurrence, Niraparib shall be resumed at a 
reduced dose and Ganetspib shall be resumed at the same 
dose. 
Grade 3* or 4 
Hyperbilirubinaemie 
Nirarparib and Ganetespib must be interrupted (for a maximum 
of up to 28 days). Patients who experience a grade  3 hepatic 
adverse event should have their liver enzymes and direct 
bilirubin checked initially within 24 hours and then every 24 to 
72 hours until clear signs of improvement, and then twice per 
week until they are stable or recovered to  grade 1.  
Ganetespib and Niraparib shall than be resumed at reduced 
dose level for a first occurrence.  Niraparib shall be 
discontinued permanently for a second occurrence. 
 
 
 
Withhold both drugs and monitor liver tests initially within 24 
hours and then every 24 to 72 hours until clear signs of 
improvement, and then at least weekly until liver test 
abnormalities resolve to Grade ≤ 1. 
 
Permanently discontinue both drugs. 


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Withhold both drugs and monitor liver tests initially within 24 
hours and then every 24 to 72 hours until clear signs of 
improvement, and then at least weekly until liver test 
abnormalities resolve to Grade ≤ 1. 
 
Permanently discontinue both drugs. 
 
*In case of ALT or AST > 3 × ULN AND bilirubin > 2 × ULN (suspected DILI) Niraparib 
and Ganetespib must be interrupted. The patient should be evaluated for the presence of 
confounding factors including malignant disease in the liver, coadministration of other 
suspect drugs, cholestasis, and viral or autoimmune hepatitis that could have caused the 
laboratory abnormalities. Other laboratory investigations of liver function such as 
international normalized ratio (INR) should be implemented as indicated. If no alternative 
cause is identified, Niraparib and Ganetespib must be permanently discontinued. Patients 
should be followed until all abnormalities have returned to normal, returned to baseline 
levels, or an alternative cause is found to explain the combination of the increased 
transaminases and total bilirubin.” 
 
 
Dose modification for Ganetespib-related gastrointestinal toxicity 
Table 30: Dose modification for Ganetespib-related gastrointestinal toxicity 
Finding 
Modification 
Grade 2 
Gastrointestinal toxicity 
Retreat with Ganetespib at same dose level 
Grade 3 
Gastrointestinal toxicity 
1st occurrence: 
hold dose; retreat with Gantespib 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. Loperamide). 
 
 


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Dose modification for Ganetespib-related QTc prolongation 
Table 31: Dose modification for Ganetespib related QTc prolongation 
Finding 
Modification 
Grade 2 
QTc prolongation  
Retreat with Ganetespib at same dose level 
Grade 3  
(> 500 ms on average of 
triplicate ECGs) 
or repeated grade 3 QTc 
prolongation 
or grade 4 QTc prolongation 
Discontinue Ganetespib treatment 
 
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  receiving 
Ganetespib. 
 
 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 transient secretory diarrhoea, limited to 24-48 hours following 
Ganetespib infusion.  
This AE is readily manageable by antidiarrheal medication (Loperamide). Prophylactic use of 
Loperamide can reduce the occurrence of diarrhoea to approximately 40%. 
 
In the EUDARIO prophylactic medication with Loperamide 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 
Loperamide.  


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Patients should take Loperamide 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,  
Loperamide 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, 
dehydration), i.v. 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. 
 
 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 19.6.4), 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 during maintenance therapy. It is permitted to omit 1 
cycle during Ganetespib maintenance therapy 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. 
 
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.  
 
 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. 


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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 %), anemia (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 (1.3 %; 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). 
 
Medications used with caution 
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. 
 
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 


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will be made by the investigator, taking into consideration the patient’s medical history and 
current QTc values. 
 
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 32.  
 
Table 32: 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 
 
 
 
 
 


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Breast Feeding 
Participants must not breast-feed while receiving protocol therapy and for 180 days following 
the last dose of protocol therapy 
 
Blood Donation 
Participants must not donate blood during the study or for 90 days after the last dose of 
protocol therapy. 
 
 Summary of known and potential risks of the study drug Niraparib 
The following adverse reactions (all CTCAE grades) have been reported in ≥ 20 % of patients 
who received Niraparib: anemia, thrombocytopenia, nausea, constipation, vomiting, fatigue, 
platelet count decreased, decreased appetite, headache, and insomnia. The median exposure 
to Niraparib in these patients was 250 days. 
 
The following adverse reactions and laboratory abnormalities have been identified in ≥ 10 to 
< 20 % of the 367 patients receiving Niraparib: neutropenia, palpitations, asthenia, neutrophil 
count decreased, dizziness, dysgeusia, dyspnea, cough and hypertension. The following 
adverse reactions and laboratory abnormalities have been identified in ≥ 1 to < 10 % of the 
367 patients receiving Niraparib: tachycardia, dry mouth, mucosal inflammation, white blood 
cell count decreased, aspartate aminotransferase increased, alanine aminotransferase 
increased and photosensitivity reaction 
 
Breast Feeding 
Participants must not breast-feed while receiving protocol therapy and for 180 days following 
the last dose of protocol therapy 
 
Blood Donation 
Participants must not donate blood during the study or for 90 days after the last dose of 
protocol therapy. 
 
 Summary of known and potential risks of non IMPs  
 Paclitaxel, Gemcitabin, Carboplatin  
Current information on the safety profile of Paclitaxel, Carboplatin and Gemcitabine 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.  
 


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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. 
 
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. 
 Study drug delivery & drug storage conditions 
The IMP Ganetespib will be provided by Aldeyra Therapeutics (Lexington, MA, USA) at no 
charge. Niraparib will be provided by TESARO (Waltham, MA, USA).  
Paclitaxel, Gemcitabine and Carboplatin are 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.  
 
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-
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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. 
 
The IMP Niraparib drug product is formulated as a dry blend of Niraparib tosylate 
monohydrate and lactose monohydrate lubricated with magnesium stearate. The active 
potency is 100 mg in size 0 purple/white hard gelatin capsule shell. 
 
