Conditions: Endometrial Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 511
Healthy volunteers: no

Brief summary:
Open-label, randomized, active-controlled, two-arm Phase III study to compare the efficacy and safety of AEZS-108 and doxorubicin.

Detailed description:
The study will include about 500 patients with endometrial cancer resistant to platinum/taxane-based chemotherapy.

Arms:
arm 1: 267 mg/m\^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles arm 2: 60 mg/m\^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles

Interventions: intervention 1: AEZS-108 / zoptarelin doxorubicin intervention 2: doxorubicin
Intervention descriptions: intervention 1: 267 mg/m\^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles intervention 2: 60 mg/m\^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles

Protocol document:
Prot_001.pdf: 
 
 
 
 
 
 
Clinical Trial Protocol 
 
 
Clinical Trial No. 
 
 
AEZS-108-050 
Clinical Phase III 
Type of Study Therapeutic confirmatory 
Title Randomized controlled study comparing AEZS-108 
with doxorubicin as second line therapy for locally 
advanced, recurrent or metastatic endometrial 
cancer 
Design Open-label, randomized, active-controlled, multicenter trial 
Versions No. 3.2: 12 September 2014 
No. 3.1: 12 March 2014 
No. 3.0: 20 November 2013 
No. 2.0: 11 July 2013 
No. 1.2.1: 29 April 2013 
No. 1.2: 13 March 2013 
No. 1.1: 19 December 2012 
EudraCT No. 2012-005546-38
 
 
Sponsor  Aeterna Zentaris GmbH 
Weismüllerstraße 50 
D-60314 Frankfurt am Main 
Germany 
 
 
 
Confidential 
This document contains confidential information of Aeterna Zentaris that must not be 
disclosed to anyone other than the recipient investigator(s) and members of the ethics 
committee.  This information should not be used for any purpose other than the 
evaluation or conduct of the clinical investigation without prior written consent of 
Aeterna Zentaris. 
No part of this document may be reproduced or stored in a retrieval system or 
transmitted in any other form or by any other means. 


 
 
 
 
 
 
 
 
 
J\ctcrnn Zcntaris 
Clmlidcnlial 
 
PROTOCOL AUTHORIZATION 
St11dy l'rotocol /\ l·'.ZS- 1OX-050 
Version 3 .2 / 12 Scp 2014 
Titlc 
Ran<lomizcd controllcd study com pa1fog AEZS-108 wi th 
doxoru bid n as second line thcrapy for locally advanccd, 
rccurrcnt or mctastatic  cndomctria)  cancer 
Opcn-labcl, randomizcd, activc-controlJed,  multicenter  trial 
 
Study  nmn bcr 
A EZS-108-050 
Version No./ Date    Vers ion 3.2 /  12 September 201 4 
 
Coordinating 
invcstigator 
(ovcra ll C.1.) 
David Scott Miller, M .D., 
F.A.C.O.G., F.A .C.S. 
Dircctor and Dallas Found ation 
Chair i n Gyneco logic Oncology 
Pro fcssor of Obstctrics & 
Gynccology 
Frcd  F. Florcncc Bioinform at ion 
Center,  #E6.102 
UT Southwcstern Mcdical Center 
5323 Harry Hincs Blvd. 
Dallas, TX 75390, U.S.A. 
Phonc 214-648-3026 
e-m a il  David.Mi llcr@UTSouthwcstern.edu 
 
 
Sponsor 
representMive * 
Herbert Sindcrma nn, PhD 
Clinical Research 
Aetcrna   Zentaris   GmbH 
We ismii l l erst r. 50 
D-603 14 Frankfurt am Main 
Germany 
Phone +4969426 02 34 29 
fux +4969426 02 34 04 
e-mail hsindermann@aezsinc.com 
 
Biosta tistician 
Michael Chcn 
TCM Groups, J nc. 
426 Mountai n Aven ue 
Berke ley Heights, NJ 07922 . 
L.S.A. 
 
Date. Signaturc 
Phone +1 908 500-9334 
fax +l 908 665-4234 
e-mail   michael.chen@tcmgroupsinc.com 
 
* Further country-specific contact details wi ll be specified in the Study Man ua l. 
 
 
2 


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Study Protocol AEZS-108-050
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Protocol Authorization by Country-specific Coordinating Investigator 
Country 
Coordinating investigator 
 
 
 
Date, Signature 
 
 
 
 
 
Investigator Agreement 
 
I have read the protocol and understand the requirements of this clinical trial. I agree to 
conduct the study in compliance with this protocol. 
 
 
 
 
 
 
 
Name of Investigator (Print Name) 
 
 
 
 
 
 
 
Signature of Investigator 
Date (DD/MMM/YYYY) 
 
 
Study site: 
 
 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 
Telephone number: 
 
 
Fax number: 
 


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Protocol Authorization and Investigator Agreement 
 
 
Investigator Agreement 
I have read the protocol and understand the requirements of this clinical trial. I agree to 
conduct the study in compliance with this protocol. I will forward the protocol to my 
Ethics Committee / Institutional Review Board for approval. 
 
 
 
 
 
 
Name of Investigator (Print Name) 
 
 
 
 
 
 
 
Signature of Investigator 
Date (DD/MMM/YYYY) 
 
 
Study site: 
 
 
 
 
Address: 
 
 
 
 
 
 
Telephone number: 
 
 
Fax number: 
 


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CONTACT PERSONS / DETAILS 
Study coordination, general issues 
For further country-specific contacts, please refer to the current list in the Study Manual. 
 
 
Notification of serious adverse events 
 
Drug Safety Aeterna Zentaris 
e-mail 
Fax 
drugsafety@aezsinc.com 
+49 (0) 69 4 26 02 – 34 12 
+1-800-767-3588 (North America / toll 
free) 
Anette Wiesemann-Fuhr 
Phone +49 (0) 69 4 26 02 – 38 42 
 
 
 
 
Central laboratory 
Analysis of tissue specimens for LHRH receptor expression 
An assay for LHRH receptor expression is currently under development and expected to 
become available and applied while this study is ongoing. Therefore, archival formalin- 
fixed and paraffin-embedded (FFPE) specimens (blocks) must be retained at the site. 
Similarly, FFPE blocks must be prepared from any fresh biopsy material obtained during 
screening. Study sites will be instructed about the timing and specific conditions of the 
specimens to be submitted. 
 
Assay of AEZS-108, doxorubicin and doxorubicinol: 
Prolytic GmbH 
c/o. Dr. Dorothee Krone 
Alt Fechenheim 34 
D-60386 Frankfurt am Main 
Germany 
Tel.: +49 69 4109 2535 
Fax: +49 69 4269 4784 
e-mail: dorothee.krone@prolytic.de 
Core lab for central evalation of ECGs (PK sub-study only): 
nabios GmbH 
c/o. Dr. Valentin Demmel 
Hirschgartenallee 27 
80639 Muenchen 
Germany 
Tel: +49 89 452 177 10 
Fax: +49 89 452 177 20 or 
+49 89 452 177 21 
e-mail: valentin.demmel@nabios.com 


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LIST OF ABBREVIATIONS AND TERMS 
ADR 
adverse drug reaction 
AE 
adverse event    
AEZS 
Aeterna Zentaris 
AGO 
 Arbeitsgemeinschaft Gynäkologische Onkologie (Gynecological cancer study 
group) 
ALAT 
alanine amino transferase (= serum glutamate pyruvate transaminase, SGPT) 
ANC 
absolute neutrophil count 
ANOVA  analysis of variance 
AP 
alkaline phosphatase 
App 
appendix 
ASAT 
 aspartate amino transferase (= serum glutamate oxalo-acetate transaminase, 
SGOT) 
ATC 
anatomic, therapeutic, chemical (classification system for drugs) 
AUC 
 area under the curve 
BP 
blood pressure BSA
 
 body surface area BW
 
           body weight                            
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CR 
complete response 
CRF 
case report form 
CRO 
Contract Research Organization 
CT 
computed tomography 
CTCAE Common Terminology Criteria for Adverse Events (NCI) 
DOX 
doxorubicin 
DLT 
dose limiting toxicity 
DRL 
Drug Reference List (WHO coding thesaurus) 
DSMB 
Data and Safety Monitoring Board 
ECHO 
echocardiography 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EF 
ejection fraction 
EOI 
end of infusion 
ESR 
erythrocyte sedimentation rate     
FFPE 
formalin-fixed and paraffin-embedded 
FIGO 
Fédération Internationale de Gynécologie et d'Obstétrique 
FSH 
follicle stimulating hormone 
GCIG 
Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate   
GnRH 
gonadotropin releasing hormone 
-GT 
gamma-glutamyltransferase 
HCG 
 human chorion gonadotropin 


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HR 
heart rate (as measured by ECG) 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Independent Review Board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
interactive web-based randomization stem 
LDH 
lactate dehydrogenase 
LH 
luteinizing hormone 
LHRH 
luteinizing hormone releasing hormone (synonym: GnRH) 
LKP 
 Leiter der Klinischen Prüfung (Study Director according to § 40 German Drug 
Law) 
LVEF 
left ventricular ejection fraction 
MedDRA Medical Dictionary for Regulatory Activities 
MDR 
multi-drug resistance 
MRI 
magnetic resonance imaging  
MUGA 
multigated radionuclide angiography 
NCI 
National Cancer Institute (U.S.) 
ORR 
 overall response rate 
OS 
overall survival 
PLD 
pegylated liposomal doxorubicin 
PD 
progressive disease 
PFS 
progression free survival 
PK 
pharmacokinetic 
PP 
per-protocol 
PR 
partial response 
PT 
preferred term (MedDRA) 
QoL 
Quality of Life 
RECIST  Response Evaluation Criteria in Solid Tumors 
RNV 
radionuclide ventriculography 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System (tradename) 
SD 
stable disease 
SOC 
system organ class (MedDRA) 
t1/2 
elimination half-life time 
TEAE 
treatment emergent adverse events 
TMF 
trial master file 
TTP 
time to progression 
ULN 
upper limit of normal range 
WBC 
white blood cell 
WHO 
World Health Organization 


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SYNOPSIS 
 
Study No. 
AEZS-108-050 
Clinical phase 
III 
EudraCT No. 
2012-005546-38 
Type of study 
Therapeutic confirmatory 
Clinical- 
Trials.gov 
NCT01767155 
Indication 
Endometrial cancer, advanced, 
recurrent or metastatic 
Title of the study 
Randomized controlled study comparing AEZS-108 with doxorubicin as second line 
therapy for locally advanced, recurrent or metastatic endometrial cancer 
 
 
Coordinating investigator(s) 
Global and North American sites: 
David Scott Miller 
University of Texas Southwestern Medical Center 
Dallas, TX 75390, USA 
European sites: 
Hani Gabra 
Imperial College London Hammersmith Campus 
London, UK 
 
 
Study centers: 
Approximately 120 study locations (CAN/Europe/Israel/USA). 
 
 
Study period planned 
3 years; Q1.2013 – 12.2015 
 
 
Objectives 
Primary: Compare the overall survival (OS) of patients treated with AEZS-108 to the OS 
of patients treated with doxorubicin. 
Secondary: Compare efficacy based on progression-free survival (PFS), overall response 
rate (ORR), and clinical benefit rate (CBR). 
Subgroup analyses of efficacy parameters in relation to tumor LHRH receptor 
expression. 
Compare safety. 
Determine the impact of these regimens on patient-reported quality of life. 
Sub-study (selected study sites only): 
Assess pharmacokinetics of AEZS-108, doxorubicin, and doxorubicinol. 
Assess acute effects of AEZS-108 and doxorubicin on electrocardiographic parameters. 
 
 
Methodology / Design 
Open-label, randomized, active-controlled, two-arm Phase III study to compare the 
efficacy and safety of AEZS-108 and doxorubicin. The study will include about 
500 patients with advanced, recurrent or metastatic endometrial cancer who have 


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progressed and who have received one chemotherapeutic (i.e., cytotoxic) regimen with 
platinum and taxane (either as adjuvant or first line treatment). 
Patients will be centrally randomized in a 1:1 ratio to receive treatment with either 
AEZS-108 (Arm A) or doxorubicin (Arm B). 
During ongoing treatment, response will be evaluated every 3 cycles; earlier reassess- 
ments should be scheduled to verify a response (no earlier than 4 weeks after first 
observation of the response) or in case of suspected progression. Patients, who have 
gone off-treatment for reasons other than progression, will be reassessed every 12 weeks 
until progression. All patients will be followed-up for survival. 
On a regular basis, at intervals no longer than 6 months, results from safety analyses will 
be submitted to an independent Data and Safety Monitoring Board (DSMB) that will 
advise the Sponsor of potentially critical findings. 
The final analysis will be performed after about 384 deaths have been observed. There 
will be two planned interim analyses; the first will be for futility only, the second will be 
for safety and efficacy. 
Based on the availability of the assay for LHRH receptor expression in tumor 
specimens, subgroup analyses stratified for extent of LHRH receptor expression will 
assess the predictive value of the LHRH receptor assay. 
A sub-study, at selected sites, will investigate the pharmacokinetics of AEZS-108, 
doxorubicin and doxorubicinol and assess the acute effects on electrocardiographic 
parameters. 
Sparse PK sampling will be performed, at all sites where feasible, to explore exposure- 
response relationships between AEZS-108 and its metabolites and measures of safety 
and efficacy. 
 
 
Number of patients planned 
Approximately 500 (250 per treatment arm). 
 
 
Inclusion criteria 
1. Women ≥ 18 years of age 
2. Histologically confirmed endometrial adenocarcinoma of any subtype. 
a. Endometrioid carcinoma 
i. Variant with squamous differentiations 
ii. Villoglandular variant 
iii. Secretory variant 
iv. Ciliated cell variant 
b. Mucinous adenocarcinoma 
c. Serous adenocarcinoma 
d. Clear cell adenocarcinoma 
e. Mixed cell adenocarcinoma 
f. Squamous cell carcinoma 
g. Transitional cell carcinoma 
h. Small cell carcinoma 
i. Undifferentiated carcinoma 


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3. Advanced (FIGO stage III or IV), recurrent or metastatic disease. 
4. Measurable or non-measurable disease that has progressed since last treatment. 
5. Patients with advanced, recurrent, or metastatic endometrial cancer who have 
received one chemotherapeutic regimen with platinum and taxane (either as adjuvant 
or as first line treatment) and who have progressed. 
6. Availability of fresh or archival FFPE tumor specimens for analysis of LHRH 
receptor expression. 
 
 
Exclusion criteria 
Safety concerns: 
1. ECOG performance status > 2. 
2. Inadequate hematologic, hepatic or renal function 
- thrombocyte count:< 100 x 109/L; 
- absolute neutrophil count (ANC):< 1.5x 109/L; 
- hemoglobin:< 5.6 mmol/L (< 9 g/dL); 
- ASAT, ALAT, AP:> 2.5 times upper limit of normal range (ULN) 
(> 5x ULN if clearly related to liver metastases); 
- creatinine, bilirubin:> 1.5x ULN. 
3. Red blood cell transfusion within 2 weeks prior to anticipated start of study 
treatment. 
4. History of myocardial infarction, acute inflammatory heart disease, unstable angina, 
or uncontrolled arrhythmia within the past 6 months. 
5. Impaired cardiac function defined as left ventricular ejection fraction (LVEF) 
< 50 % (or below the study site’s lower limit of normal) as measured by MUGA or 
ECHO. 
6. Concomitant use of prohibited therapy (as specified in Section 6.3.2). 
7. Chemo-, immune-, or hormone-therapy within 5 elimination half-life times or 4 
weeks prior to randomization, whichever is the shorter. Radiotherapy (including 
pre- or post-operative brachytherapy) within 4 weeks prior to randomization. 
8. Previous anthracycline-based chemotherapy (daunorubicin, doxorubicin, epirubicin, 
idarubicin, mitoxantrone and valrubicin), in any formulation. 
9. Anticipated ongoing concomitant anticancer therapy during the study. 
10. History of serious co-morbidity or uncontrolled illness that would preclude study 
therapy, such as active tuberculosis or any other active infection. 
11. Brain metastasis, leptomeningeal disease. 
12. Pregnant or lactating female or female of childbearing potential not employing 
adequate contraception. Women of childbearing potential must agree to employ 
adequate contraception until 6 months after the last dose of study drug, defined as 
- complete abstinence; (Note: acceptable only as “true abstinence”, i.e. when this is 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence, 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception). 
- any intrauterine device (IUD) with published data showing that the lowest 
expected failure rate is < 1 % per year; or 
- any other methods with published data showing that the lowest expected 
failure rate is less than 1 % per year. 
13. Subjects with known hypersensitivity to peptide drugs, including LHRH agonists. 


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Lack of suitability for the trial: 
22. Malignancies arising from the uterine cervix. 
23. Uterine sarcomas or mixed epithelial and mesenchymal tumors including 
carcinosarcoma, adenosarcoma, or carcinofibroma. 
14. Receipt of 2 or more prior cytotoxic chemotherapy regimens for advanced, recurrent, 
or metastatic endometrial cancer. 
15. Prior treatment with AEZS-108. 
16. Use of LHRH agonist or antagonist treatment within 6 months prior to 
randomization (see Appendix 5 for examples of drug names). 
17. Malignancy within last 5 years except non-melanoma skin cancer. 
18. Any concomitant disease or condition that would interfere with the subjects’ proper 
completion of the protocol assignment. 
19. Concomitant or recent treatment with other investigational drug (within 4 weeks 
or 5 elimination half-life times prior to anticipated start of study treatment). 
Administrative reasons: 
20. Lack of ability or willingness to give informed consent. 
21. Anticipated non-availability for study visits/procedures. 
 
Study medication, dose, and mode of administration 
AEZS-108 
INN zoptarelin doxorubicin, acetate salt
Presentation: 
100 mg lyophylisate per vial
Dosage scheme: 
267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day 
(3-week) cycles 
Note: If the body weight is +/- 10% of the body weight measured 
at day 1 of the preceding cycle, the body weight measured at day 
1 of the preceding cycle may be used for calculating the dose to 
be prepared in the pharmacy 
Maximum duration
/ dose: 
The proposed maximum duration is 9 cycles.
Treatment delay: 
up to 2 weeks in case of persisting clinically significant adverse 
reactions (except for alopecia); for details, see Protocol Section 
6.3.1.3. 
Dose reduction: 
210 mg/m2 in case of dose-limiting toxicity or delayed recovery 
 
Doxorubicin 
doxorubicin HCl (non-liposomal formulation) 
Presentation: 
commercial product (trade name, e.g., Adriamycin) 
Dosage scheme: 
60 mg/m2 by intravenous bolus injection, 1-hour intravenous 
infusion, or according to standard institution procedures, on Day 1 
of 21-day (3-week) cycles 
Note: If the body weight is +/- 10% of the body weight measured 
at day 1 of the preceding cycle, the body weight measured at day 
1 of the preceding cycle may be used for calculating the dose to 
be prepared in the pharmacy 
Dose adjustment: 
(for starting dose)
- Renal function 
at glomerular filtration rate (GFR) below 10 ml/min.: 75 % of 
calculated dose 
- Hepatic function 
at serum bilirubin 1.2 to 3.0 mg/100 mL: 50 % of calculated dose;


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Maximum duration 
/ dose: 
at serum bilirubin > 3.0 mg/100 mL: 25 % of calculated dose 
up to a cumulative lifetime dose of 550 mg/m2 
Treatment delay: 
up to 2 weeks in case of persisting clinically significant adverse 
reactions (except for alopecia); for details, see Protocol Section 
6.3.2.3. 
Dose reduction: 
(for retreatment)
50 to 75 % of starting dose if required by dose-limiting toxicity or 
delayed recovery 
Criteria for evaluation (efficacy, safety) 
1. 
Overall survival (primary efficacy endpoint). 
2a 
Efficacy: Progression-free survival (PFS), overall response rate (ORR = CR + PR) 
and clinical benefit rate (CBR) will be evaluated as CR + PR + SD for at least 3 
months. 
2b. 
Safety: adverse events, clinical laboratory, ECG and LVEF.  
2c. 
Quality of Life: EORTC QLQ30 + QLQ-EN24 questionnaires. 
2d. 
Pharmacokinetics (PK sub-study) and exposure-response relationship. 
 
 
Statistical methods 
The primary efficacy variable will be overall survival (OS). The primary analysis of the 
primary efficacy variable will be based on the ITT population. The final OS analysis, 
which is event-based, will be conducted after approximately 384 randomized patients 
have died. In the primary analysis, a log-rank test with an overall two-sided Type I error 
rate of 0.05 after taking the interim analyses into account will be used to compare OS 
between the two treatment arms via a SAS lifetest procedure. Kaplan-Meier estimates 
will be used to calculate median OS and the 95% confidence interval of the median OS. 
The proportion of patients alive at six and 12 months (from randomization date) and the 
95% confidence intervals for these estimated proportions, if appropriate, will be 
presented. 
Approximately 384 events of deaths will be required to achieve 80 % power to detect a 
treatment difference at the two-sided 0.05 significance level. It is expected that 
approximately 500 patients will be enrolled during an estimated 24-month recruitment 
period and will then be followed for 12 months to observe a total of approximately    
384 death events. In the sample size calculation, it is assumed that the median OS is   
12 months for AEZS-108 and 9 months for doxorubicin. The sample size calculation 
has taken two planned interim looks into account, the first being a futility analysis only. 
Population pharmacokinetic methodology will be applied to analyze results derived from 
sparse PK sampling and from the PK sub-study. 