Niraparib will be administered as a flat-fixed (100 mg, 200 mg or 300 mg), continuous daily 
dose. Niraparib should be swallowed whole and not opened, crushed or chewed. Food does 
not significantly affect the absorption of Niraparib; therefore, Niraparib may be taken without 
regard to meals. Participants should take doses at approximately the same times each day.  
Bedtime administration may be a potential method for managing nausea. 
Vomited doses should not be made up. 
If a participant misses a dose (greater than 12 hours from normal dosing time) of Niraparib, 
they should skip that dose and take their next dose at its regularly scheduled time. 
If Niraparib is dose reduced, participants should be instructed to continue using their current 
supply at their new dose until their supply has been exhausted.  
Participants must be instructed to return unused study drugs to the site at discontinuation or 
completion of treatment. The site personnel must ensure that the appropriate dose of each 
study drug is administered and that the drug accountability is performed and documented. 
 
Niraparib 100 mg capsules are packaged in a high-density polyethylene (HDPE) white bottle 
with a two-piece, pulp-backed, heat-induction-foil inner seal, tamper-evident cap. The label 
text of the study treatment will comply with Good Manufacturing Practice and national 
legislation to meet the requirements of the participating countries.  
All study treatment supplies must be stored in accordance with the Pharmacy Manual 
instructions and package labeling. Until dispensed to the patients, the study treatment will be 
stored in a securely locked area, accessible to authorized personnel only. 
All investigational study drug supplies in the US must be stored at 20 °C to 25 °C (68 °F to 
77 ° F); excursions are permitted between 15 °C to 30 °C (59 °F to 86 °F) (see US 
Pharmacopoeia [USP] Controlled Room Temperature) and investigation study drug supplies 
in the European Union (EU) must be stored below 30 °C. Refer to the Pharmacy Manual for 
further details. 
 
 
 
 
 


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 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. 
 
Participating sites will maintain records of the receipt, storage, and administration or 
dispensing of the study drugs, identifying (but not necessarily by name) each patient to whom 
the drug is administered or dispensed, with the patient details redacted so as to preserve the 
patient’s anonymity. Participating sites shall ensure that any shipment of study drugs is 
inspected upon receipt. Participating sites shall ensure that any notice of defect or non-
conformity is sent to the company providing the drugs within ten (10) days from receipt of the 
drugs. Latent defects which are detected later shall be immediately reported to the company 
providing the drugs for further processing within the company. Shipment of study drugs may 
be withheld at any time for failure to promptly respond to requests for production of the study 
drug records. Upon completion or termination of the study, participating sites shall follow the 
instructions of the company providing the study drugs regarding the return or disposal of all 
unused study drugs. Participating sites shall be responsible for compliance with all laws and 
regulations applicable to any destruction or disposal of study drugs at their participating site, if 
applicable. Participating sites will inform the company providing the study drug should the 
participating site determine that a recall of the study drug is required. 
 
Participating sites shall not use the study drugs except as specified in this protocol and shall 
return any unused study drug following completion of the study, giving account for any 
discrepancies and signing certificates of delivery and of returns. 
 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 anemia 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.  
• 
Other concomitant medications may be given as clinically indicated 
• 
A standard 3-5 day course of dexamethasone following the institutional 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 18.7). 
Not allowed are: 
 
Use of medications associated with a high incidence of QTc prolongation and known risk 
of TdP in subjects receiving Ganetespib should not be administered during the course of 
this trial 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  
 
Concurrent investigational agents of any type. 
 
Use of herbal remedies for cancer treatment. 
Chronic daily treatment with corticosteroids (dose >10 mg/day methylprednisolone equivalent), 
excluding inhaled steroids. 
 
Tumour necrosis factor-α inhibitors. 
 
Anti-T cell antibodies. 
 
19 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. 
 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 occurring at any time after the time of randomisation and/or treatment 
assignment, including baseline or washout periods, even if no study treatment has 
been administered. 
 
Abnormal laboratory tests (see section 19.6.4). 
 
Adverse events do not include:  
 
Pre-planned interventions/hospitalisations (see also section 19.2.1) 


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 
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.  
 
 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 outcomes 
listed above. 
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. Examples of such events are 
allergic bronchospasm, blood dyscrasias, or convulsions that may require intensive treatment 
in an emergency room or at home but do not result in hospitalization, development of drug 
dependency or drug abuse, and transmission of disease associated with the administration of 
the study drug. 
 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 


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 Treatment-Emergent Adverse Event (TEAE) 
Any event that was not present prior to the initiation of study treatment or any event already 
present that worsens in either intensity or frequency following exposure to study treatment. 
 Adverse Events of Special Interest 
Selected nonserious AEs and SAEs are also known as Adverse Events of Special Interest 
(AESI).  
 
Any AE (serious or non-serious) that is of scientific and medical concern specific to the study 
treatment, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is approproiate.  
 
AESI for Niraparib are the following: 
 
Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) 
 
Secondary cancers (new malignancies other than MDS or AML) 
 
Pneumonitis 
 
Embryo-fetal toxicity 
 
AESI should be collected and reported as follows: 
 
MDS and AML along with other secondary cancers should be reported to the Sponsor 
and TESARO upon awareness for any patient who has received niraparib (regardless 
of the timeframe since the last dose), throughout the Follow-up Assessment Period 
 
Pneumonitis should be reported to the Sponsor through 90 days after the last dose of 
study drug (or until the start of alternate anticancer therapy, whichever occurs first). 
 
Embryo-fetal toxicity should be reported as outlined in the pregnancy reporting section. 
 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.  
 
Per regulatory requirements, if an event is assessed by the Sponsor Institution as a Serious 
Unexpected Adverse Reaction (SUSAR), it is the responsibility of the Sponsor Institution to 
submit the SUSAR to the Regulatory Authorities according to applicable regulations. 
In addition, the SUSAR will be distributed to the Investigators/sites, utilizing a Council for 
International Organizations of Medical Sciences (CIOMS) report form, or the MedWatch 3500A 
form). The Investigator/site will submit a copy of the report to their respective Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and TESARO per the governing 
institutional requirements and in compliance with local laws and guidelines. 
 
 Pregnancy 
Any pregnancy that occurs during study participation must be reported to the KKS Marburg 
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 
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from the trial. KKS Marburg has the responsibility to monitor the outcome of all pregnancies 
reported during the clinical study. 
 
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. 
 
Each pregnancy must be reported by the Investigator to the KKS Marburg on an Initial 
Pregnancy Report Form within 24 hours of becoming aware of the pregnancy. Pregnancy is 
not an AE, and therefore does not need to be reported as an AE unless there is a suspicion 
that the study drug may have interfered with the effectiveness of a contraceptive medication. 
The Investigator must follow-up all pregnancies, document the course and the outcome, and 
report this information to KKS Marburg on a Pregnancy Outcome Report Form within 24 hours 
of becoming aware - even if the patient was withdrawn from the study or the study has finished. 
 
An elective abortion without complications should not be regarded as an AE, however, it should 
be reported as the outcome to the pregnancy on the Pregnancy Outcome Report Form. 
Therapeutic abortions should be reported as a treatment procedure; the reason for the 
therapeutic abortion should be reported on the Pregnancy Outcome Report Form and as an 
AE. Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy Outcome Report 
Form, reported as an SAE on the SAE Report Form (e.g., maternal serious complications, 
therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth 
defect) and reported to the KKS Marburg within 24 hours. Hospitalization for normal delivery 
of a healthy newborn should not be considered an SAE. 
 
All information, either initial or follow-up, received by KKS Marburg will be forwarded to the 
Sponsor and TESARO/Aldeyra Therapeutics. 
 
 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 v5.0 on a five-point scale (grade 1 to 5) and 
reported in detail on the eCRF. 
 
Please note that there is a distinction between serious and severe AEs: Severity is a measure 
of intensity whereas seriousness is defined by the criteria in Section 18.2. For example, a mild 
degree of gastrointestinal bleeding requiring an overnight hospitalization for monitoring 
purposes may be considered an SAE but is not necessarily severe.  
 
 


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Adverse events not listed in the CTCAE v5.0 should be graded as follows: 
 
Table 33 Grading AEs not listed in the CTCAE v5.0 
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 
 
 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). 
 
Otherwise answer NO (unlikely, probably not related or definitely not related). 
 


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 Expectedness 
The Sponsor will be responsible for determining whether an adverse event is ‘expected’ or 
‘unexpected’. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information provided in the Reference Safety Information 
of the effective Niraparib and Ganetespib Investigator Brochures (IB). 
 
 Collection and recording of adverse events 
 
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as, “How have 
you been feeling since your last study visit?” The Investigator will document the nature of AE, 
date of onset of the AE (and time, if known), date of outcome of the AE (and time, if known), 
severity of the AE, action taken with study drug as a result of the AE, assessment of the 
seriousness of the AE, and assessment of the causal relationship of the AE to study drug 
and/or study procedure. 
 
AEs, including laboratory abnormalities that are assessed as clinically significant or require 
intervention, should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be recorded as a separate AE. 
 
All SAEs will be collected from the signing of the ICF for this study through the Safety Follow-
up Visit described in Section 14.3 and reported accordingly. SAEs considered by the 
Investigator to be related to study medication are reported throughout the Follow-up 
Assessment Period.  
 
All AEs, regardless of the source of identification (e.g., physical examination, laboratory 
assessment, or reported by patient), will be documented for each patient from the time of 
randomisation and/or treatment assignment through the Safety Follow-up Visit described in 
Section 14.3.   
 
Concomitant illnesses that existed before entry into the study will not be considered AEs unless 
the illness worsens during the Treatment Period. Pre-existing conditions will be recorded as 
Medical History on any future SAE Report Forms. 
 
Disease progression is an efficacy criterion and is therefore not considered an AE or SAE 
(even if fatal). Disease progression should be documented. If AEs/SAEs occur in relation to 
disease progression that are not consistent with the natural progression of the patient’s 
disease, these AEs/SAEs must be reported per AE/SAE reporting requirements. 
 
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 19.1 for the definition of an AE. 
 


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 Follow-Up of Adverse Events 
All AEs experienced by a patient, regardless of the suspected causality, will be monitored until 
the AE or SAE has resolved, until any abnormal laboratory values have returned to baseline 
or normal levels, until stabilized with a satisfactory explanation for the changes observed, until 
the patient is lost to follow-up, or until the patient has died. 
 
If an Investigator becomes aware of an SAE after the specified follow up period and considers 
the SAE related to the study drug, the Investigator should report the SAE to the Sponsor 
according to timelines for reporting SAEs. 
 
 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. 
 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. 
 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. 
 
Clinically significant in the investigator’s judgment. 


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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. 
 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. 
 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 (recovered/resolved, recovering/resolving, not recovered/not resolved, 
recovered/resolved with sequelae, unkown, fatal) 
 
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. 
 
Pregnancies. 


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 
Adverse Events of Special Interest (AESIs, see Section 18.2.3). 
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, but is not limited to, 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. 
 
 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. All SAEs and AESIs must be reported to the KKS Marburg within 24 
hours of becoming aware of the initial SAE/AESI or any follow-up information regarding the 
SAE/AESI. 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: age, height, weight 
 
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, KKS Marburg 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 
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SUSARs will be reported to the required regulatory authorities, investigators and ethical 
committees in compliance with all reporting requirements according to local regulations and 
good clinical practice by the sponsor and/or its designees. Additionally, CIOMS reports will be 
immediately forwarded to Aldeyra and TESARO, the IDMC, the sponsor and the coordinating 
investigator. 
 
On a quarterly basis, KKS Marburg will create line listings of all serious adverse events, which 
will be distributed to the Sponsor, IDMC, coordinating investigator, TESARO, Aldeyra 
Therapeutics. On at least an annual basis, KKS Marburg will prepare the Development Safety 
Update Report (DSUR) which will be distributed to the Sponsor, TESARO and Aldeyra, the 
IDMC and the coordinating investigator. The Sponsor will forward this document to the NTGs 
for submission to the local Ethic committees.  
 
For detailed reporting procedures please refer to the SAE reporting manual. 
 
 Reporting to TESARO and Aldeyra Therapeutics 
The Investigator must report all SAEs, and all follow up information to KKS Marburg on an SAE 
Report Form within 24 hours of becoming aware of the initial event or follow-up information. 
KKS Marburg will relay this SAE information to TESARO and Aldeyra Therapeutics within one 
business day and no more than three calendar days after receiving the SAE Report Form. 
 
The Investigator must provide a causality assessment and must sign and date all SAE Report 
Forms. 
 