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FLOW CHART 
 
 
Procedures 
 
Screen
 
Cycle 1 
 
Cycle 2 to 9 
End of 
therapy 
Post 
Therapy 
Follow up
Visit / Cycle Day 
 
 
1) 
Within 
4 wks 
before 
C1 D1 
2) 
D1 
D8 + D15 
(+D22 + D29 
if retreatment 
delayed) 
3) 
 
 
 
 
4) 
3-5 weeks 
after last 
dose 
 
5) 
Every 3 
months 
 
 
6) 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
Interval history and 
symptom-directed exams 
 
X  
D1 
X 
 
Clinical assessments: Height 
(screen only), Weight ECOG 
performance status Blood 
pressure, pulse 
X 
X 
X 
X 
X 
X 
 
 
 
X 
D1 
D1 
D1 
X 
X 
X 
 
 
X (until PD) 
X (until PD) 
Adverse events 
 
Cumulative recording 7) 
(whenever observed/applicable) 
X9) 
Concomitant treatments 
X 
X  
D1 
X 
X10) 
Clinical laboratory tests 
Hematology, Chemistries, 
and Urinalysis 
LH, FSH 
Pregnancy test (ß-HCG) 
 
X 
X 
X 8) 
 
X 
 
X11) 
 
D1 4) 
D1 
 
X 
X 
 
Tumor tissue collection 
X 14)  
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics: 
- Sparse PK sampling 17) 
- PK sub-study 12) 
 
 
X 
(X)
 
 
(D2-D4) 
Cycle X D112) 
(once, if not 
done at C1) 
 
 
Cardiac function test 
LVEF (ECHO or MUGA) 
ECG (12-lead) 
X 2A) 
X 
 
 
X12) 
 
 
D212) 
End of C3, 
C6, C7, C816) 
D1 
X 
X 
X 9) 
X 9) 
Tumor imaging/evaluation 
X 2B)  
 
End of 
C3 + C6 
X 
X 
Quality of Life questionnaire 
X 
 
 
End of 
C3 + C6 
X 
X 
Survival follow-up 
 
 
 
 
 
X 
Patient registration 
X 
 
 
 
 
 
Eligibility criteria review 
X 
X15)  
 
 
 
Randomization13) 
D-1 to 
D-413) 
 
 
 
 
 


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Study treatment 
 
X  
D1 
 
 
1) A window of +/- 3 days will be allowed for scheduled visits/actions, +/- 7 days for 3 monthly follow-ups. 
If a procedure or visit falls on a public holiday, the patient should be scheduled for the next working day. 
2) Pre-study evaluations dating back more than 2 weeks prior to treatment start are acceptable. 
2A) LVEF: In absence of intercurrent chemotherapy or cardiac medical history, results dating back up to 
8 weeks will be acceptable. 
2B) Tumor imaging: Assessments of indicator lesions up to 4 weeks prior to treatment start (C1D1) will 
be considered valid for baseline evaluation. 
3) Patients who have not recovered sufficiently from treatment-related adverse events within 3 weeks may 
have their retreatment delayed by up to 2 weeks; patients who cannot be retreated 5 weeks after previous 
dose, will not receive further study treatment but will still be followed for outcome. 
4) Start of a new cycle is planned every 3 weeks unless treatment delay is required due to residual toxicity. 
Per footnote 1, a window of up to 3 days is allowed to schedule tests prior to the anticipated day of 
retreatment, to assure sufficient recovery from treatment-related adverse events ('toxicity') prior to 
dosing. 
5) A full End-of-Therapy assessment will be also required whenever a patient is being withdrawn from the 
study.  The reason(s) for discontinuation will be documented. 
6) Patients discontinuing study treatment for reasons other than disease progression will be reassessed at 
3-month intervals to assess the time to treatment failure (progression / death). 
Follow-up until progression will be suspended in patients in whom a new cancer treatment has been 
started without prior documentation of progressive disease. 
Information on survival status may be captured by telephone if no follow-up visit is scheduled for other 
reasons. 
7) If treatment was discontinued because of a drug-related adverse event (i.e., causality at least possibly 
related), the patient will be followed up as clinically indicated to assess and document the outcome. 
8) Only required in women of child-bearing potential 
9) Only a patient developing signs of cardiac failure during post-treatment follow-up will have LVEF and 
ECG evaluated; a left ventricular dysfunction of CTCAE grade 4 will be reported as an SAE. 
10) Only anticancer treatments that a patient received during post treatment follow-up for survival will be 
recorded. 
11) For tests performed by a laboratory not affiliated to study site (e.g. mid-cycle controls by the patient’s 
home doctor) copies of the external laboratory reports will be provided to the sponsor and results 
recorded in the CRF. 
12) A PK sub-study, including electrocardiographic evaluations on Day 1 and Day 2, will be conducted at 
selected investigational sites.  Procedures are described in APPENDIX 7 
13) Every effort should be made to start treatment within 4 days of randomization. 
14) Specimens from FFPE fresh biopsies if FFPE archival tumor specimens are not available. 
15) Except for Day 1 clinical laboratory tests 
16) Recommended to be conducted also at end of Cycle 7 and 8 (i.e., before start of Cycle 8 and Cycle 9, 
respectively) for both arms.  Results are to be captured on the eCRF if there is an abnormal finding. 
17) Sparse PK sampling of AEZS-108 treated patients will be performed at all investigational sites, where 
feasible. Sparse PK sampling is expected in Cycle 1 or alternatively in a subsequent cycle of ongoing 
patients, within the following time windows: 
sample #1: within 60 minutes before end of the 2-hour infusion (during 2nd half of the infusion period); 
sample #2: between 30 and 60 minutes after the end of infusion (EOI); 
sample #3: between 120 and 180 minutes after EOI; 
sample #4 (optional): between 4 and 6 hours after EOI. 


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TABLE OF CONTENTS 
Protocol Authorization .......................................................................................................... 2 
Contact Persons / Details .................................................................................................... 5 
List of Abbreviations and Terms ....................................................................................... 6 
Synopsis ................................................................................................................................ 8 
Flow Chart. ......................................................................................................................... 13 
 
1  
1.1 
BACKGROUND INFORMATION AND RATIONALE ................................ 17
Background information on LHRH receptors and endometrial cancer ......... 17
 
1.2 
Background information on AEZS-108 ........................................................ 17
 
1.3 
Rationale for the present study ..................................................................... 22
2  
OBJECTIVES .................................................................................................... 24
3  
3.1 
ETHICS ............................................................................................................24
Benefit / risk considerations .......................................................................... 24
 
3.2 
Protection of patients .................................................................................... 25
4  
STUDY DESIGN ............................................................................................... 25
5  
5.1 
PATIENT SELECTION .................................................................................... 26
Inclusion criteria ........................................................................................... 26
 
5.2 
Exclusion criteria .......................................................................................... 27
 
5.3 
Withdrawal criteria ....................................................................................... 28
 
5.4 
Replacement policy ....................................................................................... 29
6  
6.1 
DESCRIPTION OF TREATMENTS ................................................................ 29
Investigational drug – AEZS-108 ................................................................. 29
 
6.2 
Comparator drug – Doxorubicin ................................................................... 33
 
6.3 
Concomitant therapy ..................................................................................... 34
 
6.4 
Follow-up treatment (no crossover after the end of study treatment) ........... 36
7  
7.1 
ASSESSMENTS. ............................................................................................... 37
Efficacy (RECIST) ........................................................................................ 37
 
7.2 
Safety .............................................................................................................. 43
 
7.3 
Other ............................................................................................................... 48
8  
8.1 
STUDY PROCEDURES ................................................................................... 49
Patient's informed consent and registration prior to screening ...................... 49
 
8.2 
Screening procedures (within 4 weeks before start of treatment) ................. 49
 
8.3 
Randomized allocation of study treatment .................................................... 50
 
8.4 
Procedures during treatment .......................................................................... 50
 
8.5 
Procedures at end of study treatment ............................................................. 52
 
8.6 
Post-treatment follow-up ............................................................................... 53
9  
9.1 
STATISTICAL CONSIDERATIONS ............................................................... 54
Analysis populations ..................................................................................... 54
 
9.2 
Demographic and baseline characteristics .................................................... 55
 
9.3 
Treatments and medications ........................................................................... 55
 
9.4 
Primary efficacy outcome .............................................................................. 56


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9.5 
Secondary efficacy outcomes ......................................................................... 57 
9.6 
Safety analysis ............................................................................................... 57 
9.7 
Pharmacokinetics .................................................................................................... 59 
9.8 
Population pharmacokinetics .......................................................................... 59 
9.9 
Interim analyses ............................................................................................ 59 
9.10 
Power and sample size .................................................................................. 60 
10 
ADMINISTRATIVE AND GCP ISSUES ........................................................ 60 
10.1 
Essential documents for trial initiation; Trial Master Files (TMF) ............... 60 
10.2 
Subject information and consent ................................................................... 61 
10.3 
Protocol amendments ..................................................................................... 61 
10.4 
Premature termination of the trial .................................................................. 61 
10.5 
Documentation obligations ............................................................................ 61 
10.6 
Monitoring and inspections ........................................................................... 62 
10.7 
Final report and publication .......................................................................... 63 
10.8 
Archiving ................................................................................................................ 63 
11 
REFERENCES ........................................................................................................... 65 
TABLE OF APPENDICES 
APPENDIX 1: CALCULATOR / NOMOGRAM FOR DETERMINATION OF BODY 
SURFACE AREA ............................................................................................... 67 
APPENDIX 2: ECOG PERFORMANCE STATUS SCALE ............................................... 68 
APPENDIX 3: GRADING OF LEFT VENTRICULAR FUNCTION (CTCAE-V4.03) ... 69 
APPENDIX 4: POTENTIALLY CARDIOTOXIC MEDICATION .................................... 70 
APPENDIX 5: EXAMPLE OF GNRH AGONISTS AND ANTAGONISTS ..................... 70 
APPENDIX 6: QUALITY OF LIFE QUESTIONNAIRES (SAMPLE SPECIMENS) ....... 71 
APPENDIX 7: PHARMACOKINETIC SUB-STUDY ........................................................ 75 


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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Background information on LHRH receptors and endometrial cancer 
LHRH receptor expression in gynecological cancers 
LHRH, also known as GnRH, is a hormonal decapeptide produced by the hypothalamus, 
which plays a pivotal role in the regulation of the pituitary/gonadal axis, and thus, in the 
production of sex steroids. Because sex steroids have been implicated in the development 
of breast and other gynecological cancers, the role of LHRH and its receptor in these 
tumors has been studied. While breast cancers were found positive for LHRH receptors in 
up to 50 % of cases, more than 80 % of ovarian and endometrial cancers have been 
reported to have functional binding sites for LHRH [17, 21, 22], which are targeted by 
AEZS-108 (see Section 1.2.1 below). 
 
Endometrial cancer 
Cancer of the endometrium is the most common gynecologic malignancy and accounts for 
6 % of all cancers in women. The majority of the cases occur in postmenopausal women, 
with the largest number of women developing their cancers during the sixth decade. 
The most common histological form of endometrial cancer cell type (about 80 % of all 
cancers) is endometrioid adenocarcinoma [18]. Serous, clear cell, mucinous, squamous, 
and undifferentiated tumors are rarely encountered. While in many cases primary therapy 
of endometrial cancer results in cure, in some 25 % of the patients recurrences are seen, 
commonly within 3 years after diagnosis. Recurrent tumors locally confined to the vagina 
may be cured in some cases with combined surgery and radiation therapy; systemic 
recurrences are usually considered incurable and are typically treated with systemic 
therapy. 
 
Systemic drug therapy 
Patients with advanced or recurrent tumors that are progesterone receptor-negative or do 
not response to hormonal therapy should be considered for chemotherapy. 
Active agents include anthracyclines, platinum compounds, and taxanes. Observed single 
agent response rates vary between 20-35 %. Responses rates have increased when various 
combination therapies were employed although it remains unclear whether this confers any 
survival advantage [4, 15, 19]. 
Please refer to Section 1.3 for details on the selection of doxorubicin as comparator drug 
for this study. 
 
1.2 
Background information on AEZS-108 
AEZS-108 (INN zoptarelin doxorubicin, formerly known as AN-152 or ZEN-008) is a 
LHRH-cytotoxic hybrid molecule. The cytotoxic molecule doxorubicin (DOX) is 
chemically linked to the carrier molecule D-Lys6-LHRH (an LHRH agonist) which enables 
the specific binding and selective uptake of the hybrid molecule by tumors expressing 
receptors for LHRH (“drug targeting”). 


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In clinical Phase I and Phase II studies, AEZS-108 has been studied and shown therapeutic 
activity in patients with LHRH receptor-positive ovarian and endometrial cancer. Based  
on its pharmacological mode of action, AEZS-108 is expected to also be active in other 
LHRH receptor-positive cancers and studies are currently ongoing in patients with triple 
negative breast cancer, urothelial, and hormone-refractory prostatic cancer. 
For more details on AEZS-108, please refer to the current Investigator’s Brochure. See 
also Engel et al. [8] for an overview on the preclinical and clinical development of 
AEZS-108. 
 
1.2.1 
Nonclinical pharmacology and toxicology 
Mechanistic in vitro studies showed that uptake of doxorubicin into LHRH-receptor 
expressing cells was facilitated by the presence of the LHRH analog moiety. In addition, 
AEZS-108 had a greater ability to enter the nucleus of living cells compared to dead 
(photodamaged) cells. The cytotoxicity of AEZS-108 was demonstrated in several LHRH 
receptor-positive cell lines derived from estrogen-dependent human breast cancer, 
estrogen-independent mouse mammary carcinoma, ovarian, endometrial, oral and 
laryngeal cancer [13]. In LHRH receptor-negative cell lines, AEZS-108 was not active or 
significantly less active than DOX. 
In vivo xenograft tumor models in nude mice showed AEZS-108 to be effective in various 
tumor models for breast, ovarian, endometrial, and prostate. At equimolar doses, the 
efficacy of AEZS-108 was superior to that of doxorubicin and not accompanied by its 
substantial mortality. 
In pharmacokinetic studies in rats and dogs, t1/2 (1 hr) and tmax (0.08 hr) of AEZS-108 
and DOX were similar. Dose linearity for AEZS-108 was demonstrated when based on 
Cmax and AUC0-4.  The AUCs of AEZS-108 were higher (3 to 9 times in rats, 7 to 12 times 
in dogs) than those of DOX after single and multiple doses, independent of dose and sex. 
AEZS-108 is sensitive to spontaneous and/or carboxylesterase-catalyzed deconjugation 
into DOX and probably D-Lys6-LHRH-glutarate in blood plasma and aqueous solutions. 
The rate of hydrolysis of AEZS-108 in mouse serum (approx. t1/2 = 20 min.) was 
significantly higher than in human serum (approx t1/2 = 100 – 120 min.). AEZS-108 in 
microsomal liver incubations suggested a more secondary role of metabolic decomposition 
than spontaneous hydrolysis. 
In safety pharmacology studies, AEZS-108 showed no influence on 
neuropharmacological parameters or on motor coordination when examined at doses up to 
15 mg/kg given by intravenous administration. In dogs, when AEZS-108 was  
administered IV (4.8 mg/kg) over 1 hour, effects were noted as a decrease of the peripheral 
arterial blood pressure and as an increase of heart rate, cardiac output and respiratory rate 
and volume. No effects on cardiovascular, electrocardiographic, and respiratory parameters 
were observed at lower doses. 
In acute single dose toxicity studies in mice and rats, AEZS-108 (20 – 80 mg/kg intra- 
venous (IV) single dose) induced qualitatively similar signs of toxicity to DOX (10 - 40 
mg/kg single dose IV). The no-observed effect level (NOEL) and the LD50 of AEZS-108 
and DOX were similar if compared on a molar basis. 


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In acute single dose toxicity studies in mice and rats, AEZS-108 induced qualitatively 
similar signs of toxicity to equimolar doses of doxorubicin. When compared at molar 
dosages, the NOAEL and the LD50 of AEZS-108 and doxorubicin were also similar.   
Most frequent signs of toxicity were reduced motility, ataxia, dyspnea, and reduced muscle 
tone. Histopathology findings following treatment with AEZS-108 involved seminal 
vesicles and ovaries, indicating that these may be target organs. 
In repeated-dose toxicity studies in rats and dogs, AEZS-108 in doses of 0.3 to 15 mg/kg 
weekly for 4 weeks induced qualitatively similar signs of hematology toxicity to 
doxorubicin. In rats, histopathology findings, preferably following mid and high doses of 
AEZS-108, consisted of atrophy in the male and female genital tract, in the lymphatic 
system, and in the mucosa of the gastrointestinal tract. In dogs, slow infusion periods were 
required to avoid fairly pronounced signs of toxicity. Morphological changes were re- 
vealed in the male and female genital system with 1.2 to 4.8 mg/kg and in the lymphocytic 
system of animals treated with 4.8 mg/kg reflecting the cytostatic nature of AEZS-108. 
Most changes had subsided at the end of the 8-week recovery period. However, AEZS- 
108-related degeneration of the germinative epithelium of the Sertoli cells in the testes was 
still present. 
No changes were noted for electrocardiography (only dogs) and histopathology of the heart 
in both species. The lowest lethal dose of AEZS-108 following weekly administration for 4 
weeks was 15 mg/kg in rats and > 5 mg/kg in dogs. In both species, if compared on    
molar basis, the NOAEL and the lowest lethal dose of AEZS-108 and doxorubicin were 
similar. 
Local tolerance. No signs of local intolerance were found in rats, rabbits, and dogs after 
IV and in rabbits after intraarterial injection. 
 
1.2.2 
Clinical data 
Pharmacokinetics 
Following administration of 160 and 267 mg/m2 AEZS-108, maximum plasma concen- 
trations of 728 – 6661 ng/ml were measured. Because of the high variability, neither a 
dose dependency of Cmax values nor of the calculated AUC values could be shown. The 
calculated half-life and the clearance of AEZS-108 were found to be in the range of 
0.74 - 4.58 h and 0.37 – 2.67 (l/min·m2), respectively, and were independent of the dose 
level. This is an indication of dose linearity. 
At the dose levels of 160 and 267 mg/m2, the Cmax values of the active metabolite doxo- 
rubicin were measured in the range of 177 – 1580 ng/ml. The half-life and calculated 
clearance for doxorubicin were found to be in ranges comparable to those for AEZS-108. 
The doxorubicin plasma concentrations and therefore the calculated AUC values of 
doxorubicin increased with increasing dose. 
 
Safety 
The safety profile, described below is derived from the Investigator’s Brochure (edition 5, 
May 23, 2012); it is based on 3 completed clinical studies in 102 female patients (Phase I: 


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17, Phase II: 42 patients with ovarian cancer, 43 patients with endometrial cancer) and 
2 ongoing clinical studies in approximately 21 urothelial or prostate cancer patients. 
The most frequent adverse drug reactions (ADRs) i.e., AEs considered as likely or possibly 
related to AEZS-108) were hematological (anemia, leukopenia, neutropenia), cutaneous 
(alopecia), general (fatigue, mucosal inflammation) and gastrointestinal (diarrhea, nausea, 
vomiting). Table 1 of the Investigator’s Brochure provides an ‘Overview on suspected 
adverse drug reactions (ADRs) to AEZS-108’. 
Hematotoxicity was potentially dose limiting but was usually rapidly reversible and did not 
require deviation from scheduled retreatment or discontinuation of AEZS-108. In fewer 
than 10 % of the patients, retreatment was delayed due to hematotoxicity, by one to two 
weeks. Approximately 5 % of the patients received a blood transfusion, 15 % of the 
patients received G-CSF and three patients out of 102 (3 %) had a dose reduction to 
160 mg/m2. 
The most frequent serious adverse drug reactions were leukopenia, vomiting, and nausea. 
In the Phase II endometrial cancer study [7], 28 patients out of 43 (65.1 %) completed     
6 cycles of treatment. The most frequent AEs judged related to AEZS-108 were nausea 
(39.5 %), alopecia (37.2 %), fatigue (25.6 %), vomiting (20.9 %), anemia (16.3 %), and 
neutropenia (16.3 %). The most frequent grade 3 or 4 AEs judged related to AEZS-108 
were neutropenia (11.6%) and leukopenia (9.3 %). No cardiac toxicity was reported based 
on LVEF. 
Two patients out of 43 (4.7 %) died within 30 days of the last dose of AESZ-108: in one 
case, the patient died of malignant disease. The other death was due to acute respiratory 
distress syndrome and was judged unrelated to AEZS-108. SAEs (other than death) were 
observed in 13 patients out of 43 (30.2 %). In six patients out of 43 (14 %) the SAE was 
judged related to AEZS-108. They consisted of hemoglobin decreased, blood creatinine 
increased, ileus, pulmonary embolism, white blood cell count decreased and influenza-like 
illness. No AEs (other than deaths or SAEs) or abnormalities in laboratory parameters led 
to AEZS-108 discontinuation. 
The most frequent grade ≥ 3 hematological abnormalities were leukopenia, neutropenia, 
and lymphocytopenia. Leukopenia of grade ≥ 3 was observed at each cycle (in 13 % to 26 
% of the patients) and only on Day 15. Neutropenia of grade ≥ 3 was observed at each 
cycle (in 32 % to 54 % of the patients) and only on Day 15. Lymphocytopenia of grade 
≥ 3 was observed at each cycle on day 8 (in 6 % to 20 % of the patients) and in some cases 
on Day 15 and 22. Hematotoxicities were easily manageable as none were reported as a 
serious AE and/or led to AEZS-108 discontinuation. Leukopenia delayed by ≥ 7 days 
AEZS-108 administration in approximately 5 % of the patients. 
 
Efficacy 
In Phase I and Phase II studies, AEZS-108 has shown therapeutic activity in patients with 
LHRH receptor-positive ovarian and endometrial cancer. In the Phase II study in 
42 patients with advanced or recurrent ovarian cancer with LHRH positive tumors, AEZS- 
108 was shown to be active based upon an ORR of 19.0 % and a CBR of 52.4 % when 
combining RECIST and CA 125 criteria. The overall survival after single agent AEZS- 


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108 observed in this study was 12 months and compared favorably to the survival observed 
following topotecan (9.5 months) and doxorubicin (8.2 months) [11]. 
Endometrial cancer. AEZS-108 was studied in 43 advanced or recurrent endometrial 
cancer patients with LHRH positive tumor status. Given as a 2-hour IV infusion at 267 
mg/m2 every 3 weeks, it was shown to be active based upon an ORR of 30.2 % and a CBR 
of 69.8 %. The overall survival of 15 months after single agent AEZS-108 observed in this 
study was similar to the 15.3 months reported in the literature for triple combination 
chemotherapy [10]. 
A total of 43 patients were exposed to AEZS-108. The majority (97.7 %) of patients were 
Caucasian and the mean age was 66 years (range = 25 to 87 years). The mean time since 
diagnosis was 34 months (range = 7 to 151). All patients had undergone prior surgery for 
their disease while 69.8 % of the patients received prior radiotherapy. Ten patient out of 
43 (23.3 %) received chemotherapy prior study entry, which consisted of the combination 
of platinum/paclitaxel in eight patients (18.6 %). 
In the ITT population, a total of 15 responses (3 CR and 12 PR) were reported by investi- 
gators for an objective response rate (ORR) of 34.9 % and a clinical benefit rate (CBR) of 
76.7 %. A total of 13 responses (2 CR + 11 PR) were determined by the external reviewer, 
for an ORR of 30.2 % and a CBR of 69.8 % (see Table below). 
 
Tumor response 
Per investigator 
(N = 43) 
Per reviewer 
(N= 43) 
Complete response (CR) 
3 (7.0 %) 
2 (4.7 %) 
Partial response (PR) 
12 (27.9 %)a 
11 (25.6 %)a 
Stable disease (SD) 
18 (41.9 %) 
17 (39.5 %) 
Progressive disease (PD) 
7 (16.3 %)b 
7 (16.3 %)b 
Objective response rate (CR + PR) 
15 (34.9 %) 
13 (30.2 %) 
Clinical benefit rate (CR + PR + SD) 
33 (76.7 %) 
30 (69.8 %) 
Not evaluable 
3c, d 
6c, d, e 
a: Partial response not confirmed at a subsequent time point for the 3 patients. 
b: In 1 patient, the investigator reported SD at cycle 1 in the CRF.  As this tumor assessment 
had not been completed post-treatment, best overall response was based on cycle 4 assessment 
and was considered PD. 
c: Symptomatic deterioration or death due to malignancy prior to cycle 2: 2 patients 
d: Non-cancer death prior to cycle 2: 1 patient 
e: Tumor assessments not evaluable per reviewer: 3 patients. 
ORR and CBR in the per protocol population (n = 42) were not significantly different from 
the ITT population. 
The median TTP as reported by the investigators was approximately 7 months. The 
median OS was 15 months. 