It is the responsibility of the Investigator to review source documentation and describe pertinent 
information on the SAE Report Form. If supporting documentation is requested (e.g., hospital 
reports, consultant reports, death certificates, autopsy reports, etc.), the Investigator should 
highlight all relevant and pertinent information within such documents, ensure that any patient’s 
personal identifiers (including Medical Record number) are removed, and submit the 
documents with the SAE Form to KKS Marburg, which will forward all documents to TESARO 
and Aldeyra Therapeutics 
 
After receipt of the initial report, KKS Marburg will review the information and, if necessary, 
contact the Investigator to obtain further information. The Investigator must respond within 24 
hours in urgent cases and within 72 hours in all other cases to queries from KKS Marburg. All 
additional information retrieved will be forwarded by KKS Marburg to TESARO and Aldeyra 
Therapeutics. 
 
KKS Marburg SAE, Pregnancy and AESI Reporting Information 
KKS Marburg 
Fax-No.: +49 6421 28 66 559 
 
 
The information forwarded by KKS Marburg to TESARO and Aldeyra Therapeutics will be 
acknowledged according to their standard practice: 


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The practice of TESARO and Aldeyra Therapeutics is to acknowledge receipt of all safety 
information with 72 hours. KKS Marburg should resend any materials that are not 
acknowledged within this time period. 
 
 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. 
 
 Handling of safety parameters 
 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. 
 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. 
 
 Special Situations: Abuse, Misuse, Medication Errors, Overdose, and 
Accidental or Occupational Exposure 
 
 
Abuse:  is the persistent or sporadic, intentional excessive use of the study treatment 
which is accompanied by harmful physical or psychological effects.  
 
Misuse: medicinal product is intentionally and inappropriately used not in accordance 
with the authorized/approved product information. 


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 
Medication error:  is any preventable incident that may cause or lead to inappropriate 
study treatment use or patient harm while the study treatment is in the control of the 
health care professionals or patients. Such incident may be due to health care 
professional practice, product labeling, packaging and preparation, procedures for 
administration, and systems, including the following: prescribing, order communication, 
nomenclature, compounding, dispensing, distribution, administration, education, 
monitoring, and use. 
 
Overdose:  is a deliberate or accidental administration of study treatment to a study 
patient, at a dose greater than that which was assigned to that patient per the study 
protocol and under the direction of the Investigator.  If an overdose occurs, the 
Investigator and the Sponsor should be notified immediately, and the patient should be 
observed closely for AEs. Associated AEs should be treated and monitored by the 
Investigator. The dosage of study drug administered, any associated AEs, and/or 
treatment provided to the patient because of the overdose, should be documented on 
the applicable sections within the eCRF. An overdose (including an AE or SAE resulting 
from the overdose, if any) will be reported as an SAE. 
 
Accidental /Occupational exposure:  is the unintentional exposure to a study 
treatment as a result of one’s professional or non-professional occupation, or 
accidental exposure to a non-professional to whom exposure was not intended (i.e., 
study product given to wrong patient).  
 
Reporting Special Situations:  All occurrences of abuse, misuse, medication error, overdose, 
and accidental or occupational exposure with any study treatment must be reported on an SAE 
Report Form [or designated Special Form] to the Sponsor regardless of whether or not an AE 
or SAE has occurred. If the abuse, misuse, medication error, overdose, or accidental / 
occupational exposure is associated with an SAE, an SAE report form must be submitted to 
the Sponsor within 24 hours of awareness. If there is no AE or SAE, the occurrence must be 
submitted on the designated Special Form (indicate ‘no AE has occurred’) as soon as possible. 
 
 Reporting Product Complaints for Niraparib 
 
Any written, electronic or oral communication that alleges dissatisfaction related to 
manufactured clinical drug product with regards to its manufacturing, testing, labeling, 
packaging, or shipping, must be reported by the sponsor-investigator or qualified designee to 
TESARO Call Center: (EU Call Center: Tesaro@EU.ProPharmaGroup.com) within 1 working 
day of first becoming aware of the possible defect.  This report to TESARO may also be made 
by telephone to the designated TESARO representative (1-844-4TESARO) or by fax to the 
Call Center (EU Call Center: +44 (0) 1748 828801).  The product and packaging components 
in question, if available, must be stored in a secure area under specified storage conditions 
until it is determined whether the product is required to be returned for investigation of the 
defect.  If the product complaint is associated with an SAE, the SAE must be reported 
separately in accordance with the protocol, and the SAE report should mention the product 
quality complaint. 
 
 


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20 DOCUMENTATION AND DATA MANAGEMENT 
 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. 
 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. 
 
 Independent Data and Monitoring committee (IDMC) 
The IDMC 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 
IDMC for assessment. All SAEs will be forwarded to the IDMC immediately after knowledge of 
it. The IDMC can, if required, suggest to amend the protocol and in case the risk to the patients 
outweighs the potential benefit, suggest to end the study prematurely. 
The IDMC 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. Pre-
defined timepoints of safety evaluation by IDMC are after 6 and 12 patients, respectively, have 
received one cycle of Ganetespib plus Carboplatin treatment (in arms B and C; without 
recruitment stop), after 6 and 12 patients, respectively, have received one cycle of Ganetespib 
plus Nirarparib treatment (maintenance treatment in arm C; with stop of entering maintenance 
treatment for new patients in arm C until positive safety evaluation by IDMC). 
To allow for close follow-up of the trial by the IDMC they will also be provided on a continuous 
basis with the CIOMS reports for all SUSARs, the SAE line listings on a quarterly basis and 
the DSUR on a yearly basis. 


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 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. 
 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. 
 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. 
 
At mutually agreeable times, investigator will give an independent auditor (at TESARO‘s and/or 
Aldeyra‘s sole expense) access to all records and documentation (however stored) relating to 
the study or to the care of study subjects in order to determine whether the evaluated study 
related activities were conducted, and the data were recorded, analyzed and accurately 
reported according to this protocol, Good Clinical Practices (GCP), and the applicable 
regulatory requirement (s). 
 
 Reporting and publications  
 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). 
 


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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 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. 
 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 (KULeuven/BGOG, Nicole Concin) prior to submission. 
The rights of the investigator and of the KULeuven/BGOG with regard to publication and 
dissemination of the results of this trial are described in the Consortium Agreement.  
 
Any publication shall be subject to prior review by Aldeyra and TESARO. A copy of any 
proposed disclosure, including any publication, abstract, oral presentation, or poster that 
reports all or parts (interim or final) of the results of the study or study progress, is given to 
TESARO and Aldeyra for review at least thirty (30) days prior to the date of submission for 
publication (including abstracts) or of public disclosure; if required by TESARO or Aldeyra, any 
reference to TESARO‘s and/or Aldeyra‘s confidential information is deleted; and if an Invention 
(as defined hereunder) is contained in the disclosure, investigator shall defer publication or 
disclosure for up to an additional sixty (60) days from the time TESARO and/or Aldeyra notifies 
investigator that TESARO and/or Aldeyra desires patent application(s) to be filed on the 
Invention. 
 
21 ETHICAL AND LEGAL ASPECTS 
 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 
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 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. 
 
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, investigator, or a supporter 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. 
 
 Insurance 
In accordance with the Belgian Law relating to experiments on human persons dated May 7th, 
2004, sponsor shall be liable, even without fault, for any damages incurred by a trial participant 
and linked directly or indirectly to the participation to the trial, and shall provide compensation 
therefore through its insurance. 
The terms or the amount of cover of any insurance shall not relieve the sponsor of any liabilities 
under the clinical trial agreement. 
If an insurance coverage is required by local laws of participating site outside Belgium, the 
participating site shall have and maintain in full force and effect during the term of the trial 
(and following termination of the trial to cover any claims arising from the trial) adequate 
insurance coverage for possible damages linked directly or indirectly to the patients’ 
participation to the trial at participating site. 


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 Study Data 
Any inventions, methods, developments, and discoveries, whether patentable or not, relating 
to or arising from the study or made in the performance of work under the study (“Inventions”) 
shall vest in the sponsor. The participating site, its employees and investigator(s) shall promptly 
disclose to sponsor any such Inventions. 
 
Any and all study data as collected and prepared in the context of the study shall be the 
property of the sponsor. The sponsor hereby grants to the participating site a right to use the 
study data for educational purposes and patient care and in accordance with the obtained ICF. 
 
Participating site expressly agrees that notwithstanding anything herein to the contrary, any 
inventions, discoveries or innovations, whether patentable or not, shall be the property of 
sponsor in case the inventions, discoveries or innovations, whether patentable or not, are 
related to the study.  Raw data such as medical records of study subjects shall be and remain 
the sole property of the participating site. 
 Collection of investigator’s personal data 
Both prior to and during the conduct of the study, the investigator and study personnel of each 
participating site may provide Tesaro and/or Aldeyra and/or their respective designees with 
their personal data (as that term is defined under applicable law) (the “Personal Data”).  The 
processing (including use, disclosure and/or transfer) of his/her Personal Data by Tesaro, 
Tesaro‘s designee(s), Aldeyra, Aldeyra‘s designee(s) and each of their respective agents and 
affiliates as well as all governmental and  regulatory agencies (of any jurisdiction) shall be done 
for the following purposes (the “Purposes”): (a) TESARO and ALDEYRA’s respective exercise 
of rights and performance of obligations under the Investigator-Initiated Research Agreement 
between UZ Leuven and TESARO and ALDEYRA; (b) review by governmental or regulatory 
agencies; and (c) satisfying legal or regulatory requirements. The Personal Data may also be 
transferred abroad for the Purposes, even if such Personal Data is transferred to countries that 
do not ensure an equivalent level of protection as in the country where the study is taking 
place, including to the United States of America (U.S.A.). The processing of the Personal Data 
shall be lawful under article 6, subparagraph (b), (c) and (f) of the Regulation (EU) 2016/679 
(General Data Protection Regulation (GDPR)). 
 
 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 64th WMA General Assembly, Fortaleza, 
Brasil, 2013) 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 (November 2016).  
 
 


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22 REFERENCES 
1.  Sant M, et al. (2015) Survival of women with cancers of breast and genital organs in Europe 1999-
2007: Results of the EUROCARE-5 study. Eur J Cancer Oxf Engl 1990 51(15):2191–2205. 
2.  Perren TJ, et al. (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 
365(26):2484–2496. 
3.  Pujade-Lauraine E, et al. (2017) Olaparib tablets as maintenance therapy in patients with platinum-
sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, 
randomised, placebo-controlled, phase 3 trial. Lancet Oncol. doi:10.1016/S1470-2045(17)30469-
2. 
4.  Mirza MR, et al. (2016) Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian 
Cancer. N Engl J Med 375(22):2154–2164. 
5.  Kramer D, et al. (2017) Strong antitumor synergy between DNA crosslinking and HSP90 inhibition 
causes massive premitotic DNA fragmentation in ovarian cancer cells. Cell Death Differ 24(2):300–
316. 
6.  Jaber S, Toufektchan E, Lejour V, Bardot B, Toledo F (2016) p53 downregulates the Fanconi 
anaemia DNA repair pathway. Nat Commun 7:11091. 
7.  Stecklein SR, et al. (2012) BRCA1 and HSP90 cooperate in homologous and non-homologous DNA 
double-strand-break repair and G2/M checkpoint activation. Proc Natl Acad Sci U S A 
109(34):13650–13655. 
8.  Johnson N, et al. (2013) Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum 
resistance. Proc Natl Acad Sci U S A 110(42):17041–17046. 
9.  Shih I, Kurman RJ (2004) Ovarian tumorigenesis: a proposed model based on morphological and 
molecular genetic analysis. AmJPathol 164(0002–9440 (Print)):1511–1518. 
10.  Shih I, Kurman RJ (2005) Molecular pathogenesis of ovarian borderline tumors: new insights and 
old challenges. ClinCancer Res 11(1078–0432 (Print)):7273–7279. 
11.  Ahmed AA, et al. (2010) Driver mutations in TP53 are ubiquitous in high grade serous carcinoma 
of the ovary. JPathol 221(1096–9896 (Electronic)):49–56. 
12.  Integrated 
genomic 
analyses 
of 
ovarian 
carcinoma 
(2011) 
Nature 
474(1476–4687 
(Electronic)):609–615. 
13.  Wu R, et al. (2007) Mouse model of human ovarian endometrioid adenocarcinoma based on 
somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways. Cancer Cell 11(1535–
6108 (Print)):321–333. 
14.  Li D, et al. (2011) Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant 
stabilization of mutant p53 in human cancer cells. MolCancer Res 9(1557–3125 (Electronic)):577–
588. 
15.  Li D, Marchenko ND, Moll UM (2011) SAHA shows preferential cytotoxicity in mutant p53 cancer 
cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell 
DeathDiffer 18(1476–5403 (Electronic)):1904–1913. 