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1.3 
Rationale for the present study 
 
Selection of doxorubicin as comparator drug 
In recent years, there has been a trend towards use of carboplatin/taxane for first line 
chemotherapy, so that doxorubicin whether as non-liposomal or pegylated liposomal 
doxorubicin (PLD) formulation is increasingly used in second line chemotherapy. 
Moderate response rates, however, have been reported for PLD when used in patients with 
prior chemotherapy (9 %) [16], but also in patients without prior chemotherapy (11.5%) 
[14], which could have been due to the selection of patients with less favorable prognosis 
for the latter trial [19]. 
Based on the reported moderate activity of PLD when used for second line therapy of 
endometrial cancer, non-liposomal doxorubicin has been selected as comparator drug in 
this trial. 
The selection of doxorubicin as comparator drug in this trial implies that prior use of 
doxorubicin for advanced/recurrent disease is excluded. 
 
Clinical assumptions underlying the statistical planning and sample size estimate 
This study is planned to include patients who have relapsed or progressed on or after 
platinum/taxane-based chemotherapy. Therefore, the statistical plans for the present study 
are based on the following considerations. 
Overall survival of endometrial cancer patients after use of doxorubicin in first line therapy 
was found at 7 months [1] and 9 months [20]. While shorter survival could be assumed if 
the drug is used in pretreated patients, better knowledge on the use of rescue treatments and 
improved patient care could lead to similar overall survival as seen in previous (first line 
chemotherapy) study. For comparison, median overall survival in a recent Phase II      
study of ixabepilone in pretreated patients was found at 8.7+ months [5]. Thus, the current 
study is planned under the assumption of a 9 month overall survival for the control arm. 
Median OS in the recent Phase II study of AEZS-108 was 15 months; however, only 
8 patients in this study were pretreated with a platinum/taxane regimen. The best response 
in the platinum/taxane pretreated patients included 1 CR, 1 PR, and 3 SD, corresponding to 
ORR of 25% and CBR of 62.5%. While this subset of patients is too small to reliably 
estimate an OS duration, an OS duration of 12 months was thought to be an estimate to be 
used in the sample size estimate for this study. If achieved, this would represent a clinically 
important benefit, being a 33% improvement over the anticipated survival in the control 
group. 
 
Justification for the inclusion of patients without prior characterization of LHRH 
receptor status 
The proportion of endometrial cancers reported to express or over express LHRH receptors 
varies between different studies and assays used. Percentages higher than 80 % have been 
reported in the literature [17, 21, 22]. So far, no standard assay or uniform criteria have 
been established for the quantification of LHRH receptor expressing cells or for the degree 
of expression or overexpression within given cells. In addition, antibodies used in 


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immunohisto-chemistry-based assays have been found to show variable specificity 
[unpublished data, data on file]. 
Thus, a new assay for the quantification of LHRH receptor expressing cells in endometrial 
cancer specimens is being developed. Reevaluation of tissue specimens from patients who 
have been treated with AEZS-108 in previous studies may be considered to compare the 
receptor classification between the new assay and previously used assays. However, as 
these clinical studies included patients selected for LHRH receptor expression, treatment 
results are only available for patients whose tumors had been classified as LHRH receptor- 
positive. 
In order to establish the predictive value of the receptor assay, clinical results should be 
required from a study population including both patients with high and low degree of 
receptor expression, so that treatment outcome can be compared for patients with different 
extent of receptor expression. 
For this reason, the present study is planned to include patients irrespective of the LHRH 
receptor status (‘all-comers’ approach). By this approach, also patients with minimal or 
without detectable LHRH receptor expression in their tumor cells could receive treatment 
with AEZS-108. In such patients, apart from a possibly low level of not receptor-mediated 
uptake of AEZS-108, free doxorubicin, which is gradually being released from AEZS-108, 
will be available for cellular uptake and thus confer therapeutic activity. The proportion of 
patients entering the study with LHRH receptor-negative tumors is expected to be low, 
based on the finding that 61 of 66 (92.8%) specimens were classified as LHRH receptor 
positive [Emons/Gründker, unpublished data]. 
Regarding the uncertainty of LHRH receptor classification with currently available and 
previously used assays, the demonstration of a relationship between extent of receptor 
expression and therapeutic response in this trial would be the ultimate clinical proof for the 
targeting concept and serve as a component of the validation work for the assay and its use 
as a companion diagnostic. 


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2 
OBJECTIVES 
 
Primary: 
1. 
Compare the overall survival of patients treated with AEZS-108 to the OS of patients 
treated with doxorubicin 
Secondary: 
1. 
Compare efficacy based on progression-free survival (PFS), overall response rate 
(ORR), and clinical benefit rate (CBR). 
Subgroup analyses of efficacy parameters in relation to tumor LHRH receptor 
expression. 
2. 
Compare safety. 
3. 
Determine the impact of these regimens on patient-reported quality of life during and 
for up to 1 year after completion of study treatment. 
4. 
Assess the pharmacokinetics and exposure-response relationships of AEZS-108, 
doxorubicin and doxorubicinol in a PK sub-study at selected sites and by sparse PK 
sampling, respectively. 
5. 
Assess the acute effects on electrocardiographic parameters (e.g., QT/QTc interval) 
within PK sub-study. 
 
3 
ETHICS 
The study will be conducted in agreement with the protocol and the following directives 
and guidelines: 
 
Declaration of Helsinki (Seoul, Korea, October 2008). 
 
Note for guidance on Good Clinical Practice (ICH-E6: CPMP/ICH/135/95 or 
62 FR 25692). 
 
Guidance for Industry “E14 Clinical Evaluation of QT/QTc Interval Prolongation” 
(FDA, October 2005, ICH). 
 
Guidance for Industry “Exposure-response relationships” (FDA, April 2003). 
 
Guidance for Industry “Population pharmacokinetics” (FDA, February 1999). 
 
Applicable national rules and regulations. 
 
Standard Operating Procedures of Aeterna Zentaris. 
 
3.1 
Benefit / risk considerations 
No standard of care or approved drugs are available for patients with endometrial cancer 
failing on or after first line chemotherapy for advanced/recurrent disease if this comprised 
platinum/taxane-based combination chemotherapy. In prior studies, it has been shown 
that, patients with endometrial and ovarian cancer who failed after or were resistant to 
platinum/taxane-based chemotherapy, including combinations, still responded to 
AEZS-108. 


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Although the investigational drug AEZS-108 is a targeted drug that is expected to enter 
cells bearing preferentially LHRH receptors, the study is being conducted in patients who 
will not be selected for expression of this specific target. Ultimately, a patient whose  
tumor cells do not express LHRH receptors could have a higher uptake of doxorubicin if it 
was administered as free doxorubicin, not coupled to the LHRH analog. In the Phase II 
study of AEZS-108, 92.8% of the endometrial cancer specimens analyzed during 
prescreening had been classified as receptor positive, so that only about 7% of the patients 
who might have entered the study if the receptor assay had been omitted. No correlation of 
the degree of receptor expression and the tumor response was noted in this earlier study. 
Accordingly, even patients with tumors classified as LHRH receptor negative – with the 
former assay - could have a chance to benefit from treatment with AEZS-108. Ultimately, 
since doxorubicin is being gradually released during and after the infusion of AEZS-108, a 
patient with an LHRH receptor negative tumor has the chance to benefit from the uptake of 
hydrolytically released doxorubicin by the tumor. 
 
3.2 
Protection of patients 
Before initiation of the trials, the study protocol will be reviewed by the competent 
independent ethics committees (IEC). The study will be notified to the competent 
authorities. 
The patients will be informed both verbally and in writing about the nature of the study, 
the anticipated benefits and risks, the discomfort to which they may be exposed, and their 
right to interrupt their participation at any time on their own free will. They will confirm 
their consent in writing prior to inclusion. The subject's informed consent form will be 
reviewed and approved by the IEC/IRB. For investigator's obligations regarding patient 
information and consent, see Section 10.2. 
The Sponsor will insure adequate insurance coverage in the event of patient injury resulting 
from participation in the trial. Patients should be instructed to immediately notify the 
investigator of any injury that may have been caused by participation in this trial. A     
copy of the insurance conditions is included in the investigator's file. 
 
4 
STUDY DESIGN 
This is an open-label, randomized, active-controlled, two-arm Phase III study to compare 
the efficacy and safety of AEZS-108 and doxorubicin. The study will include about    
500 patients with advanced, recurrent or metastatic endometrial cancer who have 
progressed and who have received one chemotherapeutic (i.e., cytotoxic) regimen 
containing platinum and taxane (either as adjuvant or first line treatment). 
Patients will be centrally randomized in a 1:1 ratio to receive treatment with either 
AEZS-108 (Arm A) or doxorubicin (Arm B). 
During ongoing treatment, response will be evaluated every 3 cycles; earlier reassessments 
should be scheduled to verify a response (at least 4 weeks after first observation of the 
response) or in case of suspected progression. Patients, who have gone off-treatment for 
other reason than progression, will be reassessed every 12 weeks until progression. All 
patients will be followed-up for survival. 


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On a regular basis, at intervals no longer than 6 months, results from safety analyses will 
be submitted to an independent Data and Safety Monitoring Board (DSMB) that will 
advise the Sponsor of potentially critical findings. 
The final analysis will be performed after about 384 deaths have been observed. There 
will be two planned interim analyses; the first will be for futility only, the second will be 
for safety and efficacy. 
Based on the availability of the assay for LHRH receptor expression in tumor specimens, 
subgroup analyses stratified for extent of LHRH receptor expression will assess the 
predictive value of the LHRH receptor assay. 
A sub-study, at selected sites, will investigate the pharmacokinetics of AEZS-108, 
doxorubicin and doxorubicinol and assess the acute effects on electrocardiographic 
parameters. 
Sparse PK sampling will be performed, at all sites where feasible, to explore exposure- 
response relationships between AEZS-108 and its metabolites and measures of safety and 
efficacy. 
 
5 
PATIENT SELECTION 
 
5.1 
Inclusion criteria 
To be eligible for this study, a patient must meet all of the following criteria: 
1. 
Women ≥ 18 years of age 
2. 
Histologically confirmed endometrial adenocarcinoma of any subtype. 
a)Endometrioid carcinoma 
i. Variant with squamous differentiations 
ii. Villoglandular variant 
iii.Secretory variant 
iv.Ciliated cell variant 
b)Mucinous adenocarcinoma 
c)Serous adenocarcinoma 
d)Clear cell adenocarcinoma 
e)Mixed cell adenocarcinoma 
f)Squamous cell carcinoma 
g)Transitional cell carcinoma 
h)Small cell carcinoma 
i)Undifferentiated carcinoma 
3. 
Advanced (FIGO III or IV), recurrent or metastatic disease. 
4. 
Measurable or non-measurable disease that has progressed since last treatment. 
5. 
Patients with advanced, recurrent, or metastatic endometrial cancer who have 
received one chemotherapeutic regimen with platinum and taxane (either as adjuvant 
or as first line treatment) and who have progressed. 
6. 
Availability of fresh or archival FFPE tumor specimens for analysis of LHRH 
receptor expression 


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5.2 
Exclusion criteria 
A patient meeting any of the following criteria will not be eligible for this study: 
Safety concerns: 
1. 
ECOG performance status > 2. 
2. 
Inadequate hematologic, hepatic or renal function 
- thrombocyte (platelet) count: 
< 100 x 109/L; 
- absolute neutrophil count (ANC):< 1.5x 109/L; 
- hemoglobin: 
< 5.6 mmol/L (< 9 g/dL); 
- ASAT, ALAT, AP: 
> 2.5 times upper limit of normal range (ULN) 
(> 5x ULN if clearly related to liver metastases); 
- creatinine, bilirubin: 
> 1.5x ULN. 
3. 
Red blood cell transfusion within 2 weeks prior to anticipated start of study 
treatment. 
4. 
History of myocardial infarction, acute inflammatory heart disease, unstable angina, 
or uncontrolled arrhythmia within the past 6 months. 
5. 
Impaired cardiac function defined as left ventricular ejection fraction (LVEF) < 50 % 
(or below the study site’s lower limit of normal) as measured by MUGA or ECHO. 
(LVEF measurements dating back up to 8 weeks will be acceptable in the absence of 
intercurrent use of potentially cardiotoxic treatment or cardiac medical history). 
6. 
Concomitant use of prohibited therapy (as specified in Section 6.3.2). 
7. 
Chemo-, immune-, or hormone-therapy within 5 elimination half-life times or 4 
weeks prior to randomization, whichever is the shorter. Radiotherapy (including pre- 
or post-operative brachytherapy) within 4 weeks prior to randomization. 
8. 
Previous anthracycline-based chemotherapy (daunorubicin, doxorubicin, epirubicin, 
idarubicin, mitoxantrone and valrubicin), in any formulation. 
9. 
Anticipated ongoing concomitant anticancer therapy during the study. 
10. 
History of serious co-morbidity or uncontrolled illness that would preclude study 
therapy, such as active tuberculosis or any other active infection. 
11. 
Brain metastasis, leptomeningeal disease. 
12. 
Pregnant or lactating female or female of childbearing potential not employing 
adequate contraception. Women of childbearing potential must agree to employ 
adequate contraception until 6 months after the last dose of study drug defined as 
- complete abstinence; (Note: acceptable only as “true abstinence”, i.e. when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence, (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception). 
- any intrauterine device (IUD) with published data showing that the lowest 
expected failure rate is < 1 % per year; or 
- any other methods with published data showing that the lowest expected 
failure rate is less than 1 % per year. 
13. 
Subjects with known hypersensitivity to peptide drugs, including LHRH agonists. 
Lack of suitability for the trial: 
22. 
Malignancies arising from the uterine cervix 


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23. 
Uterine sarcomas or mixed epithelial and mesenchymal tumors including 
carcinosarcoma, adenosarcoma, or carcinofibroma 
14. 
Receipt of 2 or more prior cytotoxic chemotherapy regimens for advanced, recurrent, 
or metastatic endometrial cancer. 
15. 
Prior treatment with AEZS-108. 
16. 
Use of LHRH agonist or antagonist treatment within 6 months prior to randomization 
(see Appendix 5 for examples of drug names). 
17. 
Malignancy within last 5 years except non-melanoma skin cancer. 
18. 
Any concomitant disease or condition that would interfere with the subjects’ proper 
completion of the protocol assignment. 
19. 
Concomitant or recent treatment with other investigational drug (within 4 weeks 
or 5 elimination half-life times prior to anticipated start of study treatment). 
Administrative reasons: 
20. 
Lack of ability or willingness to give informed consent. 
21. 
Anticipated non-availability for study visits/procedures. 
 
5.3 
Withdrawal criteria 
A patient discontinued of study procedures prior to randomization will not be considered  
as a withdrawal but as a “screen failure”, irrespective of the reason for the discontinuation. 
Withdrawal is to be understood as a permanent removal of a patient from planned study 
procedures after randomization. This will include both, 
(i) the premature discontinuation of study treatment before delivery of the planned number 
of treatment cycles (for AEZS-108) or of the maximum allowed cumulative lifetime dose 
(for doxorubicin), and 
(ii) the discontinuation of follow-up before the primary end point of the study has been 
reached or the study has been closed. 
At any time, patients may be withdrawn from the study at their own request or on the basis 
of the investigator's clinical judgment. However, patients who request withdrawal will be 
strongly encouraged to complete follow-up assessments. 
Reasons for withdrawal from treatment and/or follow-up will be classified as follows: 
 
Lack of efficacy: the patient shows inadequate response to treatment (progressive 
disease) or deterioration. 
 
Lack of tolerability: unacceptably bad tolerability reported by the patient or 
observed by the investigator (e.g., failure to sufficiently recover from toxicity within 
2 weeks of the scheduled day of the next cycle, cardiac adverse events judged as 
possibly related to study drug). 
 
Cardiac toxicity: defined as 
o 
reduction in LVEF to < 45 %; 
o 
reduction in LVEF by ≥ 15 % points from baseline value (e.g. from 70% to 
55%); 


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o 
evidence of clinical congestive heart failure (CHF), confirmed by the 
investigator; 
o 
myocardial infarction. 
 
Intercurrent disease: any disease or condition occurring during the trial that makes 
any further participation impossible judged as unlikely related to study drug or 
relationship not assessable. 
 
Withdrawal of consent / non-compliance: the subject/patient withdraws his/her 
consent or the patient is non-compliant with study procedures; it should be attempted 
to clarify whether an adverse event may have caused the withdrawal and, if so, 
amend the AE documentation accordingly. 
 
Other reason(s): reason for discontinuation not covered by any of the above criteria 
(e.g., patient moved out of the area, investigator's decision that discontinuation is in 
the best interest of the patient, priority of an alternative treatment option). Other 
reason(s) must be specified. 
The investigator should also provide in the CRF a brief comment on each case of 
withdrawal. 
 
5.4 
Replacement policy 
There will be no replacement of patients who have been withdrawn or who dropped out 
after randomization. 
 
6 
DESCRIPTION OF TREATMENTS 
Subject will be randomly allocated to receive either: 
 
AEZS-108 - Investigational drug (Arm A) 
OR 
 
Doxorubicin – Comparator drug (Arm B). 
Details related to AEZS-108 (Arm A) are presented in Section 6.1 while those related to 
doxorubicin (Arm B) are provided in Section 6.2. Information provided in Section 6.3 to 
Section 6.4 is applicable to both, Arm A and Arm B. 
 
6.1 
Investigational drug – AEZS-108 
 
6.1.1 
Description / general issues 
Description: AEZS-108 is formulated as a powder (lyophylisate) and provided in glass 
vials containing 100 mg of the active substance, without additional excipients. The 100 
mg vials are further packaged in boxes. Vials and boxes will be labeled as shown in a 
copy in the investigator’s file. 
Retest date, manufacturing date: Trial medication may not be used after a retest date 
specified on a drug product label. Replacement of such medication with new or relabeled 
medication, indicating the revised retest date, is required. 


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Where allowed by local regulations, the label of the trial medication will specify the 
manufacturing date. Such medication may not be used after the retest date, which is 
specified in the certificate of analysis. 
Responsibility at the study center: The investigator is responsible for the appropriate 
storage and distribution of the investigational products and will observe the applicable 
regulations. The investigator may name a responsible person, e.g. pharmacist, to take care 
of the trial medication. 
Supply: Trial medication will be shipped to a responsible person at the investigator's 
institution who will check amount and condition of the drug received and will return an 
acknowledgement of receipt to Aeterna Zentaris. 
Storage: The trial medication can be stored in a refrigerator, at temperatures between      
2 and 8 ºC, protected from light. The trial medication may not be used after the specified 
retest/expiry date. 
Accountability: The responsible person at the study center has to account for all used and 
unused trial supplies of AEZS-108 and has to complete a Medication Accountability List 
that includes the following information: 
 
identification of patient (number and initials), 
 
date and quantity of drug dispensed, 
 
date and quantity of drug returned to Aeterna Zentaris. 
At the end of the trial, or as directed, residual supplies and the completed Medication 
Accountability List will be returned to Aeterna Zentaris, a copy of the completed list will 
be retained in the Investigator's file. 
The trial medication must not be used outside this protocol. 
 
6.1.2 
Reconstitution and administration 
Reconstitution and dilution: Physiological saline (0.9 % NaCl solution) will be used as 
solvent for the reconstitution and dilution of AEZS-108 solution. 
Four (4) mL of saline will be added per 100 mg vial, resulting in a concentration of 25 mg 
AEZS-108 per mL of the reconstituted solution. 
The appropriate volume of reconstituted AEZS-108 solution will be diluted with physio- 
logical saline, such as to contain the desired amount of drug substance in an infusion 
volume of about 250 mL. 
Stability in diluted solution: Not more than 1 hour should elapse between dissolution of 
the lyophylisate and the preparation of the solution for infusion. The diluted solution for 
infusion can be stored at room temperature, but must be completely infused within 7 hours 
after dissolution of the lyophilisate. 
Administration (Infusion): The administration schedule is as follows: 


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Dose: 
267 mg/m2; 
For each treatment course, dose calculation will take into account the 
body surface area (BSA) as derived from the patient's height and current 
body weight. (Note: If the body weight is +/- 10% of the body weight 
measured at day 1 of the preceding cycle, the body weight measured at 
day 1 of the preceding cycle may be used for calculating the dose to be 
prepared in the pharmacy). Appendix 1 provides a nomogram and 
reference to online BSA calculators for the determination of the BSA.
Route: 
Intravenous infusion over a period of about 2 hours
Frequency: 
Every Day 1 of 21-day (3-week) cycles 
Duration: 
The proposed maximum duration is 9 cycles. 
An individual patient will be withdrawn from study as soon as disease 
progression indicates treatment failure or poor tolerability requires 
withdrawal. (see Section 5.3 for withdrawal criteria). 
Premedication 
Recommended prophylactic antiemetic: 8 mg dexamethasone (see 
Section 6.3) 
Warning: 
Paravenous administration must be avoided: In rabbits, paravenous 
injection resulted in inflammatory reaction and necrosis of muscle cells. 
Extravasation may occur with or without an accompanying stinging or 
burning sensation, even if blood returns well on aspiration of the 
infusion needle. If any signs or symptoms of extravasation have 
occurred, the infusion should be immediately terminated and restarted in 
another vein. 
In the case of extravasation during infusion, it should be treated 
according the guidelines for therapy of doxorubicin extravasates. In 
addition to general treatment procedures for cytostatic extravasates, 
dimethyl sulphoxide (DMSO) 99 % should be applied to the entire 
extravasation area every 3 - 4 hours for at least 14 days. 
6.1.3 
Treatment modifications / delay of treatment 
Any deviation from the planned dosing schedule must be commented on in the CRFs. 
Delay of re-treatment: Subsequent cycles of study treatment should not begin before a 
patient has recovered to CTCAE Grade 1 from a drug-related adverse event (i.e., causality 
at least possibly related) that the investigator feels is clinically significant. No treatment 
delay is required for alopecia or anemia for which supportive therapy should be given 
according to study sites’s clinical practice (see also 6.3.1.3). Re-treatment may be 
postponed for up to 2 weeks. A patient who has not recovered within 5 weeks after the last 
dose should be withdrawn and followed up as required. 
 