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16.  Zhou D, Liu Y, Ye J, Ying W, Ogawa LS, Inoue T, Tatsuta N, Wada Y, Koya K, Huang Q, Bates RC, 
Sonderfan AJ. (2013) A rat retinal damage model predicts for potential clinical visual disturbances 
induces by Hsp90 inhibitors. Toxicol Appl Pharmacol. 273(2):401-9.  
17.  Zhou D, Teofilovici F Liu Y, et al. (2012) Associating retinal drug exposure and retention with the 
ocular toxicity profiles of Hsp90 inhibitors. J Clin Oncol. 30 (suppl;abstr 3086). 
18.  Cysyk R, Parker R, Barchi J Jr, Steeg P, Hartman N, Strong J. (2006) Reaction of geldanamycin and 
C17-substituted analogues with glutathione: product identifications and pharmacologiscal 
implications. Chem Res Toxicol 19(3):376-81). 
19.  Giesinger JM, et al. (2016) Replication and validation of higher order models demonstrated that a 
summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol 69:79–88. 
20.  Bonnetain F, et al. (2010) Time until definitive quality of life score deterioration as a means of 
longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma. 
Eur J Cancer Oxf Engl 1990 46(15):2753–2762. 
21.  Oken MM, et al. (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5(6):649–655. 
22.  Eisenhauer EA, et al. (2009) New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer Oxf Engl 1990 45(2):228–247. 
 


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23 APPENDICES 
Appendix A – 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. (21)  
Also see: http://www.ecog.org/general/perf_stat.html (last accessed: 05.09.2013) 
 
 
 
 


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Appendix B – CTCAE (version 5.0) 
 
The NCI Common Terminology Criteria for Adverse Events version 5.0, instituted 
27Nov2017, is available at:  
https://www.eortc.be/services/doc/ctc/CTCAE_v5_Quick_Reference_5x7.pdf  
 
 
 
 


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


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Appendix D – Tumour assessment (RECIST) 1.1 (Eisenhauer et al. 2009 (22)) 
 
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 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 


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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 four lesions 
respectively will be recorded). 


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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. 
 
Evaluation of best overall response 
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 


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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. (20) 
 
 


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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 16 December 2017. 
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 
not be administered during the course of the trial. 
 
Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Route 
Amiodarone 
Cordarone®, 
Pacerone®, Nexterone® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral, 
injection 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiesteras
e 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, many 
others 
oral, 
injection, 
suppository 
Cilostazol 
Pletal® 
Phospodiesterase 
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 oral, nasal 
Disopyramide 
Norpace® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral, 
injection 
Dofetilide 
 Tikosyn® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 
Domperidone 
Motilium®, Motillium®, 
Motinorm Costi®, 
Nomit® 
Anti-nausea 
Nausea, vomiting 
oral, 
injection, 
suppository 


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Donepezil 
Aricept® 
Cholinesterase 
inhibitor 
Dementia 
(Alzheimer’s 
disease) 
oral 
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®, 
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 
Ibogaine 
None 
Psychedelic 
Narcotic addiction, 
unproven 
oral 
Ibutilide 
Corvert® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
injection 
Levofloxacin 
Levaquin®, Tavanic® 
Antibiotic 
Bacterial Infection 
oral, 
injection 
Levomepromazi
ne 
Nosnan®, Nozinan®, 
Levoprome® 
Antipsychotic 
Schizophrenia 
oral, 
injection 


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Levomethadyl  Orlaam® 
Opiate 
Pain control, 
narcotic 
dependence 
oral 
Levosulpride 
Lesuride®, Levazeo®, 
Enliva® (with 
rabeprazole) 
Antipsychotic 
Schizophrenia 
Oral, 
injection 
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 
Ondansetron 
Zofran®, Anset®, 
Ondemet®, Zuplenz®, 
Emetron®, Ondavell®, 
Emeset®, Ondisolv®, 
Setronax® 
Anti-emetic 
Nausea, vomiting 
oral, 
injection, 
suppository 
Oxaliplatin 
Eloxatin® 
Antineoplastic 
Agent 
Cancer 
injection 
Papaverine HCl none 
Vasodilator, 
Coronary 
Diagnostic adjunct injection 
Pentamidine 
Pentam® 
Antibiotic 
Pneumocystis 
pneumonia 
Injection, 
inhaled 
Pimozide 
Orap® 
Anti-psychotic 
Tourette's tics 
oral 
Probucol * 
Lorelco® 
Antilipemic 
Hypercholesterole
mia 
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 
Roxithromycin Rulide®, Xthrocin®, 
Roxl-150®, Roxo®, 
Surlid®, Rulide®, 
Biaxsig®, Roxar®, 
Roximycinv®, 
Roxomycin®, Rulid®, 
Tirabicin®, Coroxin® 
Antibiotic 
Bacterial infection oral 
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, inhaled 


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Sultopride 
Barnetil®, Barnotil®, 
Topral® 
Antipsychotic, 
atypical 
Schizophrenia 
oral, 
injection 
Terfenadine * 
Seldane® 
Antihistamine 
Allergic rhinitis 
oral 
Terlipressin 
Teripress®, 
Glypressin®, Terlipin®, 
Remestyp®, Tresil®, 
Teriss® and others 
Vasoconstrictor 
Septic shock 
injection 
Terodiline 
Micturin®, Mictrol® (non 
bethanechol) 
Muscle relaxant 
Bladder spasm 
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 16 December 2017. 
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 
oral, 
injection 
Aripiprazole 
Abilify®, Aripiprex® 
Anti-psychotic, 
atypical 
Schizophrenia, Adjunct 
for Depression 
oral, 
injection 
Artenimol + 
piperaquine 
Eurartesim® 
Animalarial 
Malaria 
oral 
Asenapine 
Saphris®, Syscrest® 
Antipsychotics, 
atypical 
Schizophrenia 
sublingual 
Atazanavir 
Reyataz® 
Anti-viral 
HIV/AIDS 
oral 
Atomoxetine 
Strattera® 
Norepinephrine 
reuptake inhibitor 
ADHD 
oral 
Bedaquiline 
Sirturo® 
Antibiotic 
Tuberculosis, drug 
resistant 
oral 
Bendamustine 
Treanda®, 
Treakisym®, 
Ribomustin®, Levact® 
Alkylating agent 
Leukemia, lymphoma 
injection 
Benperidol 
Anquil®, Glianimon® 
Anti-psychotic 
Antipsychotic 
oral 
Betrixaban 
Bevyxxa® 
Anticoagulant 
Anticoagulant 
oral 
Bortezomib 
Velcade®, Bortecad® 
Proteasome 
inhibitor 
Multiple 
Myeloma,lymphoma 
injection 
Bosutinib 
Bosulif® 
Tyrosine kinase 
inhibitor 
Leukemia 
oral 
Buprenorphine 
Butrans®, Belbuca®, 
Bunavail®, Buprenex® 
Opioid receptor 
modulator 
Narcotic addiction and 
pain 
Sublingual, 
topical, 
injection 
Cabozantinib 
Cometriq® 
Anti-cancer 
Renal cell carcinoma 
oral 
Capecitabine 
Xeloda® 
Anti-cancer 
Cancer (GI, Breast) 
oral 
Ceritinib 
Zykadia® 
Kinase Inhibitor 
Cancer (Lung) 
oral 
Clofazimine 
Lamprene® 
Antimycobacterial 
Leprosy 
oral 
Clomipramine 
Anafranil® 
Antidepressant, 
Tricyclic 
Depression 
oral, 
injection 


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Clozapine 
Clozaril®, Fazaclo®, 
Versacloz® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral 
Crizotinib 
Xalkori® 
Kinase inhibitor 
Anti-cancer 
oral 
Cyamemazine 
Tercian® 
Antipsychotic 
Schizophrenia, 
sedation 
oral, 
injection 
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 
Deutetrabenazine 
Austedo® 
Vesicular 
monamine 
transporter 2 
inhibitor 
Chorea (Huntington’s 
disease) 
oral 
Dexmedetomidine 
Precedex®,  Dexdor®,  
Dexdomitor® 
Sedative 
Sedation 
injection 
Dolasetron 
Anzemet® 
Anti-nausea 
Nausea, vomiting 
oral, 
injection 
Efavirenz 
Sustiva® and others 
Antiretroviral 
HIV 
oral 
Eliglustat 
Cerdelga® 
Glucosylceramide 
synthase inhibitor 
Gaucher’s disease 
oral 
Epirubicin 
Ellence®, 
Pharmorubicin®, 
Epirubicin Ebewe® 
Anti-cancer 
Cancer 
injection 
Eribulin mesylate 
Halaven® 
Anti-cancer 
Metastatic breast 
neoplasias 
injection 
Ezogabine 
(Retigabine) 
Potiga®, trobalt® 
Anticonvulsant 
Seizures, Partial 
oral 
 
 
 
 
 
Felbamate 
Felbatol® 
Anti-convulsant 
Seizure 
oral 
Fingolimod 
Gilenya® 
Sphingosine 
phospate 
receptor 
modulator 
Multiple Sclerosis 
oral 
Fluorouracil (5-FU) 
Adrucil®, Carac®, 
Efudex®, Efudix®, 
others 
Anticancer 
Cancer 
injection 
Flupentixol 
Depixol®, Fluanxol® 
Dopamine 2 and 
5HT2a antagonist 
Schizophrenia 
oral, 
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, 
suppository 
Iloperidone 
Fanapt®, Fanapta®, 
Zomaril® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral, 
injection 
Imipramine 
(melipramine) 
Tofranil® 
Antidepressant, 
Tricyclic 
Depression 
oral 


EUDARIO 
 
 
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Inotuzumab 
ozogamicin 
Besponsa® 
Antineoplastic 
agent 
Acute Lymphocytic 
Leukemia 
injection 
Isradipine 
Dynacirc® 
Anti-hypertensive 
High blood pressure 
oral 
Ketanserin 
Sufrexal® 
Antihypertensive 
Hypertension 
oral 
Lapatinib 
Tykerb®, Tyverb® 
Anti-cancer 
Breast cancer, 
metastatic 
oral 
Levantinib 
Lenvima® 
Anticancer 
Cancer 
oral 
Lithium 
Eskalith®, Lithobid® 
Anti-mania 
Bipolar disorder 
oral, 
injection 
Lopinavir and 
ritonavir 
Kaletra®, Lithobid® 
Viral protease 
inhibitor 
HIV/AIDS 
oral 
Melperone 
Bunil®, Buronil®, 
Eunerpan® 
Antipsychotic, 
atypical 
Schizophrenia 
oral, 
injection 
Midostaurin 
Rydapt® 
Anti-cancer 
Acute myeloid 
leukemia 
oral 
Mifepristone 
Korlym®, Mifeprex® 
Progesterone 
antagonist 
Pregnancy 
Termination 
oral 
Mirabegron 
Myrbetriq® 
Beta3 adrenergic 
antagonist 
Overactive bladder 
oral 
Mirtazapine 
Remeron 
Anti-depressant, 
Tetracyclic 
Depression 
oral 
Moexipril/HCTZ 
Uniretic®, Univasc® 
Anti-hypertensive 
High blood pressure 
oral 
Necitumumab 
Potrazza® 
Antipcancer 
Lung cancer 
injection 
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 
Nusinersen 
Spinraza® 
Antisense 
oligonucleotide 
Spinal muscular 
atrophy 
injection 
Ofloxacin 
Floxin® 
Antibiotic 
Bacterial infection 
oral, 
injection 
Osimertinib 
Tagrisso® 
Tyrosine kinase 
inhibitor 
Cancer 
oral 
Olanzapine 
Zyprexa®, Zydis®, 
Relprevv® 
Anti-psychotic, 
atypical 
Schizophrenia, bipolar 
oral, 
injection 
Oxytocin 
Pitocin®, Syntocinon® 
Oxytocic 
Labor stimulation 
injection 
Paliperidone 
Invega®, Xepilon® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral, 
injection 
Palonosetron 
Aloxi® 
Antiemetic 
Nausea 
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 
Perphenazine 
trilafon®, 
Etrafon/Triavil, 
Decentan® 
Antipsychotic 
Schizophrenia 
oral, 
injection 