Dose reduction: Any of the following drug-related adverse events (i.e., causality at least 
possibly related) will require a dose modification, if its duration exceeds the indicated 
period: 
 
Grade 4 neutropenia [ANC < 500/mm3] lasting 7 days or more 


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 
Grade 3 febrile neutropenia lasting for more than 7 days 
[Grade 3 defined as: ANC < 1000/mm3 with a single temperature of >38.3 °C 
(101 °F) or a sustained temperature of ≥ 38 °C (100.4 °F) for more than one hour] 
 
Grade 4 febrile neutropenia (of any duration) 
[Grade 4 defined as: Life-threatening consequences; urgent intervention indicated] 
 
Grade 3 thrombocytopenia [Platelet count: < 50,000 – 25,000/mm3] persistent at the 
scheduled time of re-dosing (i.e. blood sample on the day before re-dosing) and 
associated with a clinical risk of bleeding (presenting, e.g. as hemorrhagic diathesis: 
petechial rash, especially affecting tunica mucosa in oral cavity, gingival rash or 
petechial skin rash associated with prolonged bleeding time, e.g. in the Duke 
bleeding time test) 
 
Any other Grade 4 hematological toxicity (except for lymphocytopenia) lasting 
7 days or more 
 
Grade 3 nausea/vomiting/diarrhea lasting 5 days or more despite optimal medical 
management. 
If any of the above dose-limiting toxicities occurs and re-treatment is indicated after the 
toxicity has resolved to ≤ Grade 1 within the allowed period for a treatment delay, then 
dosing will be resumed with a dose reduction. 
 
Dose Level 
AEZS-108 Dose (mg/m2) 
Starting Dose 
267 
1st Dose Reduction 
(approximate 20 % reduction) 
210 
2nd Dose Reduction 
(approximate 40 % reduction) 
160 
 
The dose reduction is permanent; no dose re-escalation to the original dose should be 
permitted once a dose has been reduced. Only 2 dose reductions per patient will be 
allowed. Patients who cannot tolerate the lowest dose will be discontinued and may 
receive other treatments at the investigator's discretion. 
Supportive therapy (see also Section 6.3.1): Hematopoietic growth factors or transfusion 
of blood components may be administered as needed, e.g. in case of a delayed 
hematological recovery or in case of hematological toxicities with a shorter duration than 
specified above for DLTs. 
 
6.1.4 
Emergency measures 
A specific antidote in case of AEZS-108 overdose is not available. Close observation 
should be performed and adequate supportive care provided; adverse events/reactions 
should be treated symptomatically. 
Adverse reactions that were observed under treatment with AEZS-108 at the proposed 
dosing schedule are summarized in the Section 1.2.2. 


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6.2 
Comparator drug – Doxorubicin 
Commercially available doxorubicin products approved for use at the investigator’s site 
will be used for the treatment of patients randomly allocated to Arm B. The trade name of 
the product used will be documented in the CRFs. 
 
6.2.1 
Description / general issues 
Dry powder formulations, as well as ready-to-use solutions for intravenous use are 
allowed. The selection is at the discretion of the investigator, in line with applicable rules 
or regulations at study site. 
All applicable instructions, warnings, and precautions in the prescribing information of the 
product used will be followed. References below to specific sections of the Prescribing 
Information should be verified with the prescribing information of the product actually 
used. 
 
6.2.2 
Reconstitution and administration 
See corresponding Sections of the Prescribing Information. 
6.2.3 
Treatment modifications / delay of treatment 
 
Dosage scheme: 
60 mg/m2 by intravenous bolus injection, 1-hour 
intravenous infusion, or according to standard institution 
procedures, on Day 1 of 21-day (3-week) cycles 
Note: If the body weight is +/- 10% of the body weight 
measured at day 1 of the preceding cycle, the body weight 
measured at day 1 of the preceding cycle may be used for 
calculating the dose to be prepared in the pharmacy. 
Dose adjustment: 
(for starting dose) 
- Renal function 
at GFR below 10 ml/min.: 75 % of calculated dose 
- Hepatic function
at serum bilirubin 1.2 to 3.0 mg/100 mL: 50 % of calculated 
dose; at serum bilirubin > 3.0 mg/100 mL: 25 % of calculated 
dose 
Maximum duration 
/ dose: 
up to a cumulative lifetime dose of 550 mg/m2 
Treatment delay: 
Subsequent cycles of study treatment should not begin before a 
patient has recovered to CTCAE Grade 1 from a drug-related 
adverse event (i.e., causality at least possibly related) that the 
investigator feels is clinically significant. No treatment delay 
is required for alopecia or anemia for which supportive therapy 
should be given according to study sites’ clinical practice    
(see also 6.3.1.3). Re-treatment may be postponed for up       
to 2 weeks. A patient who has not recovered within 5 weeks 
after the last dose should be withdrawn and followed up as 
required.Note that some Prescribing Information cite the 
criteria used in study NSABP B-15, using a 


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doxorubicin/cyclophosphamide combination regimen: When 
necessary, the next cycle of treatment was delayed until the 
absolute neutrophil count was ≥ 1000 cells/mm3 and the 
platelet count was ≥ 100,000 cells/mm3 and nonhematologic 
toxicities had resolved. 
Dose reduction: 
(for retreatment) 
75 % of the starting doses for neutropenic fever/infection. 
Doxorubicin dosage must be reduced in case of 
hyperbilirubinemia as follows: 
 
Plasma bilirubin concentration 
(mg/dL) 
Dosage 
reduction (from 
starting dose) 
1.2 - 3.0 
50 % 
3.1 - 5.0 
75 % 
For further information on treatment modifications, see Sections Dosage and 
Administration of the Prescribing Information. 
6.2.4 
Emergency measures 
See Sections Warnings and Overdosage in the Prescribing Information. 
6.3 
Concomitant therapy 
All concomitant medications and therapies (prescribed and non-prescribed) must be 
recorded in the case report form, with trade name (generic name), route or formulation, 
dosing scheme, the indication and start and stop dates of administration. Any change 
during the study should be documented as well. 
 
6.3.1 
Permitted therapy 
 
6.3.1.1 
Antiemetics 
Vomiting was not a dose-limiting toxicity in the phase I clinical trial with AESZ-108. In 
phase II clinical trials completed in endometrial (n = 43) and ovarian (n = 42) cancer 
patients, no vomiting of grade 3 or 4 was observed following AEZS-108 at a dose of 267 
mg/m2. 
According to the current ASCO guideline for “Antiemetics in Oncology” (2011) [3], 
AEZS-108 should be considered a chemotherapeutic agent with “low emetic risk” and 
therefore, before start of AEZS-108 infusion, prophylactic antiemetic treatment with 8 mg 
dexamethasone is recommended. 
If additional symptomatic antiemetic treatment is needed, this should be started with an 
antiemetic with predominantly local/peripheral mode of action, like metoclopramide 
(Paspertin®), alizapride (Vergentan®). 


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If local/peripheral type antiemetics prove to be ineffective in a given patient, antiemetics 
with a predominantly central mode of action (5-HT3-antagonist, e.g. ondansetron 
(Zofran®)) will be used. 
Antiemetics that were started as symptomatic treatment should also be given as 
prophylactic treatment in subsequent treatment cycles of the same patient. 
 
6.3.1.2 
Anti-allergic treatment 
In case of an allergic reaction, treatment should consist of a step-by-step approach of 
general measures, such as adequate shock positioning, volume substitution, and the 
administration of appropriate drugs like epinephrine (0.1 to 1.0 mg), H1-and H2-receptor 
antagonists (dimetidene 4.0 to 8.0 mg, cimetidine 200 to 400 mg), and corticosteroids 
(prednisolone 0.5 to 1.0 g). 
In patients that have experienced an allergic reaction during treatment with AEZS-108, 
prophylactic anti-allergic medication (like combined application of dimetidene and 
cimetidine) should be administered in subsequent treatment cycles. 
 
6.3.1.3 
Other 
The following are permitted: 
 
In case of a delayed hematological recovery, hematopoietic blood components may 
be administered as needed. 
 
Colony stimulating factors should not be administered prophylactically during the 
first cycle of AEZS-108 or doxorubicin. From cycle 2 onwards, prophylactic use is 
at the discretion of the treating physician. 
Therapeutic use of colony stimulating factors in patients with hematotoxicity is 
permitted in any cycle. 
 
Supportive and palliative treatment without an anticancer effect (nutritional, 
transfusional support, pain control, bisphosphonates for bone metastases, etc.). 
 
6.3.2 
Prohibited therapy 
Concomitant medication and treatments that may not be administered are: 
 
concomitant anticancer therapies (including treatment with another investigational 
drug and chemo-, immune-, hormone-, or radiotherapy, but excluding irradiation of 
non-indicator lesions for symptom relief), 
 
live vaccines 
 
amiodarone 
 
sotalol. 
 
6.3.3 
Interaction with other medicinal products and other forms of 
interaction 
AEZS-108 may interact with other medicinal products in the same manner as doxorubicin. 
Therefore, based on doxorubicin’s Prescribing Information, the following is a list of drugs 


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(other than those listed in section 6.3.2) potentially requiring precautions also when used 
with AEZS-108: 
 
Amphotericin B 
 
Antiepileptic drugs such as carbamazepine, phenytoin, valproate 
 
Cardioactive drugs, such as calcium channel blockers(e.g. verapamil) 
 
Cyclosporin 
 
Cimetidine 
 
Clozapine 
 
Digoxin 
 
Heparin 
 
Hepatotoxic drugs 
 
Inducers of CYP450, such as rifampicin and barbiturates 
 
Inhibitors of CYP450, such as fluvoxamine, ciprofloxacin, gemfibrozil, fluconazole, 
bupropion, cinacalcet, fluoxetine, paroxetine, quinidine, indinavir, nelfinavir, 
ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, 
suboxone and telithromycin 
 
Progesterone 
 
Radiation therapy (preceding, concomitant or subsequent) 
 
Ritonavir 
 
Substances influencing the bone-marrow function such as amidopyrine derivatives, 
antiretroviral drugs, chloramphenicol, phenytoin, sulphonamides 
 
Uric acid lowering agents 
Examples of precautions are monitoring of cardiac function, monitoring of 
hemato/hepato/nephrotoxicity and dose adjustment. The investigator is referred to 
doxorubicin’s Prescribing Information to identify which precaution(s) must be applied 
specifically to each drug listed above also when used concomitantly with AEZS-108. 
 
6.4 
Follow-up treatment (no crossover after the end of study treatment) 
For a patient who requires further treatment for her malignant disease, after the end of 
study treatment with AEZS-108 or doxorubicin, the selection and timing of such treatment 
is at the discretion of the investigator. As there is no standard of care treatment in these 
cases, he/she will take into account the current signs and symptoms of the disease and, 
where applicable, any persisting drug-related adverse events (i.e., causality at least 
possibly related). 
A patient who fails on either study treatment will NOT be allowed to cross over to the 
alternative study treatment. 


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7 
ASSESSMENTS 
The following endpoints will be assessed: 
1. 
Overall survival (primary efficacy endpoint). 
2a 
Efficacy: progression-free survival (PFS), overall response rate (ORR = CR + PR), 
and a clinical benefit rate (CBR) will be evaluated as CR + PR + SD for at least 3 
months. 
2b. 
Safety: adverse events, clinical laboratory, ECG and LVEF.  
2c. 
Quality of Life: EORTC QLQ30 + QLQ-EN24 questionnaires. 
Pharmacokinetic and electrocardiographic parameters of the PK sub-study are described in 
APPENDIX 7 of the protocol. 
Evaluation of exposure-response relationship and population pharmacokinetic evaluations 
will be described in the Statistical Analysis Plan. 
 
7.1 
Efficacy (RECIST) 
Response and progression will be evaluated using the international criteria proposed by the 
revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[6]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
During ongoing treatment, patients should be re-evaluated for response every 3 cycles (i.e. 
every 9 weeks). 
The following text is a summary of RECIST 1.1. 
 
7.1.1 
Confirmatory Measurement 
A subsequent scan must be obtained no earlier than 4 weeks following the initial 
documentation of an objective status of either complete response (CR) or partial response 
(PR). 
Note: During ongoing treatment, the next scheduled follow-up measurement would be due 
after three more cycles, i.e., 9 weeks later in absence of treatment delays).  In order not to 
miss the confirmation of the response, or if a patient will go off treatment, a separate 
imaging session should be scheduled, however, no earlier than 4 weeks after the previous 
imaging. 
 
7.1.2 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with the study drug. 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 


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Evaluable Non-Target Disease Response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
 
7.1.3 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray, as >10 mm with CT scan, or ≥10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area will be considered 
measurable (and eligible as target lesion) if they have developed or progressed after the 
irradiation. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease (not 
applicable in this study), ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected based on 
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 that can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 


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Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
7.1.4 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g. skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g. skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific   
MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible. 
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. 


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Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
Tumor markers (not applicable in this study) 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g. residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an effusion 
may be a side effect of the treatment) and progressive disease. 
 
7.1.5 
Response Criteria 
 
7.1.5.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30 % decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20 % increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20 %, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
7.1.5.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 


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Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
7.1.5.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
Table 1: Response for patients with measurable disease (i.e., target disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 


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Table 2: Tumor response for patients with non-measurable disease (i.e., non-target 
disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised. 
7.1.6 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 
 
7.1.7 
Progression-Free Survival (PFS) 
PFS is defined as the time elapsed from randomization to the date of documented 
progression or death, whichever comes first. For surviving patients without progression 
who begin alternative treatment, PFS will be censored at the last date of documented 
progression-free status prior to starting alternative treatment. Similarly, losses to follow up 
will be censored at the last date of documented progression-free status. 
 
7.1.8 
Overall response rate (ORR) 
ORR i.e. overall response rate is defined as the sum of the complete and partial response 
rate as detailed in Section 7.1.5. 
 
7.1.9 
Overall Clinical benefit rate (CBR) 
CBR is defined as the sum of the complete response and partial response and stable disease 
rate as detailed in Section 7.1.5. 
Additionally, we define clinical benefit as non-progression at 9 weeks with no toxicity 
requiring termination of treatment. 


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7.1.10 
Overall survival 
Overall survival (OS) is defined as the elapsed time from randomization to death from any 
cause. For surviving patients, follow-up will be censored at the date of last contact. 
 
7.2 
Safety 
 
7.2.1 
Adverse events 
 
7.2.1.1 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An adverse event (AE) can 
therefore be any unfavorable and unintended sign including an abnormal laboratory (or 
vital, ECG etc.) findingA, symptom or diseaseB temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
A 
Documentation rules for abnormalities in laboratory finding, vital signs, 
ECG etc. are specified in Section 7.2.1.3. 
B 
This will also include intercurrent diseases and accidents observed during 
treatment period as well as corresponding events during drug-free periods, 
under placebo or in a reference group receiving drug or non- drug 
therapy. 
Serious adverse event (SAE) means any untoward medical occurrence that at any doseA: 
 
results in death, 
 
is life-threateningB, 
 
requires inpatient hospitalization or prolongation of existing hospitalizationC, 
 
results in persistent or significant disability or incapacity, 
 
is a congenital anomaly / birth defect or 
 
is another medically important conditionD. 
A 
All events that meet the definition of an SAE but, in the opinion of the 
treating investigator, are clearly expected from the patient’s disease or 
related to disease progression (i.e., there exists no reasonable possibility 
that they were caused by the study drug) should be recorded on the case 
report forms only and do not require the reporting as an SAE (as defined 
in protocol Section 7.2.1.4). This will also apply to patient’s death that is 
clearly attributed to the underlying malignant disease. 
B 
The term “life-threatening” in the definition of “serious” refers to an 
event in which the patient is at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if 
it were more severe. 


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C. 
Hospitalization for elective treatment of a pre-existing condition that did 
not worsen during the clinical investigation is not considered an AE. 
Admittance to an emergency room for observation without being 
admitted to the hospital may be considered an AE, but is not considered 
as an SAE. Hospitalization or nursing home admission for the purpose 
of caregiver respite is not considered an AE. Hospitalizations for 
symptoms of progressive disease are not considered an SAE. 
Complications that occur during hospitalization are AEs, and if a 
complication prolongs hospitalization, the event is considered serious. 
D 
Medically important conditions that may not result in death, be life 
threatening or require hospitalization may be considered as SAE when, 
based upon appropriate medical judgment, they may jeopardize the 
patient or may require intervention to prevent one of the outcomes listed 
in the definition above. Examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse [Ref: Federal Register 
§312.32 IND safety reports]. 
Please note: The term “severe” is often used to describe the intensity (severity) of an event 
(as in mild, moderate, or severe pain); the event itself may be of relatively minor medical 
significance (such as severe headache). This is not the same as “serious”, which is based 
on patient/event outcome or action criteria usually associated with events that pose a threat 
to patient's life or vital functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
Severity Grading 
The NCI Common Terminology Criteria for Adverse Events (version 4.03 or subsequent 
ones) are to be used for the grading of severity of symptoms and abnormal findings. A 
copy of the document is included in the investigator’s file (see also: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
For adverse events not covered by the NCI-CTCAE grading system, the following 
definitions will be used: 
 
Grade 1 - Mild: awareness of sign, symptom, or event, but easily tolerated 
 
Grade 2 - Moderate: discomfort enough to cause interference usual activity and 
may warrant intervention 
 
Grade 3 - Severe: incapacitating with inability to do usual activities or significantly 
affects clinical status, and warrants intervention 
 
Grade 4 - Life-threatening: immediate risk of death (Note: will require reporting as 
an SAE) 
Causality assessment 
The investigator will assess the causal relationship of an AE/SAE to the study drug using 
the following categories and definitions. 


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 
Likely (at least 3 of the following conditions must apply): 
o 
AE had a reasonable temporal relationship to administration of trial 
medication; 
o 
AE could not readily have been produced by the subject’s clinical state or have 
been due to environmental or other interventions; 
o 
AE followed a known pattern of response to the trial medication; 
o 
AE disappeared or decreased with reduction in dose or cessation of the trial 
medication. 
 
Possible (at least 2 of the following conditions must apply): 
o 
AE had a reasonable temporal relationship to administration of trial 
medication; 
o 
AE could not readily have been produced by the subject’s clinical state; 
o 
AE could not readily have been due to environmental or other interventions; 
o 
AE followed a known pattern of response to the trial medication. 
 
Unlikely (at least 2 of the following conditions must apply): 
o 
AE did not have temporal relationship to administration of trial medication; 
o 
AE could readily have been produced by the subject’s clinical state; 
o 
AE could have been due to environmental or other interventions;     
o 
AE did not follow known pattern of response to the trial medication; 
o 
AE did not reappear or worsen with reintroduction of the trial medication. 
 
Unrelated: 
o 
AE was clearly due to extraneous causes (e.g. underlying disease, 
environment). 
 
7.2.1.2 
Procedures in case of adverse events 
Throughout the study, the patient will be questioned and/or examined by the Investigator  
or his/her designee for evidence of adverse events. The questioning of patients with regard 
to the possible occurrence of adverse events should be as non-specific as possible. 
However, given that it is the site’s responsibility to follow up all AEs, specific questions 
related to previously reported AEs with regard to their resolution or continuation must be 
asked. 
All adverse events occurring during a study have to be documented, regardless of any 
assumption of a causal relationship, on the respective AE CRF. All events that occurred 
during the screening period should be documented as medical history. The investigator 
should ensure, e.g. by telephone call to the trial subject, to record all events that occurred 
within 28 days after the last exposure to study drug. 
Documentation of adverse events includes date of onset and offset, pattern, duration, 
severity, impact, actions taken, seriousness, and outcome. The investigator should also 


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evaluate the probability of a causal relationship of the adverse event to the study 
medication as likely, possible, unlikely, or unrelated. Information provided in the 
Investigator’s Brochure may support this evaluation. 
 
7.2.1.3 
Documentation of routine safety parameters 
A value outside the normal or reference range in a routine safety assessment, such as 
clinical laboratory, vital signs, or ECG, may signify an adverse finding. If the investigator 
considers the abnormality as clinically significant/relevant, as defined below, he should 
also record this on the CRF Adverse Events [Note: A clinically significant abnormality 
observed prior to first administration of study treatment should be recorded as update of 
the CRF Medical History]. If the findings contribute to a clinical diagnosis, such as 
hepatitis in case of increased liver enzymes, this diagnosis should be recorded as adverse 
event. 
An abnormality must be considered as clinically significant, if 
 
it represents a serious adverse event, or 
 
it led to premature discontinuation of the study, or 
 
it required a therapeutic measure, or 
 
in the judgment of the investigator - it indicates a medically relevant condition or 
risk, without meeting any of the above criteria. 
 
7.2.1.4 
Reporting of serious adverse event 
The investigator must report serious adverse events (SAE) occurring or observed from the 
day of first administration of the investigational drug on and until 4 weeks after last 
administration of the investigational drug (development of impaired cardiac function (ex. 
grade 4 left ventricular systolic dysfunction) within 1 year after last administration of 
study drug should also be reported as an SAE); see page 2 for contact persons and 
email/phone/fax numbers. As soon as possible, but in no case later than 24 hours after the 
SAE has been noted, the “Serious Adverse Event Report” form (copies included in the 
Investigator's File) should be sent by email, whether or not complete information is 
available within this period. In case of incomplete information, the investigator has to 
provide follow-up information as soon as possible, again using the SAE report form. 
Regarding hospitalization, please refer to Section 7.2.1.1, footnotes A and C for 
circumstances that will determine the consideration as SAE and need for reporting on an 
SAE form to AEZS drug safety. 
All events that meet the definition of serious but, in the opinion of the treating investigator, 
are clearly expected from the patient’s disease or related to disease progression (i.e., there 
exists no reasonable possibility that they were caused by the study drug) should be reported 
on the case report forms and do not require immediate reporting on an SAE form.          
This will also apply to patient’s death that is clearly attributed to the underlying malignant 
disease. 
Reports will be evaluated by Aeterna Zentaris and authorities will be informed according 
to national or international regulations. The same information will also be made available 
to principal investigators of other currently ongoing trials with the same study medication. 
 
46 


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7.2.2 
Clinical laboratory tests 
The following clinical laboratory tests will be performed in the laboratory of each center. 
Clinical laboratory tests will comprise the following parameters: 
 
Panel name 
Laboratory parameters included 
Hematology 
leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes 
(platelets); differential white blood cell count (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils) 
Chemistries 
 
- Enzymes 
AST/SGOT, ALT/SGPT, gamma-GT, alkaline phosphatase, LDH 
- Substrates 
total protein, total bilirubin, creatinine, urea, uric acid 
- Electrolytes 
sodium, potassium, calcium 
Urinalysis 
glucose*, protein*, microalbumin** 
Hormones 
luteinizing hormone (LH), follicle stimulating hormone (FSH) 
Pregnancy test 
ß-HCG (in serum; for women of childbearing potential only) 
* In case there is no possibility for evaluation of the parameters provided above semiquantitative dipstick 
analysis will be accepted 
** In cases where 24-hour urine is not available to determine microalbumin, the microalbumin/creatinine 
ratio or microalbumin-specific urine sticks may be used instead. 
For each value outside the normal range, the investigator must classify the clinical 
significance/relevance of the abnormality following the criteria defined above, in Section 
7.2.1.3. 
 