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Pilsicainide 
Sunrythm® 
Anti-arrhythmic 
Arrhythmia 
oral, 
injection 
Pimavanserin 
Nuplzaid® 
Antipsychotic, 
atypical 
Psychosis, Parkinson’s 
disease 
oral 
Pipamperone  
Dipiperon (E.U) 
Antipsychotic 
Schizophrenia 
oral 
Primaquine 
phosphate 
 
Anti-malarial 
Malaria 
oral 
Promethazine 
Phenergan® 
Anti-psychotic / 
Anti-emetic 
Nausea 
oral, 
injection, 
suppository 
Prothipendyl 
Dominal®, 
Largophren®, 
Timoval®, Timovan®, 
Tumovan® 
Antipsychotic 
Schizophrenia 
oral, 
injection 
Ribociclib 
Kisqali® 
Cyclin dependent 
kinase inhibitor 
Breast cancer 
oral 
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 
 
 
 
 
 
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® 
Immunosuppress
ant 
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 
Tiapride 
Tiapridal®, Italprid®, 
Sereprile®, Tialaread®, 
Tiaryl®, Tiaprim®, 
Tiaprizal®, Sereprid®, 
Tiapridex® 
Selective D2, D3 
dopamine 
antagonist 
Alcoholism, withdrawal 
oral, 
injection 
Tipiracil and 
Trifluridine 
Lonsurf® 
Anti-cancer 
Metastatic colorectal 
cancer 
oral 
Tizanidine 
Zanaflex®, Sirdalud® 
Muscle relaxant 
Spasticity 
oral 
Tolterodine 
Detrol®, Detrusitol® 
Muscle relaxant 
Bladder spasm 
oral 
Toremifene 
Fareston® 
Estrogen 
agonist/antagonis
t 
Anti-cancer 
oral 
Trimipramine 
Surmontil®, 
Rhotrimine®, Stangyl® 
Antidepressant, 
Tricyclic 
Depression 
oral 
Tropisetron 
Navoban®, Setrovel® 
Antiemetic 
Nausea, vomiting 
oral, 
injection 


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Valbenazine 
Ingrezza® 
Vesicular 
monamine 
transporter 2 
inhibitor 
Tardive dyskinesia 
oral 
Vardenafil 
Levitra® 
Phosphodiesteras
e inhibitor 
Vasodilator 
oral 
Vemurafenib 
Zelboraf® 
Kinase inhibitor 
Anti-cancer 
oral 
Venlafaxine 
Effexor®, Efexor® 
Anti-depressant, 
SNRI 
Depression 
oral 
Vorinostat 
Zolinza® 
Anti-cancer 
Lymphoma 
oral 
Zotepine 
Losizopilon®, 
Lodopin®, Setous® 
and Zoleptil® 
Antipsychotic, 
atypical 
Schizophrenia 
oral 
 
 
 


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Appendix H – Unpublished data of preclinical data: Combination of Ganetespib with 
PARP-inhibitor Niraparib 
 
To assay for a possible cooperation of Ganetespib with PARP inhibitors, we treated cells 
derived from ovarian cancer with Ganetespib and Olaparib, alone or in combination. In these 
assays, the cells were seeded as follows in 6-well plates: per well, we seeded 25000 Ovcar5 
cells, 40000 Ovcar3 cells, 60000 Kuramochi cells, and 60000 Cov362 cells. Ovcar5 and 
Cov362 cells were cultured in DMEM, Ovcar3 and Kuramochi cells were cultured in RPMI , 
each with 10% FCS and antibiotics 
 
The following drug concentrations were used. 
- 
Ovcar3:   
10 µM Olaparib, 30 nM Ganetespib 
- 
Ovcar5 :  
10 µM Olaparib, 12 nM Ganetespib 
- 
Cov362:  
6 µM Olaparib, 50 nM Ganetespib 
- 
Kuramochi:  10 µM Olaparib, 40 nM Ganetespib 
The cells were first incubated with Olaparib for 24 h, and then with Olaparib and Ganetespib 
simultaneously for an additional 48 h. In controls, either or both of the drugs were omitted and 
replaced by the DMSO solvent. The cells were then analyzed by visual inspection (Figure 5). 
In the cells treated by the drug combinations, we observed extensive morphological changes 
that were at least compatible with cell death. This was not observed to the same extent with 
single drugs or control treatment. 
 
 
Figure 5: Combination of Ganetespib and Olaparib synergize in OvCa cells 
Subsequently, the accumulation of phospho-H2AX, a marker of DNA damage and cell death, 
was evaluated by immunoblot analysis (Figure 6). Here again, the combination yielded a far 
stronger accumulation of the Phosphoprotein than the single treatments. 


EUDARIO 
 
 
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Figure 6: Combination treatment with Ganetespib and Olaparib leads to accumulation of DNA damage 
Finally, we investigated the appearance of cell death by a combined staining with annexin V 
(binding phosphatidylserine to indicate apoptose) and 7AAD to indicated death-induced 
membrane permeability (Figure 7). Again, the drug combination strongly increased the 
appearance of dead cells, mostly by apoptosis, and to a markedly greater extent than the 
single drugs. 
 
Figure 7: Combination treatment with Ganetespib and Olaparib leads to increased induction of 
apoptosis 
In addition, we evaluated the accumulation of phospho- (gamma) H2AX by quantitative 
immunofluorescence, obtaining comparable results as by immunoblot analysis (Figure 8, cf. 
Figure 6) 


EUDARIO 
 
 
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Figure 8: IF-Analysis, gammaH2AX, 96 well format 
All these results indicate a cooperation between Olaparib and Ganetespib in cell killing. 
Correspondingly, we and others have previously observed that BRCA1 levels depend on 
HSP90 activity, suggesting that Ganetespib, through decreasing BRCA1 stability, might 
sensitize the cells towards Olaparib (much like BRCA1 mutations). Regardless of the 
mechanism, however, the data are indicative of drug cooperation.