7.2.3 
Vital parameters, body weight, and performance status 
Vital parameters to be recorded comprise systolic and diastolic blood pressure, and pulse. 
Body weight shall be recorded in kg (rounded to closest integer). Note: the current body 
weight shall be used for the estimation of the body surface area (Appendix 1), as the basis 
for the total dose to be administered. (Note: If the body weight is +/- 10% of the body 
weight measured at day 1 of the preceding cycle, the body weight measured at day 1 of the 
preceding cycle may be used for calculating the dose to be prepared in the pharmacy). 
Performance status will be recorded according to the ECOG/Zubrod scale (see Appendix 
2). 
The investigator should comment in the respective section of the CRF on a change 
compared to screening that is considered as clinically relevant. Such comment should - as 
far as possible - provide some explanation for the change. For obligations regarding 
documentation of abnormalities in vital signs as AE see Section 7.2.1.3. 
 
7.2.3.1 
ECG 
The ECG will be recorded as scheduled in the flow-chart by means of a 12-lead (I, II, III, 
aVR, aVL, aVF, V1-V6) ECG system over a duration of 10 sec while the subjects will rest 
in supine position. The chart speed will be set at 25 mm/sec. The ECG patterns will be 
analyzed qualitatively with particular emphasis on changes in the T-wave duration and 


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morphology. The following will be computed by the ECG machine: heart rate, time 
intervals such as PQ/PR, QRS and QT interval, the heart rate corrected QTc interval 
calculated according to Bazett’s formula (QTcB = QT/√RR) or Fridericia’s formula   
(QTcF = QT/3√RR), where QTc is the QT interval corrected for rate, and RR is the interval 
from the onset of one QRS complex to the onset of the next QRS complex, measured in 
seconds. 
The investigator should comment on the CRF on any deviation from normal that is 
considered clinically significant/relevant. If a finding is considered as clinically significant 
as defined in above, in Section 7.2.1.3, it must also be documented on the CRF Adverse 
Events. 
For recording and evaluation of ECGs within the pharmacokinetic sub-study, refer to 
Appendix 7 of the protocol. 
 
7.2.3.2 
Left ventricular ejection fraction (LVEF) 
Cardiac function will be monitored by either echocardiography (ECHO) or radionuclide 
ventriculography (RNV) / multigated radionuclide angiography (MUGA). The technique 
used for assessment should be consistent throughout the trial for a given patient. 
RNV/MUGA should be used where good quality ECHO images cannot be obtained from a 
patient, e.g., because of concomitant lung disease. 
If test results indicate deterioration in cardiac function during the study, the benefit of 
continued therapy should be carefully evaluated against the risk of producing irreversible 
cardiac damage. Patients with LVEF < 30% are at significant risk of congestive heart 
failure. See Section 5.3 for withdrawal criteria. 
 
7.3 
Other 
 
7.3.1 
Characterization of LHRH receptor expression in tumor tissue 
It is planned to determine the expression of LHRH receptors in patients' tumor specimens 
('receptor status') and to correlate the receptor status with clinical outcome data. 
An assay for LHRH receptor expression is currently under development and may become 
available prior to the end of patient recruitment. Therefore, archival FFPE specimens 
(blocks) must be retained at the site. Similarly, FFPE blocks must be prepared from any 
fresh biopsy material obtained during screening. Study sites will be instructed about the 
timing and specific conditions of the specimens to be submitted. 
 
7.3.2 
Quality of life (QoL) 
QoL will be measured by the EORTC QLQ-C30 questionnaire [2, 9], supplemented by the 
Endometrial Cancer Module (QLQ-EN24) which is designed for patients with all stages of 
endometrial cancer treated with pelvic surgery, chemotherapy, radiotherapy or  
concomitant radio/chemotherapy [12]. 
Specimens of both questionnaires are provided in Appendix 6. 


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7.3.3 
Pharmacokinetic investigations 
Detailed instructions for the collection, processing, storage and shipment of samples for 
pharmacokinetic investigations will be provided in a separate manual. 
7.3.3.1 
Sparse PK sampling 
Sparse PK sampling of AEZS-108-treated patients will be performed at all investigational 
sites where feasible. Sparse PK sampling is expected in one cycle, either Cycle 1 or 
alternatively in a subsequent cycle of ongoing patients. The windows for the sampling are 
defined as follows: 
 
Sample # Time Window 
1 
within 60 minutes before end of the 2-hour infusion 
2 
between 30 and 60 minutes after the end of infusion (EOI) 
3 
between 120 and 180 minutes after EOI 
4* 
between 4 and 6 hours after EOI 
*) optional, depending on feasibility 
 
7.3.3.2 
PK sub-study 
The pharmacokinetic sub-study will be conducted at selected investigational sites; it is 
planned to involve 40 patients, 20 patients from each study arm. Procedures are described 
in APPENDIX 7 of the protocol. 
 
8 
STUDY PROCEDURES 
A flow chart of the study procedures is displayed on page 13. 
 
8.1 
Patient's informed consent and registration prior to screening 
A patient who has been identified as a potential candidate for the study will be informed 
about the study, based on the IRB/IEC approved written patient information. 
Each patient who has given written informed consent will be registered into an interactive 
web-based response system (IWRS) before starting study-specific screening procedures. 
The IWRS will issue a unique, 4-digit patient number that will be used to identify the 
patient on all study-related documents and specimens. 
 
8.2 
Screening procedures (within 4 weeks before start of treatment) 
The following information will be obtained and screening tests will be performed within 
28 calendar days before start of study treatment, i.e., Cycle 1 Day 1: 
 
Medical history and concomitant diseases (general and cancer-related history 
including prior treatment) 


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 
Clinical assessments (physical examination, ECOG performance status and vital 
signs with height, weight, blood pressure, pulse) 
o 
Clinical laboratory (hematology, chemistries, urinalysis, hormones, 
pregnancy test (in serum) for women of childbearing potential) 
 
Cardiac function: 
o 
12-lead electrocardiogram (ECG) 
o 
Left ventricular ejection fraction (LVEF): Echocardiogram or MUGA 
Note: In absence of intercurrent chemotherapy or cardiac medical history, 
results dating back up to 8 weeks will be acceptable. 
 
Tumor imaging (CT or MRI): Appropriate radiographic procedures to document 
extent of disease 
Note: For a given patient, the same imaging method must be used at screening and 
at follow-up assessments. 
 
Quality of Life: EORTC questionnaires 
 
Tumor tissue specimens for LHRH receptor assay: FFPE archival tumor 
specimen or – where available – FFPE fresh biopsies obtained during screening will 
be retained for later analysis. 
Patients who are found to be ineligible will be registered in the IWRS as “Screen failure”. 
The reason for screen failure will be captured categorically. Apart from demographic 
patient characteristics, no other detailed screening data will be captured. 
 
8.3 
Randomized allocation of study treatment 
Patients who meet the eligibility criteria will be randomly allocated by central 
randomization in a 1:1 ratio to receive either AEZS-108 (Arm A) or doxorubicin (Arm B). 
Start of study treatment (Cycle 1 Day 1) should be scheduled for the nearest feasible date, 
to ensure that screening investigations, in particular laboratory investigations or 
measurements, have been performed within 28 days prior to treatment start. 
 
8.4 
Procedures during treatment 
 
8.4.1 
Procedures on Cycle 1 Day 1 (date of first study treatment) 
After randomization, but prior to first administration of study treatment, each patient will 
have the following assessments and tests: 
 
Interval history and symptom-directed examination 
Findings to be recorded as Medical History / Concomitant Disease/Condition 
 
Clinical assessments (including ECOG performance status, blood pressure, pulse, 
and weight for BSA and dose calculation) 
 
Clinical laboratory tests (hematology, chemistries, urinalysis) 
 
Eligibility criteria review 
In the absence of new findings that would violate any of the eligibility criteria, 


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except for Day 1 clinical laboratory tests, the patient may receive the allocated study 
treatment. 
 
Study treatment 
Administration of allocated study medication at the recommended starting dose. 
 
Sparse PK sampling (AEZS-108 treated patients only) 
Blood collections within the following time windows:     
sample #1: within 60 minutes before end of the 2-hour infusion 
sample #2: between 30 and 60 minutes after the end of infusion (EOI) 
sample #3: between 120 and 180 minutes after EOI; 
sample #4 (optional): between 4 and 6 hours after EOI. 
A patient, in whom sparse PK sampling was not possible in Cycle 1, may have the 
samples taken at any subsequent cycle. It is not planned to have repetitive sparse 
sampling of the same patient during multiple cycles. 
 
PK substudy (instead of ‘sparse PK sampling’, at selected investigational sites 
only) 
Procedures related to the PK substudy are described in Appendix 7 of the protocol. 
 
8.4.2 
Weekly procedures during Cycle 1 
Once weekly controls during Cycle 1 will include the following: 
 
Clinical assessments (including blood pressure and pulse) 
 
Clinical laboratory tests (hematology, chemistries, urinalysis) 
 
Adverse event recording. 
Retreatment is planned in 3-weekly intervals, i.e. Day 1 of new cycle is corresponding to 
Day 22 of the previous cycle. In case of incomplete recovery from hematological toxicity 
or adverse events, re-treatment may be delayed for up to 2 weeks, i.e. with appropriate 
supplementary weekly controls on Day 29 and Day 35 (see Section 6.1.3). 
 
8.4.3 
Procedures on Day 1 of Cycle 2-9 
It will be allowed to schedule tests up to 3 days before the planned Cycle Day 1, to ensure 
availability of safety-relevant results prior to dosing. 
 
Interval history and symptom-directed examination 
Adverse changes to be recorded as Adverse Events 
 
Clinical assessments (including ECOG performance status, blood pressure, pulse, 
and weight for BSA and dose calculation). Note: If the body weight is +/- 10 % of 
the body weight measured at day 1 of the preceding cycle, the body weight measured 
at day 1 of the preceding cycle may be used for calculating the dose to be prepared in 
the pharmacy. 
 
Clinical laboratory tests (hematology, chemistries, urinalysis, hormones) 


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 
Cardiac function: 
o 
12-lead electrocardiogram (ECG) 
 
Study treatment 
If dose-limiting toxicities have been observed in a previous cycle, the dose of the 
study treatment will be reduced in the next cycle (as well as in further cycles), as 
specified in Section 6.1.3 or 6.2.3. 
 
Sparse PK sampling (AEZS-108 treated patients only) 
A patient in whom sparse PK sampling was not possible in Cycle 1 may have the 
samples taken at any subsequent cycle. It is not planned to have repetitive sparse 
sampling of the same patient during multiple cycles. 
Blood collections within the following time windows:     
sample #1: within 60 minutes before end of the 2-hour infusion 
sample #2: between 30 and 60 minutes after the end of infusion (EOI) 
sample #3: between 120 and 180 minutes after EOI; 
sample #4 (optional): between 4 and 6 hours after EOI. 
 
8.4.4 
Procedures during Cycle 2-9 
Depending on hematological toxicities and any safety issues observed during Cycle 1, 
scheduling of hematological controls and/or other investigations is at the discretion of the 
investigators. For tests performed by a laboratory not affiliated with the study site (e.g. 
mid-cycle controls by the patient’s home doctor) copies of the external laboratory reports 
will be provided to the sponsor and results reported in the CRF. 
Adverse findings in such controls/investigations/diaries that the investigator considers as 
clinically important/significant will be recorded as Adverse Event. 
 
8.4.5 
Procedures at the end of Cycle 3 and 6 
The following assessments will be performed at end of Cycle 3 and Cycle 6, i.e. together 
with the assessments required to assure continuation of study treatment with Cycle 4 and 
Cycle 7, respectively. 
 
Cardiac function: 
o 
Left ventricular ejection fraction (LVEF): echocardiogram or MUGA 
Note: Recommended to be conducted also at end of Cycle 7 and 8 (i.e., before start 
of Cycle 8 and Cycle 9, respectively) for both arms. Results are to be captured on 
the eCRF if there is an abnormal finding. 
 
Quality of Life: questionnaires 
 
Tumor imaging (CT or MRI): evaluation of time-point response by comparison 
with target and non-target lesions defined at screening (baseline) 
 
8.5 
Procedures at end of study treatment 
A patient who is going off study treatment (see Section 5.3) – will have the 
assessments/investigations specified below. 


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As an end-of-cycle assessment, it should be scheduled 3 to 5 weeks (Day 21 to 35) after 
the last dose. Additional visits/assessments may be indicated to follow-up unresolved 
adverse events. 
 
Interval history and symptom-directed examination 
 
Clinical laboratory tests (hematology, chemistries, urinalysis, hormones) 
 
Cardiac function: 
o 
12-lead electrocardiogram (ECG) 
o 
Left ventricular ejection fraction (LVEF): Echocardiogram or MUGA 
 
Quality of Life: questionnaires 
 
Tumor imaging (CT or MRI): evaluation of time-point response by comparison 
with target and non-target lesions defined at screening (baseline) 
 
Final evaluations: best response, reason for discontinuation, investigator's overall 
judgment on tolerability of study treatment 
 
8.6 
Post-treatment follow-up 
A patient developing signs of cardiac failure during post-treatment follow-up will have 
LVEF and ECG evaluated; a left ventricular dysfunction of CTCAE Grade 4 will be 
reported as an SAE. 
 
8.6.1 
Follow-up until progression 
Whenever possible, a patient who has discontinued study treatment for other reason than 
progressive disease will be followed up at 3-monthly intervals until progression including 
the following assessments: 
 
Clinical assessments (including ECOG performance status, blood pressure, pulse) 
 
Tumor imaging (CT or MRI): evaluation of time-point response by comparison 
with target and non-target lesions at time of Best Response 
 
Quality of Life: questionnaires 
Anticipated exceptions from follow-up will be “withdrawal of consent”, “lost to follow- 
up”, “patient moved”. 
Follow-ups until progression will be suspended in patients in whom a new cancer 
treatment has been started without prior documentation of progressive disease. The start 
date of the new systemic therapy (or local therapy directed to lesions on which response 
assessment was based) will be documented. 
 
8.6.2 
Follow-up for survival 
For patients going off study, survival information will be collected at 3-month intervals, 
telephone contact is acceptable. 


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9 
STATISTICAL CONSIDERATIONS 
The sections of the Statistical Considerations describe the statistical methods to be used to 
analyze the efficacy and safety. These methods may be revised and updated due to reasons 
such as regulatory requirements or need for further clarifications. The final analysis plan 
will be documented in a formal statistical analysis plan (SAP) that must be finalized before 
database lock. The SAP will include details on how variables will be derived, how  
missing data will be handled, and how censoring procedures will be applied to time to event 
related variables as well as the details on statistical methods to be used for safety and 
efficacy analyses. The final clinical study report will discuss deviations from the SAP, if 
any. 
Unless otherwise stated, all analyses will be performed using SAS Version 9 and all 
hypothesis tests will be conducted at a two-sided significance level of 0.05. 
Summary tabulations will display the number of observations, mean, standard deviation, 
median, minimum, maximum, and appropriate percentiles for continuous variables, and the 
number and percentage by category for categorical data. Summaries will present data by 
treatment arm and overall, if appropriate. The data listings will include all available 
efficacy and safety data. 
 
9.1 
Analysis populations 
The following populations will be used for statistical analysis. 
 
9.1.1 
Intent-to-treat population 
The Intent-to-Treat (ITT) population will consist of all randomized patients. Analyses of 
this population will assign patients the treatment they were scheduled to receive, regardless 
of any errors of dosing or dose modifications. 
 
9.1.2 
Safety population 
The safety population will include all randomized patients who received at least one dose 
of study treatment. In the safety analyses, patients will be included in the treatment arm 
that they have actually received. 
 
9.1.3 
Per protocol population 
The Per-Protocol (PP) population will include all randomized patients without major 
protocol deviations. What constitutes a major protocol deviation will be determined and 
documented prior to database lock. Protocol deviations will also be presented in the 
clinical study report. 


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9.2 
Demographic and baseline characteristics 
The two treatment arms will be assessed descriptively for comparability of demographic 
and baseline characteristics. Data to be evaluated will include at least age, race, and 
components of disease severity assessment. 
 
9.3 
Treatments and medications 
 
9.3.1 
Prior treatment for endometrial cancer 
Use of prior treatment for endometrial cancer will be presented as frequency counts and 
percentages. Descriptive statistics for the number of prior lines of therapy will also be 
presented. Prior chemotherapy will be coded using the World Health Organization (WHO) 
dictionary and summarized by treatment arms for the safety population. 
 
9.3.2 
Prior and concomitant medications 
All medications recorded on the CRFs will be coded using the WHO dictionary. Prior and 
concomitant medications will be summarized by treatment arm in the safety population by 
anatomical therapeutic chemical (ATC) class level 4 and WHO Drug base substance 
preferred name. 
Prior medications are defined as medications with stop dates occurring before the date of 
first administration of study treatment. Concomitant medications are defined as 
medications with start dates occurring on or after the date of first administration of study 
treatment but no later than 30 days after the last administration of study treatment. 
Medications with start and stop dates that overlap the date of first administration of study 
drugs will be summarized as both prior and concomitant medications. 
 
9.3.3 
Study treatment 
Study treatment exposure (e.g., number of treatment cycles, total drug exposed) will be 
summarized by treatment arm in the ITT and safety populations. 
Treatment modifications will be summarized by treatment arm in the ITT and safety 
populations for each of the study treatments separately. The number and percentage of 
patients with doses delayed (withheld) and doses reduced, and reasons for these dose 
changes will be summarized by treatment cycle. 
A summary of the number and percentage of patients receiving subsequent alternative 
anticancer therapy after discontinuation of study treatment will be presented by treatment 
arm in the ITT population. 


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9.4 
Primary efficacy outcome 
 
9.4.1 
Definition 
The primary efficacy outcome is overall survival (OS). Overall survival will be defined as 
the days between randomization and the date of documented death for 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. 
 
9.4.2 
Primary analysis 
The primary efficacy analysis will be performed using the ITT population. The final 
analysis, which is event-based, will be conducted after approximately 384 randomized 
patients have died. In the primary analysis, a log-rank test with an overall two-sided Type  
I error rate of 0.05 after taking the interim analyses into account will be used to compare 
OS between the two treatment arms via a SAS lifetest procedure. Kaplan-Meier estimates 
will be used to calculate median OS and the 95 % confidence interval of the median OS. 
The proportion of patients alive at six and 12 months (from randomization date) and the 95 
% confidence intervals for these estimated proportions, if appropriate, will be presented. 
A Cox model with treatment effects will be used to estimate the hazard ratio and perform 
hypothesis testing. The estimated hazard ratio and the 95 % confidence interval of the 
hazard ratio will be presented. 
 
9.4.3 
Sensitivity analyses 
The following sensitivity OS analyses will be performed: 
1. 
Patients who changed treatment will be censored at the day the patient received the 
new treatment; 
2. 
PP analysis. 
Additional sensitivity analyses may be performed as appropriate. 
 
9.4.4 
Subgroup analyses 
OS will also be analyzed for the following subgroups: 
1. 
Age (≤ 64 and > 64 years of age) 
2. 
Staging (FIGO stage III or IV) 
Additional subgroup analyses may be performed if appropriate. In particular, if the 
strength of the LHRH receptor expression can be classified, subgroup analyses based on 
the strength of LHRH receptor expression will be performed. 
 
9.4.5 
Exploratory analyses 
Exploratory analyses to evaluate potential risks/benefits factors may also be performed. 


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9.5 
Secondary efficacy outcomes 
 
9.5.1 
Progression free survival (PFS) 
Progression-free survival will be defined as the days between randomization and the date 
of documented progression or death for any cause. Criteria for disease progression can be 
found in Section 7.1.7. 
For patients whose progression status cannot be determined, their PFS data will be 
censored at the last adequate progression assessment date that the patient is confirmed to 
have no progression. 
Hypothesis testing between the two treatment arms will be performed using a log-rank test. 
For each treatment arm, the median time to progression will be estimated using the 
Kaplan-Meier method and the 95 % confidence interval of the median will be reported. 
 
9.5.2 
Overall response rate (ORR) and clinical benefit 
The ORR for each treatment arm will be estimated as the proportion of responders, defined 
as a patient whose best overall response is PR or better during the treatment period. All 
responses must be confirmed at least 4 weeks after the initial response is seen. Tumor 
assessments will occur every 3 cycles (± 7 days) during ongoing treatment then every 
3 months (± 7 days) thereafter while the patient is on study. The last assessment will occur 
either when progression is confirmed or when approximately 384 randomized patients have 
died 
Hypothesis testing between the two treatment arms will be performed using a Mantel- 
Haenszel test. The odds ratio and 95 % confidence interval of the odds ratio will be 
presented. 
Clinical benefit is defined as having stable disease or better lasting for at least 9 weeks. 
Clinical benefit rate will be analyzed using the same methods for the ORR analyses. 
 
9.5.3 
Quality of life 
Change from baseline in Quality of life will be analyzed via an ANOVA model with 
treatment effect and baseline quality of life score. The treatment effect and treatment 
difference will be estimated and the 95 % confidence interval of the estimates will be 
presented. 
 
9.6 
Safety analysis 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, as 
well as on clinically significant changes in the patient’s physical examination, vital signs, 
and clinical laboratory results. Safety analyses will be performed using the safety 
population. Safety variables will be tabulated and presented according to the treatment the 
patient actually received. Exposure to study treatment and reasons for discontinuation of 
study treatment will also be tabulated. 


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9.6.1 
Adverse events 
Each AE and SAE term reported will be mapped to a preferred term (PT) using the 
MedDRA dictionary. The investigator will classify the severity of AEs using the NCI 
CTCAE v4.03 and will assess the relationship of each event to study treatment. 
All AEs and SAEs occurring on study will be listed by patient. The frequency and 
percentages of patients with treatment-emergent adverse events (TEAEs) will be tabulated 
by system organ class (SOC) and PT, where treatment-emergent is defined as any AE that: 
 
Occurs after randomization and through the follow-up of the last treatment cycle or, 
if an SAE, until the event has resolved or stabilized, 
 
Is considered treatment-related regardless of the start date of the event, or 
 
Is present before randomization but worsens in intensity. 
TEAEs that are considered at least possibly related to study treatment will be tabulated as 
well as deaths, SAEs, and events resulting in treatment discontinuation. 
At each level of summarization, a patient will be counted only once for each AE, SOC, or 
PT experienced within that level. In the summation for AE severity, within each level of 
AE, SOC, or PT experienced, the one with the highest severity will be included. In the 
summation for AE’s relationship to the study drug, within each level of AE, SOC, or PT 
experienced, the one with the closest relationship to the study drug will be included. 
 
9.6.2 
Laboratory test results 
Continuous laboratory tests will be summarized by treatment arm across time on study 
using descriptive statistics for actual values and for changes from baseline. Where 
applicable, shift from baseline in NCI CTCAE grade and by high/low flags (where NCI 
CTCAE grades are not defined) will be presented by treatment arm and time. The 
frequency of clinically significant abnormal laboratory values will be tabulated. 
 
9.6.3 
Other safety outcomes 
 
9.6.3.1 
Vital signs 
Vital signs will be summarized by treatment arm across time on study using descriptive 
statistics for actual values and for changes from baseline. 
 
9.6.3.2 
ECG 
Descriptive analyses of ECG findings and intervals for both absolute and results and 
changes from baseline parameters will be performed. This will be done using listings, 
tables, and graphs, where appropriate. 
The analyses will include: 
 Absolute and changes of frequency of abnormalities 
 Central tendency analysis for absolute and changes from baseline in cardiac 
intervals 
 Outlier analysis for absolute and changes from baseline in cardiac intervals. 


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In addition, the relationship between drug exposure and QT/QTc interval changes will be 
explored using scatter plots and regression analyses. 
 
9.6.3.3 
LVEF 
LVEF will be summarized by treatment arm across time on study using descriptive 
statistics for actual values and for changes from baseline. 
 
9.7 
Pharmacokinetics 
 
9.7.1 
Demographics 
Descriptive statistics of key demographic features of patients who completed the PK sub- 
study will be provided. 
 
9.7.2 
Pharmacokinetic parameters 
The plasma concentrations will be used for non-compartmental pharmacokinetic 
evaluation with WinNonlin®. Calculated parameters will be reported with maximally    
2 significant digits. Non-rounded values will be used for calculations. Therefore, minor 
variations in values may occur. 
Descriptive statistics rather than inferential analyses will be provided, with tabulated and 
graphical displays of data and accompanying statistical commentary, where appropriate. 
Where possible, the following parameters will be determined for each patient: 
 AUC, area under the curve 
 Cmax, peak observed concentration 
 Tmax, time of peak concentration 
 Apparent terminal elimination half-life 
 Clearance 
 Derived parameters for parent drug and metabolites 
9.8 
Population pharmacokinetics 
Population pharmacokinetic methodology will be applied to analyze results derived from 
sparse PK sampling and from the PK sub-study. Details of the analyses to be performed 
will be specified in the Statistical Analysis Plan. 
9.9 
Interim analyses 
The Data and Safety Monitoring Board (DSMB) will review data periodically throughout 
the trial. The DSMB may recommend stopping the trial for safety at any time or for 
futility at the interim looks. Two planned interim analyses will be conducted, one for 
futility only and one for both safety and efficacy. The first for a futility analysis only will 
be conducted at 1/3 of information time (i.e., approximately at 128 death event time). The 
interim efficacy/safety analysis is planned at 50 % of information time (when 
approximately 192 death events take place). 
In the interim efficacy/safety analysis, OS, the primary efficacy outcome of the study, will 
be analyzed using a two-sided log-rank test. The Lan-DeMets implementation of the 
O’Brien Fleming boundary will be employed to control the overall non-binding Type I 


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error rate at 0.05. The nominal p-values for the planned second interim and the final 
analyses will be 0.003051 and 0.049002, respectively. 
 
9.10 
Power and sample size 
Approximately 384 events of deaths will be required to achieve 80 % power to detect a 
treatment difference at the overall two-sided 0.05 significance level after taking the 
planned efficacy/safety interim look into account. It is expected that approximately   
500 patients will be enrolled during an estimated 24-month recruitment period and will 
then be followed for 12 months to observe a total of approximately 384 death events. In 
the sample size calculation, it is assumed that the median OS is 12 months for the group 
with investigational treatment (AEZS-108) and 9 months for the control group 
(doxorubicin). The sample size calculation has taken the interim analyses into 
consideration. 
 
10 
ADMINISTRATIVE AND GCP ISSUES 
The coordinating investigator has been informed in detail about the properties of the 
investigational drug. This included a review of the current version of the Investigator's 
Brochure (copy included in the Investigator's File). In multicenter trials, this information 
will also be made available to each locally responsible (principal) investigator. 
 
10.1 
Essential documents for trial initiation; Trial Master Files (TMF) 
No study medication will be shipped to an investigational site before: 
 
the final protocol has been signed, 
 
the insurance for the participants has been issued, and 
 
the trial has been authorized by or notified to regulatory authority(ies) (where 
required), 
and before the locally responsible (principal) investigator has provided to the sponsor the 
following “essential documents” (ICH-GCP): 
 
Written ethics committee (IEC/IRB) note on the review of the clinical trial protocol 
and informed consent form (and of other trial related documents as required locally) 
 
Signed Agreement on Study Conduct according to protocol (required for each center 
in a multicenter study) 
 
Signed Financial Agreement (between sponsor and each investigator/institution) 
 
List of Authorized Study Personnel 
 
Curriculum vitae of the principal investigator (updated, dated, and signed) 
 
Signed form pertinent to US 21 CFR 54 (Financial Disclosure; Form FDA 3455) 
 
Signed form pertinent to US 21 CFR 312 (Statement of Investigator; Form FDA 
1572; mandatory for investigators in the US only) 
Documents that the locally responsible investigator may provide to the sponsor at a later 
date, but not later than the first monitoring visit during the ongoing study: 


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 
Curricula vitae of sub-investigators (updated, dated, and signed) 
 
Current laboratory normal ranges and documentation of laboratory certification (if 
applicable ) (in multicenter trials required from each participating institution) 
Both the sponsor and the investigator will maintain Trial Master Files (TMF) for the 
“essential documents” as specified by ICH-GCP. The sponsor will provide each principal 
investigator with a TMF, the Investigator's File, containing the relevant documents for the 
investigator's site. TMFs will be kept and updated by the sponsor and the investigator, 
respectively. 
 
10.2 
Subject information and consent 
Based on the text of the subject (patient) information and consent form approved by the 
competent IEC/IRB, it is the investigator’s obligation to: 
 
inform each subject accordingly and to allow sufficient time to decide whether or not 
to participate in the study; 
 
give patients, relatives or, if necessary, legal representatives the opportunity to 
enquire about details of the trial and to answer any questions regarding the study; 
 
ensure that the consent form has been signed and dated by her/himself and by the 
subject prior to study entry. 
10.3 
Protocol amendments 
Any modification of the protocol has to be agreed upon between the coordinating 
investigator and sponsor in form of a written amendment and not implemented until signed 
by both parties. All protocol amendments should be forwarded to the EC/IRB. 
Amendments involving patients’ safety, change in study design or a dose of study drug 
exceeding the dose-range planned in the escalation process) must be approved by each 
EC/IRB prior to implementation. Principal investigators from all participating institutions 
will have to acknowledge the receipt of the amendment. 
 
10.4 
Premature termination of the trial 
The sponsor reserves the right to terminate the trial for well-documented reasons. 
Instructions will be provided if assessments beyond the regular per protocol procedures 
should be necessary. If the coordinating investigator concludes that termination of the trial 
may be required, he will immediately provide his evidence to the sponsor. An investigator, 
who wishes to discontinue his trial participation, will immediately inform the sponsor of  
his decision. 
 
10.5 
Documentation obligations 
 
10.5.1 
Data collection / electronic case report forms (eCRFs) 
All trial data will be recorded on electronic CRFs (eCRF) supplied by the sponsor. Access 
to the eCRF will be restricted and password-controlled to the investigator and authorized 
co-workers according to the list of Authorized Study Personnel. Case report forms should 
be completed in English. Generic names for concomitant medications may be entered in 
the local language. 


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All data entries into eCRFs must be supported and verifiable from source documents to be 
retained in patient/hospital files. 
Detailed guidance on the use of the eCRFs will be provided in a separate data entry 
training manual. 
 
10.5.2 
Confidentiality of data 
Personal patient data will be kept confidential. CRFs or other documents submitted to the 
sponsor will identify a patient by initials and number only. Each investigator will keep in 
his file a Screening/Enrolment Log + Patient Identification List (including complete name 
and date of birth of each patient; original of the list in the investigator’s file; on request, a 
copy without full names and address should be submitted to the sponsor). To allow 
compliance with GCP principles, each patient will be asked for consent regarding the 
access to source documents for monitoring, audits, and inspections. The agreement, 
covering also the use of the data for analysis has to be documented in writing, together 
with the written informed consent for trial participation. 
 
10.6 
Monitoring and inspections 
 
10.6.1 
Trial monitoring and data collection 
The monitor and other nominated personnel of the sponsor will contact and visit the 
investigator's site regularly. The anticipated frequency is one visit or other contact every 
6-8 weeks. 
Amongst others, the following items will be reviewed: 
 
trial progress, 
 
compliance with the protocol, 
 
completion of CRFs, 
 
storage and accountability of trial drug, 
 
source data verification. 
Monitoring visits will be recorded in a Monitoring Log at the investigator's site, and at the 
end of the trial, a copy of the completed form will be returned to the sponsor. 
Source data verification (verification of data by comparing CRF entries with original 
laboratory reports and other patient records of the investigator): Data to be checked for 
each patient (100 % level) will include: patient identification, informed consent (procedure 
and dated signature), selection criteria, drug administration, adverse events, and primary 
efficacy parameter. Other efficacy and safety parameters will be checked at a 20 % level. 
Any changes or corrections of CRF entries will be made by the investigator or by 
authorized study personnel. The investigator should retain records of the changes and 
corrections. 
 
10.6.2 
Data handling and processing 
After receipt of CRFs, the monitor/clinical research associate will check these for 
completeness, legibility, and plausibility of the data. Additional checks will be performed 


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upon computerization (e.g. range checks, crosschecks). Where required, the investigator 
will be asked for supplemental information or CRF corrections. 
 
10.6.3 
Audits and inspections 
Audits and inspections may be carried out by the sponsor's quality assurance department, 
local authorities, or authorities to whom information on this trial has been submitted. All 
documents pertinent to the trial must be made available for such inspection after an 
adequate announcement. Informed consent of patients participating in this study has to 
include the consent in this access to source documents. The anticipated frequency of 
audits and inspections done by the sponsor during the study will not exceed 2 visits for 
each study center. 
 
10.7 
Final report and publication 
A report will be prepared under the responsibility and according to the standards of the 
sponsor. It will include the statistical analysis and raw data listings of efficacy and safety 
data. Safety data will also be summarized in the synopsis with special emphasis on 
suspected serious unexpected adverse drug reactions. It will be submitted to the 
coordinating investigator for acknowledgement and signature. 
It is the policy of Aeterna Zentaris to encourage the presentation and publication of data 
resulting from clinical trials. 
The following principles will be followed for the definition of authorship in multicenter 
trials: 
 
Authorship will include investigators who have recruited at least 10% of the total 
number of evaluable patients. 
 
The authors sequence should usually reflect the number of evaluable patients 
enrolled by the corresponding principal investigator. 
The authorship will also include representatives of the sponsor. 
Draft versions of abstracts or manuscripts must be made available to the co-authors and to 
the sponsor before any presentation of results or submission for publication. At least 3 
weeks should be allowed for review and comment of an abstract and 4 weeks in case of a 
full paper, respectively. Multiple review cycles are usual for full papers and respective 
planning must account for this. 
10.8 
Archiving 
The investigator must keep the following documents for at least 10 years beyond the end of 
the trial if the sponsor does not explicitly allow earlier disposal: patient identification codes, 
records of informed consent, IEC/IRB approval letter, dispensing logs, monitoring logs, 
CRF copies including copies of data clarification forms, correspondence, source documents 
including original reports of test results, and other “essential documents” (ICH- GCP) 
pertaining to the conduct of the trial. No document pertinent to the trial should be 
destroyed without prior written agreement between the sponsor and the investigator. 
Should the investigator wish to assign these records to another party or move them to 
another location, written agreement must be obtained from the sponsor. 


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The sponsor will archive the originals of protocol, CRFs, and Medication Accountability 
List. 


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11 
REFERENCES 
1. 
Aapro MS, van Wijk FH, Bolis Get al. Doxorubicin versus doxorubicin and cisplatin in 
endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC 
Gynaecological Cancer Group. Ann Oncol. 2003 Mar;14(3):441-8. 
2. 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner 
H, Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub 
S, Sneeuw KCA, Sullivan M, Takeda F. The European Organisation for Research and 
Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical 
trials in oncology. Journal of the National Cancer Institute 1993;85: 365-376. 
3. 
Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, Chesney M, Clark- 
Snow RA, Flaherty AM, Freundlich B, Morrow G, Rao KV, Schwartz RN, Lyman GH; 
American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology 
clinical practice guideline update. J Clin Oncol. 2011 Nov 1;29(31):4189-98. Epub 2011 Sep 
26. Review. 
4. 
Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C, Sessa C; ESMO 
Guidelines Working Group. Endometrial cancer: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol. 2011 Sep;22 Suppl 6:vi35-9. 
5. 
Dizon DS, Blessing JA, McMeekin DS, Sharma SK, Disilvestro P, Alvarez RD. Phase II trial 
of ixabepilone as second-line treatment in advanced endometrial cancer: gynecologic 
oncology group trial 129-P. J Clin Oncol. 2009 Jul 1;27(19):3104-8. Epub 2009 May 18. 
6. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009 Jan;45(2):228-47. 
7. 
Emons G, Kaufmann M, Gorchev G, Tsekova V, Gründker C, Günthert AR, Hanker LC, 
Velikova M, Sindermann H, Engel J, Schally AV. Dose escalation and pharmacokinetic study 
of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH 
receptor-positive tumors. Gynecol Oncol. 2010 Dec;119(3):457-61. Epub 2010 Sep 9. 
8. 
Engel J, Emons G, Pinski J, Schally AV. AEZS-108 : a targeted cytotoxic analog of LHRH for 
the treatment of cancers positive for LHRH receptors. Expert Opin Investig Drugs. 2012 
Jun;21(6):891-9. Review. 
9. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001. 
10. Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, Kline R, Burger RA, 
Goodman A, Burks RT. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel 
plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J 
Clin Oncol. 2004 Jun 1;22(11):2159-66. 
11. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial 
ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus 
topotecan. J Clin Oncol. 2001 Jul 15;19(14):3312-22. 
12. Greimel E, Nordin A, Lanceley A, Creutzberg CL, van de Poll-Franse LV, Radisic VB, 
Galalae R, Schmalz C, Barlow E, Jensen PT, Waldenström AC, Bergmark K, Chie WC, 
Kuljanic K, Costantini A, Singer S, Koensgen D, Menon U, Daghofer F; EORTC Quality of 
Life Group. Psychometric validation of the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC 
QLQ-EN24). Eur J Cancer. 2011 Jan;47(2):183-90. Epub 2010 Sep 28 


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13. Günthert AR, Gründker C, Bongertz T, Schlott T, Nagy A, Schally AV, Emons G 
Internalisation of cytotoxic analog AN-152 of luteinizing hormone-releasing hormone induces 
apoptosis in human endometrial and ovarian cancer cell lines independent of multi drug 
resistance 1(MDR-1) system. Am J Obstet Gynecol. 2004; 191: 1164-1172. 
14. Homesley HD, Blessing JA, Sorosky J, Reid G, Look KY. Phase II trial of liposomal 
doxorubicin at 40mg/m2 every 4 weeks in endometrial carcinoma: a Gynecologic Oncology 
Group study. Gynecol Oncol. 2005;98(2):294-298. 
15. Humber CE, Tierney JF, Symonds RP, Collingwood M, Kirwan J, Williams C, Green JA. 
Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review 
of Cochrane collaboration. Ann Oncol. 2007 Mar;18(3):409-20. Epub 2006 Dec 5. Review. 
16. Muggia FM, Blessing JA, Sorosky J, Reid GC. Phase II trial of the pegylated liposomal 
doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology 
Group study. 2002;20(9): 2360-2364. 
17. Nagy A, Schally AV. Targeting of cytotoxic luteinizing hormone-releasing hormone analogs 
to breast, ovarian, endometrial, and prostate cancers. Biol Reprod 2005;73: 851-859. 
18. Plataniotis G, Castiglione M; ESMO Guidelines Working Group. Endometrial cancer: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21 
Suppl 5:v41-5. 
19. Temkin SM, Fleming G. Current treatment of metastatic endometrial cancer. Cancer Control. 
2009 Jan;16(1):38-45. Review. 
20. Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, Liao S. Phase 
III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a 
Gynecologic Oncology Group study. J Clin Oncol. 2004;22(19): 3902-3908. 
21. Völker P, Grundker C, Schmidt O, Schulz K-D, Emons G. Expression of receptors for 
luteinizing hormone-releasing hormone in human ovarian and endometrial cancers: frequency, 
autoregulation, and correlation with direct anti-proliferative activity of luteinizing-hormone 
releasing hormone analogs. Am J Obstet Gynecol 2002;186: 171-179 
22. Westphalen S, Kotulla G, Kaiser F, Krauss W, Werning G, Elsasser HP, Nagy A, Schulz KD, 
Grundker C, Schally AV, Emons G. Receptor mediated antiproliferative effects of the 
cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines. Int J 
Oncol. 2000;17(5):1063-9. 


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APPENDIX 1: CALCULATOR / NOMOGRAM FOR 
DETERMINATION OF BODY SURFACE AREA 
For a BSA calculator, see: http://www.medcalc.com/body.html (use DuBois formula). For 
BSA and dose calculator, see: http://www.halls.md/body-surface-area/bsa.htm. 
Source of the nomogram below: http://www.smm.org/heart/lessons/nomogram_adult.htm. 
 


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


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APPENDIX 3: GRADING OF LEFT VENTRICULAR FUNCTION 
(CTCAE-V4.03) 
Adverse Event Category: Cardiac general 
Adverse Event / Short Name: Left ventricular systolic dysfunction 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
- 
- 
Symptomatic due 
to drop in ejection 
fraction responsive 
to intervention 
Refractory or poorly 
controlled heart failure 
due to drop in ejection 
fraction; intervention 
such as 
ventricular assist device, 
intravenous vasopressor 
support, or heart 
transplant indicated 
Death 
 
Adverse Event Category: Investigations 
Adverse Event / Short Name: Ejection fraction (EF) decreased 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
- 
Resting EF 
50 – 40 %; 
10 – 19 % drop 
from baseline 
Resting EF 
39 – 20 %; 
> 20 % drop 
from baseline
Resting EF 
< 20 % 
Death 
 
Source: CTCAE v4.03 publish date: June 14, 2010) 
(see: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_5x7.pdf) 


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APPENDIX 4: POTENTIALLY CARDIOTOXIC MEDICATION 
Not applicable (this appendix was deleted per protocol amendment no. 3). Instead, please 
refer to protocol Section 6.3.2 (Prohibited therapy) and Section 6.3.3 (Interaction with 
other medicinal products and other forms of interaction). 
 
 
APPENDIX 5: EXAMPLE OF GNRH AGONISTS AND 
ANTAGONISTS 
Use of the following drugs is excluded within 6 months prior to study entry. 
 
GNRH agonists: triptorelin, buserelin, leuprorelin, goserelin 
 
GNRH antagonists: cetrorelix, ganirelix, degarelix, abarelix, ramorelix 


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APPENDIX 6: QUALITY OF LIFE QUESTIONNAIRES (SAMPLE 
SPECIMENS) 
EORTC QLQ-C30 questionnaire 
 


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EORTC Endometrial Cancer Module (QLQ-EN24) 
 


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APPENDIX 7: PHARMACOKINETIC SUB-STUDY 
1 
BACKGROUND INFORMATION .................................................................. 76 
1.1 
Introductory Remarks ..................................................................................... 76 
1.2 
Pharmacokinetics of AEZS-108 .................................................................... 76 
1.3 
Pharmacokinetics of doxorubicin .................................................................. 79 
1.4 
Acute effects of doxorubicin on cardiac function ......................................... 80 
2 
OBJECTIVES .................................................................................................... 81 
3 
ETHICS ............................................................................................................ 81 
3.1 
Benefit / risk considerations ......................................................................... 81 
3.2 
Protection of patients .................................................................................... 81 
4 
STUDY DESIGN ............................................................................................... 82 
4.1 
Sample size and statistical considerations .................................................... 83 
5 
PATIENT SELECTION .................................................................................... 83 
6 
BLOOD SAMPLING AND PROCESSING AT STUDY SITES .................... 83 
6.1 
Time schedule of blood sampling (and ECG monitoring) ............................ 83 
6.2 
Blood sampling and processing .................................................................... 85 
6.3 
Storage and shipment of frozen plasma samples ........................................... 85 
7 
BIOANALYTICAL PROCEDURES ................................................................ 86 
8 
ECG MONITORING. ........................................................................................ 86 
9 
REFERENCES ................................................................................................... 87 


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1 
BACKGROUND INFORMATION 
 
1.1 
Introductory Remarks 
This Appendix provides details on the PK sub-study referred to in the clinical trial protocol 
AEZS-108-050 and described briefly in Section 7.3.3. 
While targeted uptake of AEZS-108 by binding to LHRH receptors and internalization of 
bound AEZS-108 is the intended mode of action, circulating AEZS-108 also undergoes a 
hydrolytic cleavage releasing doxorubicin, the drug substance administered in the 
comparator arm. Therefore, the sub-study will also include patients treated with the 
comparator drug doxorubicin. In addition PK parameters of doxorubicinol, which is 
expected as the main metabolite of doxorubicin in both treatment arms, will be evaluated. 
Availability of PK data for all three analytes - AEZS-108, doxorubicin, and doxorubicinol 
- should help to better understand similarities and differences in therapeutic and safety 
results of the clinical study. 
The PK-sub-study will be performed in selected sites of this multi-center and multi- 
national study. Only patients who take part in the main study will be eligible for inclusion 
in the sub-study. Sub-study specific procedures described here do not replace any of the 
procedures described for the main study. 
 
1.2 
Pharmacokinetics of AEZS-108 
AEZS-108 (INN zoptarelin doxorubicin) is an LHRH-cytotoxic hybrid molecule. The 
cytotoxic molecule doxorubicin (DOX) is chemically linked to the carrier molecule 
D-Lys6-LHRH (an LHRH agonist) which enables the specific binding and selective uptake 
of the hybrid molecule by tumors expressing receptors for LHRH (“drug targeting”). 
In non-clinical pharmacokinetic (PK) studies in rats and dogs, the t1/2 (1 hr) and tmax 
(0.08 hr) of AEZS-108 and DOX were similar. Dose linearity for AEZS-108 was 
demonstrated when based on Cmax and AUC0-4h. The AUCs of AEZS-108 were higher 
(3 to 9 times in rats, 7 to 12 times in dogs) than those of DOX after single and multiple 
doses, independent of dose and sex. 
Only preliminary PK data from studies in human subjects are available. Following 
administration of 160 and 267 mg/m2 AEZS-108 in a Phase I/II study [Emons et al., 2010], 
maximum plasma concentrations of 728 – 6661 ng/mL were measured. Because of the 
high variability, partly attributable to procedural deficiencies, neither a dose dependency of 
Cmax values nor of the calculated AUC values could be shown. The calculated half life and 
the clearance of AEZS-108 were found to be in the range of 0.74 - 4.58 h and 
0.37 - 2.67 l/min·m2, respectively, and were independent of the dose level. This is an 
indication of dose linearity. 
At the dose levels of 160 and 267 mg/m2, the Cmax values of the active metabolite doxo- 
rubicin were measured in the range of 177 – 1580 ng/mL. The ranges of half life and 
calculated clearance for doxorubicin, ranging 0.78 – 4.71 h and 0.33 – 1.43 l/min·m2, 
respectively, were comparable to those for AEZS-108. The doxorubicin plasma 
concentrations and therefore the calculated AUC values of doxorubicin increased with 
increasing doses. 


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Recently, preliminary PK data have become available from an ongoing Phase I/II study in 
urothelial cancer (Study AEZS-108-046; unpublished data on file). In this study, sampling 
was scheduled 1 hour (h) after start of the infusion, within 10 minutes before end of the 
infusion (EOI), then 30 minutes, 1h, 2h, 3h, 4h, 6h, and 24h after EOI. Figure 1 shows the 
time courses of AEZS-108 and doxorubicin for 4 patients (3 males: #8, 10 and 11; 
1 female: #9) who received AEZS-108 as a 2-hour infusion at the dose of 267 mg/m2. In 
patient #8, the EOI sample was actually taken few minutes after EOI, thus explaining the 
higher concentration of doxorubicin in the sample taken 1h after the start of the infusion. 
In patient #11 (3-001), the EOI sample was hemolytic, thus possibly explaining the lower 
concentration of doxorubicin measured in this sample. Table 1 shows the ranges for Cmax 
and AUC of AEZS-108 and doxorubicin concentrations for 4 patients after the AEZS-108 
dose of 267 mg/m2. 
Table 1: 
Range of Cmax and AUC values after AEZS-108 dose of 267 mg/m2 
[N=4] 
Cmax [ng/mL] 
AUC [ng x h/ mL 
AEZS-108 
2862 - 5985 
5704 – 12585 
Doxorubicin 
645* – 1814 
3848 – 5501* 
*hemolyzed sample 
AEZS-108 is sensitive to spontaneous and/or carboxylesterase-catalyzed deconjugation 
into DOX and probably D-Lys6-LHRH-glutarate in blood plasma and aqueous solutions. 
The rate of hydrolysis of AEZS-108 in mouse serum (approx. t1/2 = 20 minutes) was 
significantly higher than in human serum (approx t1/2 = 100 – 120 minutes). Investigations 
on the stability of AEZS-108 in microsomal liver incubations of both rat and man 
suggested a secondary role of metabolic decomposition compared with spontaneous 
hydrolysis. 
The metabolism and excretion of doxorubicin that is hydrolytically released after 
intravenous administration of AEZS-108 is expected to be similar to the fate of 
intravenously administered doxorubicin [Speth et al., 1988]. 


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AEZS-108 
Patients (267mg/m2) 
7500 
Patient 8 
Patient 9 
Patient 10 
5000 
Patient 11 
 
 
2500 
 
 
 
0 
0 
6 
12 
18 
24 
time (h) 
Doxorubicin 
Patients (267mg/m2) 
2500 
Patient 8 
2000 
Patient 9 
Patient 10 
1500 
Patient 11 
 
1000 
 
500 
 
0 
0 
6 
12 
18 
24 
time (h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1:   AEZS-108 and doxorubicin plasma concentration during and after a 
2-hour intravenous infusion of AEZS-108 at 267 mg/m2 
plasma concentration 
(ng/ml) 
plasma concentration 
(ng/ml) 


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1.3 
Pharmacokinetics of doxorubicin 
PK studies in patients with various types of tumors undergoing either single or multi-agent 
therapy have shown that doxorubicin follows a multiphasic disposition after intravenous 
injection. The initial distribution half-life of approximately 5 minutes suggests rapid tissue 
uptake of doxorubicin, while its slow elimination from tissues is reflected by a terminal 
half-life of 20 to 48 hours. Steady-state distribution volumes exceed 20 to 30 L/kg and are 
indicative of extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 
20 mL/min/kg and is predominately by metabolism and biliary excretion. Approximately 
40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its 
metabolites appear in the urine during the same time period. Binding of doxorubicin and its 
major metabolite, doxorubicinol, to plasma proteins is about 74 to 76% and is independent 
of plasma concentration of doxorubicin up to 2 mM. Enzymatic reduction at the 7-position 
and cleavage of the daunosamine sugar yields aglycones which are accompanied by free 
radical formation, the local production of which may contribute to the cardiotoxic activity 
of doxorubicin. Disposition of doxorubicinol in patients is formation rate limited. The 
terminal half-life of doxorubicinol is similar to doxorubicin. The relative exposure of 
doxorubicinol, compared to doxorubicin ranges between 0.4 and 0.6. In urine, < 3% of the 
dose was recovered as doxorubicinol over 7 days. The literature contains no information 
regarding gender related differences in the pharmacokinetics of doxorubicin and 
doxorubicinol. 
PK parameters for doxorubicin and doxorubicinol after a 1-hour infusion of doxorubicin 
have been reported from a study in patients with small cell lung cancer (SCLC) [Piscitelli 
et al., 1993], The study included 35 patients (24 males / 11 females) of which 4 subjects 
were classified as having impaired liver function defined as a GGT > 3 times normal and a 
bilirubin > 1.0 mg/dL. Doxorubicin at doses ranging of 45 to 72 mg/m2 was administered 
in combination with cyclophosphamide (1000 mg/m2) and vincristine (2 mg). 
Figure 2 shows a scatter plot for the AUC of doxorubicin by dose of doxorubicin, and 
Table 2 summarizes the mean PK parameters for doxorubicin and doxorubicinol. 
The patients with impaired liver function showed a significantly (p < 0.05) slower 
clearance (239 versus 666 ml/min/m2), larger AUC (4610 versus 1834 ng • hr/mL) and 
longer elimination half-life (49.3 versus 25.6 hours) compared with patients with normal 
hepatic function. 


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Figure 2:   Doxorubicin dose and area under the concentration-time curve (AUC) in 
individual patients with (triangles) and without (circles) liver impairment 
 
Table 2: 
Mean pharmacokinetic parameters of doxorubicin and doxorubicinol in 
patients with small cell lung cancer 
 
 
1.4 
Acute effects of doxorubicin on cardiac function 
Early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia and/or 
electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. 
Tachyarrhythmias, including premature ventricular contractions and ventricular 
tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also 
been reported. These effects do not usually predict subsequent development of delayed 


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cardiotoxicity, are rarely of clinical importance, and are generally not considered an 
indication for the suspension of doxorubicin treatment. 
Accordingly, a standard 12-lead ECG recording and ‘rhythm strip’ evaluation is 
considered sufficient for the monitoring of cardiac effects within this PK sub-study, which 
is limited to Cycle 1 dosing. 
 
2 
OBJECTIVES 
To assess the pharmacokinetics of AEZS-108 after intravenous infusion over 2 hours. 
To assess the exposure to AEZS-108’s metabolites doxorubicin and doxorubicinol after a 
2-hour intravenous infusion of AEZS-108 at 267 mg/m2 in comparison to the exposure to 
doxorubicin and doxorubicinol after a short-term (1-hour) intravenous infusion of 
doxorubicin at 60 mg/m2. 
To assess the acute effects of intravenously administered AEZS-108 and doxorubicin on 
electrocardiographic parameters. 
 
3 
ETHICS 
 
3.1 
Benefit / risk considerations 
The investigations planned in this sub-study are important for a better understanding of 
how AEZS-108 works, i.e., how the reversible chemical fixation of doxorubicin to an 
LHRH agonist affects the exposure of patients to doxorubicin and its main metabolite 
doxorubicinol. 
It is not anticipated, however, that the results of this pharmacokinetic sub-study are 
immediately relevant for the assessment of the outcome or for the management of the study 
treatment in the individual patient. 
Risks associated with blood sampling for PK analysis include local pain, hematoma, and 
infection. The risks are similar to the risks associated with blood sampling for routine 
safety tests. 
 
3.2 
Protection of patients 
Before initiation of the sub-study, the corresponding protocol amendment of the study 
protocol will be reviewed by the competent independent ethics committees (IEC) for the 
study sites involved in the sub-study. The sub-study will be notified to the competent 
authorities. 
The patients will be informed both verbally and in writing about the nature of this 
pharmacokinetic sub-study, the anticipated benefits and risks, the discomfort to which they 
may be exposed, and also their right to interrupt their participation at any time of their own 
free will. They will confirm their consent in writing prior to inclusion. The subject’s 
informed consent form specific to this sub-study will be reviewed and approved by the 
IEC. 


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The Sponsor will insure adequate insurance coverage in the event of patient injury 
resulting from participation in this sub-study. Patients should be instructed to immediately 
notify the investigator of any injury that may have been caused by participation in this sub- 
study. A copy of the insurance conditions is included in the investigator’s file. 
 
4 
STUDY DESIGN 
Only selected study sites, which are equipped for and experienced in the sampling, 
processing, and storage of blood samples for drug concentration measurements will 
participate in this sub-study to Study AEZS-108-050. 
It is planned that about 40 patients who have been randomly allocated to treatment with 
either AEZS-108 or doxorubicin (i.e., about 20 patients allocated to each treatment group) 
will take part in this PK sub-study. 
Whereas the core protocol of the clinical study allows doxorubicin to be administered 
either as a bolus injection or a short term (up to 1 hr) infusion according to the study site’s 
routine practice, the statistical evaluation of pharmacokinetic parameters requires the use 
of the same duration of infusion for all patients participating in the PK sub-study. The 
duration of the infusion of doxorubicin for the PK sub-study (Cycle 1) is being defined at 
1 hour, which will allow mid- and end-of-infusion sampling in both the investigational and 
comparator group. Note: As the PK sampling is limited to Cycle 1, investigators will be 
free to use a different mode of administration (e.g., bolus injection) for subsequent 
treatment cycles for study participants, according to the institution’s routine practice. 
AEZS-108 and doxorubicin will be given as an intravenous infusion. If a peripheral vein is 
used for the infusion, the blood samples must be collected from a contralateral vein. 
Pharmacokinetic investigations will be limited to Cycle 1, with blood sampling at pre- 
defined time points up to 72 hours after the start of the infusion. Samples will be analyzed 
for the plasma concentrations of AEZS-108, doxorubicin and doxorubicinol in the 
investigational arm (Arm A) and for doxorubicin and doxorubicinol in the comparator arm 
(Arm B). 
Plasma concentrations of AEZS-108, doxorubicin, and doxorubicinol will be measured 
using validated methods. 
The main PK parameters to be evaluated will include: 
 AUC, area under the curve 
 Cmax, peak observed concentration 
 Tmax, time of peak concentration 
 Apparent terminal elimination half-life 
 Clearance 
 Derived parameters for parent drug and metabolites 
 
Further PK parameters may be calculated for each patient, where possible. 


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ECGs will be recorded before, during and after the end of the infusion as well as at the 
blood sampling time points around the expected Tmax of the metabolites and 24 hours after 
end of the respective infusion. The ECGs will be evaluated for possible effects on the heart 
rate and electrocardiographic parameters. 
 
4.1 
Sample size and statistical considerations 
This is an exploratory study in which the pharmacokinetics of the investigational drug 
AEZS-108 and the comparator drug doxorubicin will be evaluated for a descriptive 
analysis. Based on published data on the pharmacokinetics of doxorubicin, a sample size of 
20 patients for each arm is proposed, to provide a more detailed description than is 
currently available for the key pharmacokinetic parameters of AEZS-108, doxorubicin, and 
doxorubicinol. 
Based on preliminary pharmacokinetic data available from an ongoing study in bladder 
cancer patients, a variability of AEZS-108 similar to that for doxorubicin may be expected. 
Since collection of only a limited number of samples (‘sparse sampling’) over a limited 
period (about 2-3 terminal elimination half-lives) is feasible within this sub-study, the 
comparison of the metabolite profiles will be orienting / exploratory / descriptive in nature. 
 
5 
PATIENT SELECTION 
To be eligible for this sub-study, a patient must meet all of the eligibility criteria defined in 
the core protocol of Study AEZS-108-050. About 40 patients allocated to treatment with 
either AEZS-108 or doxorubicin will be asked to participate in this PK sub-study. 
Because of the descriptive, exploratory nature of the analyses, patients who have been 
withdrawn or who dropped out before completion of the PK blood sampling will not be 
replaced. Since the blood samples will be collected only over a short period, a high rate of 
early discontinuations from sub-study procedures is not anticipated. 
 
6 
BLOOD SAMPLING AND PROCESSING AT STUDY SITES 
 
6.1 
Time schedule of blood sampling (and ECG monitoring) 
The following table indicates the targeted time for blood sampling, the window for 
acceptable deviations from the targeted sampling time and the reference point for the 
window in relation to the start or end time of the infusion. 
With regard to the shorter infusion duration for doxorubicin, the sampling schedule for the 
post-infusion samples for both treatment groups is defined in relation to the end-of- 
infusion (EOI), as shown in Table 3. At the indicated time points, ECGs will be recorded 
within a time window of 10 minutes prior to the corresponding blood collection times. 


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Table 3: Schedule for blood sampling and ECG recording 
# 
Time relative to infusion 
Sampling time window 
12-lead ECG 
(up to 10 minutes 
before blood 
sampling) 
1 
Pre-Dose 
Up to 30 minutes before the 
start of the infusion 
ECG #1 
2 
Mid of infusion a) 
After the start of the infusion: 
AEZS-108: 60 +/- 2 minutes 
Doxorubicin: 30 +/- 2 minutes 
ECG #2 
3 
End of Infusion (EOI) a) 
Up to 5 minutes before EOI 
ECG #3 
4 
30 minutes after EOI b) 
+/- 2 minutes 
ECG #4 
5 
1 hour after EOI b) 
+/- 2 minutes 
ECG #5 
6 
2 hours after EOI b) 
+/- 2 minutes 
ECG #6 
7 
4 hours after EOI b) 
+/- 2 minutes 
(no ECG) 
8 
6 hours after EOI b) 
+/- 2 minutes 
(no ECG) 
9 
24 hours after EOI b) 
+/- 2 hours 
ECG #7 
10 
48 hours after EOI b) 
+/- 4 hours 
(no ECG) 
11 
72 hours after EOI b) 
+/- 4 hours 
(no ECG) 
a) Scheduled duration/end of infusion is 2 hours for AEZS-108 and 1 hour for doxorubicin; an 
infusion pump should be used to ensure the desired rate and duration of the infusion; 
b) EOI (end of infusion); all subsequent sampling times refer to the actual end of infusion 
 
A 2-minute window is acceptable for all time points on Day 1, except for the end of 
infusion (EOI) sample which must NOT be taken after the end of infusion. Therefore 
sampling up to 5 minutes before the end of infusion is acceptable for the EOI sample. The 
actual time of the EOI must be recorded and will direct the timing of post-EOI sampling 
times. 
While the targeted duration of the infusion is 2 hours for AEZS-108 and 1 hour for 
doxorubicin, the actual duration of the infusion may vary slightly. As the plasma 
concentration of the infused drug will rapidly decrease after EOI due to tissue distribution, 
the EOI sample must be taken shortly before (!) the EOI has been reached, in order to 
reliably determine the maximum plasma concentration (Cmax). For the timing of the post- 
EOI samples, it is important to determine the actual EOI, so that the distribution of the 
administered drug, in the case of AEZS-108 the hydrolytic release of doxorubicin, can be 
evaluated reliably. 
The time when the blood sampling actually occurred (hh:mm) has to be documented in the 
respective source document and CRF. Deviations outside these time limits must be 
commented upon. 


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6.2 
Blood sampling and processing 
Blood samples (5.4 mL) will be collected into appropriately labeled potassium 
ethylenediamine tetraacetate (K-EDTA) tubes (purple top) at the times indicated. The 
specimen will be completely and gently inverted at least 10 times (and kept on ice prior to 
centrifugation) followed by centrifugation in a refrigerated centrifuge (2-8°C) at 1500g for 
10 minutes. The plasma must be transferred into cryovials (200 µL/vial). 
The labels of the cryovials have to provide at least the following: 
 Study ID: AEZS-108-050 
 Site code 
 Subject ID number 
 Scheduled sampling time (as named as in the column named ‘Scheduled time of blood 
sampling and ECG recording’ in Table 3). 
The actual sampling time (in the format hh:mm, using 24 hour clock) will be provided by 
the site in a sampling record, to enable calculation of any deviations from the scheduled 
sampling time. 
 
6.3 
Storage and shipment of frozen plasma samples 
Within 30 minutes of the sampling time, the cryovials must be stored at -20 °C. 
Storage at -20 °C should not exceed a period of 3 months. Unless a subsequent study 
patient is expected to enter the PK sub-study within the next month, shipments to the 
bioanalytical facility should be arranged within 1 month after collection, so that samples 
can be analyzed within 3 months from collection, possibly together with samples received 
from other sites participating in this sub-study. 
One set of the split samples for a given sampling series will be sent to the bioanalytical 
facility, together with a copy of the sampling records. The second set of the split samples 
will be retained as reserve, in case of problems with the shipment of the first set. 
Shipment address: 
Prolytic GmbH 
c/o. Dr. Dorothee Krone 
Alt Fechenheim 34 
D-60386 Frankfurt am Main, Germany 
Tel.: +49 69 4109 2535 
Fax: +49 69 4269 4784 
e-Mail: dorothee.krone@prolytic.de 


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7 
BIOANALYTICAL PROCEDURES 
Concentrations of AEZS-108, doxorubicin, and doxorubicinol in human plasma samples 
will be analyzed by validated methods. The processing of the plasma samples is based on a 
liquid/liquid phase extraction. For undiluted test samples, the lower limits of quantification 
(LLOQ) of the methods are about 5 ng/mL for all analytes. 
All plasma test samples will be stored at approx. –20 C after arrival at the test facility. 
Stability of analytes during storage at -20°C and after repeated freeze/thaw cycles has been 
shown [Ref. 4]. 
Calibration standards prepared by spiking human blank plasma with each analyte will be 
used for each analytical run. Quality control (QC) samples will be analyzed together with 
each batch of test samples. QC samples, containing each analyte at three concentration 
levels (low, medium, high) will be spiked by an independent person. Calibration curves 
will be established based on the calibration standard results for each analyte. The HPLC 
software will be used to calculate the concentrations of the test and QC samples on the 
basis of the corresponding calibration curve. 
The acceptance criteria for the calibration standards in analytical batches can be 
summarized as follows: 75 % of the total number of standards, or a minimum of six 
standards, should be accepted, if the back-calculated value is within ± 15 % of the nominal 
value (except for the lowest concentration calibration standard, where the criterion is 
± 20 % of the nominal value). Acceptance criteria for the quality control samples in 
analytical batches are defined accordingly: If more than one third of the QC samples or all 
QC samples of the same concentration level differ by more than 15 % from the 
theoretical values, the analytical series will not be accepted and the relevant test samples 
will be re-analyzed. 
 
8 
ECG MONITORING 
Prior to collection of the PK blood samples #1 (predose) through #6 (2 hours after EOI), 
and prior to collection of the PK blood sample #7 (24 hours after EOI), triplicate standard 
12-lead ECG will be recorded using the ECG equipment at the site. For immediate safety 
assessment the investigator will evaluate each ECG record for abnormalities or changes of 
ECG parameters. The results of the ECG evaluation will be recorded in the eCRF module 
for the PK sub-study. 
In addition all changes in the ECG that are considered ‘clinically relevant’ will be recorded 
in the Adverse Events section of the eCRF for the core study. 
All recorded paper ECG printouts will also be sent to an ECG core laboratory for central 
evaluation. Therefore, the original paper ECGs will be collected by the ECG core lab while 
hardcopies will be retained at the study site. 
At the core lab the ECGs will be evaluated by a board certified cardiologist with particular 
emphasis on T and U wave morphology. In addition the core lab will measure the intervals 
RR, PQ (PR), QRS, and QT interval from the digitized wave forms using the core lab’s 
validated procedures and programs. 


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From the RR and QT intervals the heart rate and the heart rate corrected QTc interval will 
be calculated according to Bazett’s and Fridericia’s formula. 
The resulting categorical and continuous variables will be analyzed statistically for 
possible influences of the study drugs on cardiac safety parameters. 
 
9 
REFERENCES 
1. 
Emons G, Kaufmann M, Gorchev G, Tsekova V, Gründker C, Günthert AR, Hanker 
LC, Velikova M, Sindermann H, Engel J, Schally AV. Dose escalation and 
pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to 
doxorubicin, in women with LHRH receptor-positive tumors. Gynecol Oncol. 2010 
Dec;119(3):457-61. 
2. 
Speth PA, van Hoesel QG, Haanen C. Clinical pharmacokinetics of doxorubicin. Clin 
Pharmacokinet. 1988 Jul;15(1):15-31. Review. 
3. 
Piscitelli SC, Rodvold KA, Rushing DA, Tewksbury DA. Pharmacokinetics and 
pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin 
Pharmacol Ther. 1993 May;53(5):555-61. 

SAP_000.pdf: 
Doc. Ref. No.: AEZS-108-050_SAP_4 / FINAL
March 10, 2017
Statistical Analysis Plan
Study AEZS-108-050 / Phase III
Randomized controlled study comparing AEZS 108 with
doxorubicin as second line therapy for locally advanced,
recurrent or metastatic endometrial cancer




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Document History


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Version
Date
Changes made since previous version
0.01
November 15,
2012
First version
1.0
March 13, 2013
Specified two key secondary efficacy variables (PFS and ORR) that
will be tested using hierarchical procedures to protect overall Type
I Error and deleted time to progression as a secondary efficacy
endpoint.
1.01
March 13, 2014
Section 8 added to describe the analysis of data coming from the
PK sub-study. Update of Flow chart from protocol version 3.1.
1.02
December 19,
2014
Reference to latest version of protocol
Study objectives adapted to reflect t
objectives
Details on PK analyses removed because this will be taken up in
separate supplements. In SAP only summary is presented
1.03
January 23, 2015
Details on analysis of QoL included
2
March 23, 2015
Inclusion of definition of modified ITT population (used for
sensitivity analysis on OS primary endpoint)
Second final version
3
September 26,
2016
Removal of LHRH receptor related analysis due to non-availability
of corresponding receptor assay and data
Inclusion of sub-analyses for setting of prior chemotherapy
(adjuvant vs advanced). Populations (safety and ITT) are also
specified for summary table
Inclusion of sub-analyses for key secondary efficacy endpoints
Inclusion of analysis of prophylactic/symptomatic
antiemetic/antiallergic concomitant treatment
Patient disposition summaries will also include number of subjects
in modified ITT and PP (next to ITT and safety populations)
More detailed specification of how Study Treatment Exposure
summary will be made
Supportive and sensitivity analyses on primary efficacy endpoint
OS is redefined: -different censoring; - definition of different
covariates used in exploratory analyses of the effect of baseline
characteristics and other covariates (see section 7.1.3 for details)
Supportive and sensitivity analyses on secondary efficacy endpoints
ORR and PFS is redefined (identical to analyses on OS)
In section 9.1. Adverse events, certain details on content of AE
listings is given
9.2. Laboratory assessments: for WBC, neutrophils (absolute
value) and thrombocytes extra shift table only considering
cycle 1 lab results is foresee
9.5. Cardiac assessments is extended and more detailed (both for
ECG and LVEF)
4
March 10, 2017
In 4. General conventions: -add AEZS-108 and Doxorubicin will be
used; -elaborate on definition of baseline


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In 5.1. Disposition: correct typo in country abbreviations per
territory
In 6.1. Prior In 6.1. Treatment for Endometrial Cancer: remove ITT
and explain how to analyze
In 6.2. Prior and Concomitant Medications: explain how to analyze
In 6.3. Study treatment exposure: addition of summaries will be
made on patients receiving prophylactic antiemetic treatment per
treatment cycle, and patients receiving anti-allergic treatment per
treatment cycle
Efficacy analysis:
For backward selection in multivariate Cox model and logistic
regression model: the significance level to retain a variable in the
model will be set at 10%
Sensitivity analysis for ORR: logistic regression models will be
used. For ORR, in addition: duration of overall response, duration
of stable disease and duration of follow-up will be analyzed
PFS will be analyzed in the subset of patients from MITT that have
CR, PR or SD as best overall response
Slight adaptation in description for mixed model approach for
analysis of questionnaires
Adverse event analysis:
Clarification of time on treatment (date of last dose before AE onset
C1D1) and time since last dose (start date of AE
date of last
dose before AE onset).
Addition: If treatment-relatedness is missing, AE will be considered
as RELATED.
Extra AE tables by PT only (>= certain cut-off)
Addition of tables for serious TEAEs grade 3/4 and 5
ECG: update of formulas for calculation of QTcB and QTcF
Addition of Appendix E: list of TLFs


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List of Abbreviations
Abbreviation
Definition
AE
adverse event
ANC
absolute neutrophil count
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BSA
body surface area
BUN
blood urea nitrogen
CR
complete response
CT
Computerized Axial Tomography
CTCAE
Common Terminology Criteria for Adverse Events
°C
degrees Celsius
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
ICH
International Conference on Harmonization
ITT
intent-to-treat
MITT
modified intent-to-treat
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MRI
magnetic resonance imaging
NC
no change
NCI
National Cancer Institute
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
Pharmacokinetics
PR
partial response
PT
MedDRA Preferred Term
SAE
serious adverse event
SOC
MedDRA System Organ Class
TEAE
treatment-emergent adverse event


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Table of Contents
1
INTRODUCTION......................................................................................... 9
2
STUDY DESCRIPTION ............................................................................... 9
2.1
Study Objectives...................................................................................... 9
2.2
Study Design ............................................................................................ 9
2.3
Randomization and Blinding ............................................................... 10
3
ANALYSIS POPULATIONS....................................................................... 10
3.1
Intent-to-Treat Population................................................................... 10
3.2
Modified Intent-to-Treat Population .................................................. 10
3.3
Safety Population .................................................................................. 10
3.4
Per Protocol Population........................................................................ 11
4
GENERAL CONVENTIONS....................................................................... 11
4.1
Definition of Baseline............................................................................ 11
4.2
Definition of Time ................................................................................. 11
4.3
Tumor Assessment Schedule................................................................ 12
4.4
Missing and Partial Data...................................................................... 12
4.5
Software ................................................................................................. 12
4.6
Changes to Planned Analyses............................................................... 12
5
DESCRIPTION OF THE STUDY POPULATIONS........................................ 12
5.1
Disposition.............................................................................................. 12
5.2
Demographic and Baseline Characteristics........................................ 13
5.3
Medical History..................................................................................... 13
5.4
History of Endometrial Cancer ........................................................... 13
5.5
Baseline Comparisons........................................................................... 13
6
TREATMENTS AND MEDICATIONS......................................................... 13
6.1
Prior Treatment for Endometrial Cancer .......................................... 13
6.2
Prior and Concomitant Medications................................................... 14
6.3
Study Treatment Exposure .................................................................. 14
6.4
Study Treatment Modifications........................................................... 14


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6.5
Subsequent Anticancer Therapy ......................................................... 15
7
EFFICACY ANALYSES............................................................................. 15
7.1
Primary Efficacy Outcome
Overall Survival .................................. 15
7.2
Secondary Efficacy Outcomes.............................................................. 16
7.3
Interim Analyses ................................................................................... 23
7.4
Adjustments for Multiplicity................................................................ 23
7.5
Power and Sample Size Justification................................................... 24
8
PHARMACOKINETICS............................................................................. 24
9
SUMMARIES OF MEASURES OF SAFETY ................................................. 24
9.1
Adverse Events ...................................................................................... 25
9.2
Laboratory Assessments....................................................................... 26
9.3
Vital Signs .............................................................................................. 27
9.4
Physical Examination ........................................................................... 27
9.5
Cardiac Assessments............................................................................. 27
9.6
ECOG Performance Status.................................................................. 29
10
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ........... 29
10.1
Data Quality Assurance........................................................................ 29
11
REFERENCES .......................................................................................... 29
12
APPENDICES............................................................................................ 30
12.1
Appendix A - Time and Events Schedule ........................................... 30
12.2
Appendix B - Progressive Disease and Response Algorithm ............ 32
12.3
Appendix C - ECOG Performance Status Criteria ........................... 33
12.4
Appendix D - Imputation Rules for Missing Dates............................ 35
12.5
Appendix E
List of Tables/Graphs and Listings............................. 37
List of Statistical Tables......................................................................................... 37
List of Graphs ......................................................................................................... 42
List of Listings......................................................................................................... 43


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1
INTRODUCTION
This statistical analysis plan (SAP) is based on:
Protocol AEZS-108-050, protocol version 3.2, dated September 12, 2014
FDA guidance on cancer trial endpoints (Guidance for Industry Clinical Trial
Endpoints for the Approval of Cancer Drugs and Biologics)
EMA Guideline on the evaluation of anticancer medicinal products in man
(EMA/CHMP/205/95)
ICH guidelines E9 (Statistical Principles for Clinical Trials).
The purpose of this document is to provide details on study populations and on how the
variables will be derived, how missing data will be handled, and how censoring procedures
will be applied to time to event related variables as well as details on statistical methods to
be used to analyze the safety and efficacy data from the study.
The document may evolve over time, for example, to reflect the requirements of protocol
amendments or regulatory requests. However, the final SAP must be finalized, approved
by the Sponsor, and placed on file before the database is locked prior to the final analysis.
Deviations from the approved plan will be noted in the clinical study report.
2
STUDY DESCRIPTION
2.1
Study Objectives
The primary objective of this study is:
Compare the overall survival (OS) of patients treated with AEZS-108 to the OS of
patients treated with doxorubicin.
The secondary objectives include:
Compare efficacy based on progression-free survival (PFS), objective response rate
(ORR) and clinical benefit rate (CBR).
Compare safety.
Determine the impact of these regimens on patient-reported quality of life during
and for up to 1 year after completion of study treatment.
Assess the pharmacokinetics and exposure-response relationships of AEZS-108,
doxorubicin and doxorubicinol in a PK sub-study at selected sites and by sparse PK
sampling, respectively.
Assess the acute effects on electrocardiographic parameters (e.g., QT/QTc interval)
within PK sub-study.
2.2
Study Design
This is an open-label, randomized, active-controlled, two-arm Phase III study to compare
the efficacy and safety of AEZS-108 and doxorubicin. The study will include about
500 patients with advanced, recurrent or metastatic endometrial cancer who have


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progressed and who have received one chemotherapeutic (i.e., cytotoxic) regimen with
platinum and taxane (either as adjuvant or first line treatment).
Patients will be centrally randomized in a 1:1 ratio to receive treatment with either
AEZS-108 (Arm A) or doxorubicin (Arm B).
During ongoing treatment, response will be evaluated every 3 cycles; earlier reassessments
should be scheduled to verify a response (at least 4 weeks after first observation of the
response) or in case of suspected progression. Patients, who have gone off-treatment for
reasons other than progression, will be reassessed every 12 weeks until progression. All
patients will be followed-up for survival.
On a regular basis, at intervals no longer than 6 months, results from safety analyses will
be submitted to an independent Data and Safety Monitoring Board (DSMB) that will
advise the Sponsor of potentially critical findings.
The final analysis will be performed after about 384 deaths have been observed. There
will be two planned interim analyses; the first will be for futility only, the second will be
for safety and efficacy.
Based on the availability of the assay for LHRH receptor expression in tumor specimens,
subgroup analyses stratified for extent of LHRH receptor expression was planned to assess
the predictive value of the LHRH receptor assay. Due to non-availability of a validated
assay, no such stratified analyses can be performed.
2.3
Randomization and Blinding
This is an open-label study.
3
ANALYSIS POPULATIONS
3.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) population will consist of all randomized patients. Analyses of
this population will assign patients the treatment they were scheduled to receive, regardless
of any errors of dosing or dose modifications. Patients who received treatment in the
group that is different from the one to which they have been randomized to, will be noted
in the CSR.
3.2
Modified Intent-to-Treat Population
A modified Intent-to-Treat (MITT) population will consist of all randomized patients, who
received at least one dose of study treatment, i.e. the MITT population will exclude
patients who never received study treatment.
3.3
Safety Population
The safety population will include all randomized patients who received at least one dose
of study treatment. In the safety analyses, patients will be included in the treatment arm
that they have actually received. Patients who are included in a treatment group that is
different from the one to which they have been randomized will be noted.


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3.4
Per Protocol Population
The Per-Protocol (PP) population will include all randomized patients without major
protocol deviations. What constitutes a major protocol deviation will be determined and
documented prior to database lock. Protocol deviations will also be presented in the
clinical study report.
4
GENERAL CONVENTIONS
Unless otherwise stated, all analyses will be performed using SAS Version 9.2 or higher
and all hypothesis tests will be conducted at a two-sided significance level of 0.05. P-
values will be presented with 3 decimals and p-values that are less than 0.001 will be
presented as < 0.001.
Continuous (non-survival related) data will be summarized using descriptive statistics:
number of observations (n), mean, standard deviation (SD), median, minimum, and
maximum. Frequencies and percentages will be used to summarize categorical (discrete)
data. Presentations of categorical data will generally suppress percentages for items where
the count is zero in order to draw attention to the nonzero counts. In general, mean,
standard deviation, median, 25th and 75th percentiles, minimum, maximum, and
percentages will be presented with one decimal.
Unless otherwise stated, confidence intervals, when presented, will be constructed at the
two-sided 95 % level. For binomial variables, the 95 % confidence intervals will be
constructed using the normal approximation without continuity correction.
In the tables the following indication for treatment will be used: AEZS-108 and
Doxorubicin. Data listings will show data presented in the summary tables by study drug,
country, center and patient number.
4.1
Definition of Baseline
In general, the last observed measurement prior to first administration of study treatment
will be considered the baseline measurement. In practice, for questionnaires, LVEF and
ECG baseline is defined as screening visit. For laboratory parameters, vital signs and
ECOG cycle 1 day 1 (C1D1) is considered as baseline. If C1D1 assessment is not available
or if assessment on C1D1 is not before first treatment, screening value will be taken as
baseline value. If date of first treatment is missing, screening value will be taken as
baseline value.
4.2
Definition of Time
For the purpose of summarizing efficacy data, time will be defined relative to the date of
randomization. Unless otherwise stated, for visits (or events) that occur on or after
randomization, time is calculated as:
time (days) = visit date (event date)
date of randomization + 1.
For visits (or events) that occur prior to randomization, time is calculated as:
time (days) = visit date (event date)
date of randomization to study treatment.


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defined as:
days since first/last dose = event date
date of first/last dose.
Events that occur on the same day as the first/last dose will therefore be described as
occurring zero days from the first/last dose. In most cases, listings will include the number
of days since first/last dose of AEZS-108/comparator (doxorubicin).
4.3
Tumor Assessment Schedule
Tumor assessments will occur every 3 cycles (± 7 days) during ongoing treatment, then if
required beyond the end of treatment every 3 months (± 7 days) while the patient is on
study. The last assessment will occur when approximately 384 randomized patients have
died.
4.4
Missing and Partial Data
In general, other than for partial dates, missing data will not be imputed and will be treated
as missing.
The algorithms for imputation of partial dates vary depending upon the
parameter and are presented in Section 12.4 (Appendix D - Imputation Rules for Missing
Dates.)
4.5
Software
Unless otherwise stated, all analyses will be conducted using SAS Version 9.2 or higher.
4.6
Changes to Planned Analyses
Draft versions of the SAP will be numbered sequentially as Version x-1.0i. The final
approved version will be numbered as Version x.0. The Clinical Study Report will
document any change made after database lock.
5
DESCRIPTION OF THE STUDY POPULATIONS
The paragraphs below specify presentations of data for both the ITT and safety
populations. If, however, the two populations are almost the same (i.e., safety population
is 95 % or more than the ITT population), then only the ITT tables will be presented. A
summary of differences between the two populations will be noted in the CSR.
5.1
Disposition
Patient disposition summaries will be presented by treatment arm and will include the
number of patients enrolled, randomized, the number and percentage of randomized
patients in the ITT, the modified ITT, the PP, and the safety populations. The summaries
will also include the reasons for permanent discontinuation of study treatment and study.
Disposition by investigational sites and by territory will also be presented. Trial territories
are defined as follows:
- North America: US, CA;
- W/N-Europe/Israel: AT, BE, DE, DK, ES, FI, GB, IE, IL, IT, NL, NO, PL;
- Eastern Europe: BG, BA, BY, CZ, RU, UA, RO.


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5.2
Demographic and Baseline Characteristics
A summary of demographics and baseline characteristics will be presented by treatment
arm for the ITT and safety populations.
The demographic characteristics consist of age, age category (defined below), sex,
ethnicity, race, and Eastern Cooperative Oncology Group (ECOG) performance status.
Baseline height and weight will also be presented using standard descriptive statistics.
Age (years) will be calculated as (date of informed consent
date of birth) / 365.25.
Age categories: < 65 years and 65 years or older, will be presented using frequencies and
percentages.
also be reported.
5.3
Medical History
A data listing will present medical history. If useful for interpretation of the results of the
study, a table will summarize the data.
5.4
History of Endometrial Cancer
including time since initial diagnosis to randomization, primary diagnosis. Summaries will
be prepared for the ITT and safety populations and will display the information by
treatment arm and overall. All details of endometrial cancer history (including origin of
tumor specimen) will also be listed.
5.5
Baseline Comparisons
The two treatment arms will be assessed descriptively for comparability of demographic
and baseline characteristics. Data to be evaluated will include at least age, sex, race, and
components of disease severity assessment and disease status (e.g., locally advanced,
recurrent or metastatic endometrial cancer).
6
TREATMENTS AND MEDICATIONS
6.1
Prior Treatment for Endometrial Cancer
Use of prior treatment for endometrial cancer will be presented as subject frequency counts
and percentages for the safety population. Descriptive statistics for type of drugs per
patient will also be shown. Participants are only counted once for each type of therapy.
Prior chemotherapy will be coded using the World Health Organization (WHO) dictionary
and summarized by treatment arms for the safety population;
By WHO Drug base substance preferred name using frequency counts and
percentages
By regimen number using frequency counts and percentages on unique
combinations of WHO Drug base substance preferred names.


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For platinum and taxane based treatment the use as adjuvant or advanced treatment will be
specified.
6.2
Prior and Concomitant Medications
All medications recorded on the CRFs will be coded using the WHO dictionary. Prior and
concomitant medications will be summarized by treatment arm in the safety population by
anatomical therapeutic chemical (ATC) Class Level 4 and WHO Drug base substance
preferred name. Participants are only counted once for each preferred term.
Prior medications are defined as medications with stop dates occurring before the date of
first administration of any study treatment component. Concomitant medications are
defined as medications with start dates occurring on or after the date of first administration
of any study treatment component and no more than 30 days after the last administration of
any study treatment. Medications with start and stop dates that bracket the date of first
administration of any study treatment will be summarized as both prior and concomitant
medications.
For the purpose of summarizing prior and concomitant medications, incomplete
medication start and stop dates will be imputed as detailed in Section 12.4. Based on
imputed start and stop dates, medications that clearly stopped prior to date of first
administration of any study treatment component will be included in the prior medications
table, and medications that clearly started on or after date of first administration of any
study treatment component will be included in the concomitant medications table. All
other medications will be included in both the prior and concomitant medications tables.
6.3
Study Treatment Exposure
Study treatment exposure will be summarized by treatment arm in the ITT and safety
populations.
The following will be summarized by treatment arm using descriptive statistics:
number and percentage of patients who received at least one dose
duration of exposure per patient, calculated as (date of last dose [start date of last
cycle]
date of first dose [start date of first cycle] + 1),
number of doses (cycles) received per patient,
cumulative dose (in mg/m2) received per patient,
patients receiving prophylactic antiemetic treatment per treatment cycle, and
patients receiving anti-allergic treatment per treatment cycle.
In addition, a table will be made summarizing duration of cycle 1 administration and
duration of administration
all cycles combined.
6.4
Study Treatment Modifications
Treatment modifications will be summarized by treatment arm in the ITT and safety
populations for each randomly assigned study treatment.


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The number and percentage of patients with doses delayed (withheld) and doses reduced,
and reasons for these dose changes will be summarized by treatment cycle. The total
number of dose delays and reductions will be shown.
6.5
Subsequent Anticancer Therapy
A summary of the number and percentage of patients receiving subsequent anticancer
therapy after discontinuation of study treatment will be presented by treatment arm in the
ITT population.
7
EFFICACY ANALYSES
7.1
Primary Efficacy Outcome
Overall Survival
The primary efficacy outcome is overall survival (OS).
7.1.1
OS: Definition
OS is defined as the time from randomization to death for any cause during the study.
Patients without confirmed vital status are censored on the day they are last known alive.
Every reasonable effort will be made to establish vital status of each patient on the last day
of the study, that is, the clinical cutoff date established after approximately 384 patients
have died. OS will be calculated as follows:
For those who die during the study,
overall survival (days) = date of death
randomization date + 1;
For those who are alive or vital status cannot be determined at the end of the study,
overall survival (days) = date of censoring
randomization date + 1, with
censor indicator indicating a censor.
7.1.2
OS: Primary Analysis
The primary analysis of OS will be performed using the ITT population.
The primary efficacy analysis will be performed using the ITT population. The final
analysis, which is event-based, will be conducted after approximately 384 randomized
patients have died. In the primary analysis, a log-rank test with an overall two-sided Type
I error rate of 0.05 after taking the interim analyses into account will be used to compare
OS between the two treatment arms via a SAS lifetest procedure. Kaplan-Meier estimates
will be used to calculate median OS and the 95 % confidence interval of the median OS.
The proportion of patients alive at six and 12 months (from randomization date) and the 95
% confidence intervals for these estimated proportions, if appropriate, will be presented.
A Cox model with treatment effects will be used to estimate the hazard ratio and perform
hypothesis testing. The estimated hazard ratio and the 95 % confidence interval of the
hazard ratio will be presented.


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7.1.3
Supportive and Sensitivity Analyses
To assess the robustness of the study results, supportive analyses of OS will be performed
using modified ITT and per protocol population. In addition, the following sensitivity OS
analyses will be performed, if appropriate:
Patients will be censored at the time when they received other non-protocol required
anticancer treatment, if applicable.
Patients will be censored at the time when they drop out of the study due to AEs.
Exploratory analyses of the effect of baseline characteristics and other covariates will be
conducted using Cox regression models. Cox models with treatment (forced into the
model) and different (see listed underneath) covariates each at the time, and a global Cox
model with treatment (forced into the model) and different covariates using backward
selection will be made. The significance level to retain a variable in the model will be set at
10%. The following covariates will be considered:
Age (entered as continuous covariate)
Endometrial cancer type: Type I vs Type II
Type I: endometrioid, squamous, adenocarcinoma
Type II: serous, clear cell, mixed, carcinosarcoma
II as medically appropriate)
Histology: endometrioid vs serous vs clear cell vs squamous cell carcinoma vs
other
Tumor grade: Gx vs G1 vs G2 vs G3 vs G4 vs other
Prior radiotherapy (yes vs no)
Time since diagnosis (< 12 months vs
12 months)
Stage of disease at study entry (advanced or recurrent disease vs metastatic disease)
Potential center-effects
Territory (North America vs W/N-Europe vs Eastern Europe)
- North America: US, CA
- W/N-Europe/Israel: AT, BE, DE, DK, ES, FI, GB, IE, IL, IT, NL, NO, PL
- Eastern Europe: BG, BA, BY, CZ, RU, UA, RO
Recruitment volume (
)
- low recruiter: < 10 patients/site
- high recruiter: >10 patients/site
7.2
Secondary Efficacy Outcomes
The study has two key secondary efficacy outcomes: progression free survival (PFS) and
overall response rate (ORR).


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7.2.1
ORR and Clinical Benefit: Definitions
The ORR for each treatment arm will be estimated as the proportion of responders, defined
as a patient whose best overall response is PR or better during the treatment period. All
responses must be confirmed at least 4 weeks after the initial response is seen. Tumor
assessments will occur every 3 cycles (± 7 days) during ongoing treatment then, if required
beyond the end of treatment, every 3 months (± 7 days) while the patient is on study. The
last assessment will occur either when progression is confirmed or when approximately
384 randomized patients have died.
Clinical benefit is defined as having stable disease or better lasting for at least 9 weeks.
7.2.2
ORR and Clinical Benefit: Primary Analysis
The ITT population will be used to test the effects of AEZS-108 and comparator on ORR.
Hypothesis testing between the two treatment arms will be performed using a Mantel-
Haenszel test. The corresponding odds ratio will be also estimated. The 95 % confidence
interval of the ORR will be reported via normal approximation without continuity
correction.
Clinical benefit rate will be analyzed using the same methods for the ORR analyses.
7.2.3
ORR: Supportive and Sensitivity Analysis
ORR will also be analyzed for the modified ITT and PP population, and logistic regression
models analogous as defined for OS (see Section 7.1.3) will be made.
In addition, duration of overall response and duration of stable disease will be analyzed by
means of time-to-event analysis (see details in section 7.1.2). Duration of overall response
is defined for subjects with CR or PR as best overall response as duration from the first
time when criteria for a response (PR or CR) were met until first observation of PD. If PD
is not reached, the subject is censored at date of last visit with adequate assessment.
Duration of stable disease is defined as duration from start of treatment until first
observation of PD for patients with SD as best overall response. If PD is not reached, the
subject is censored at date of last visit with adequate assessment. If subject did not receive
treatment, date of randomization will be taken as start date.
Moreover, duration of follow-up will be summarized and median duration will also be
estimated by means of K-M analysis (i.e. reversing OS censoring).
7.2.4
PFS: Definition
PFS is defined as the number of days between randomization and the date of progression
or death that occurred up to the end of study. PFS for patients who progress and then
subsequently die will be the number of days between randomization and the date of
progression is first observed.
Progression should be confirmed as specified. PFS data will be censored for subjects
whose PFS status cannot be determined. The table below summarized rules of determining
the dates of progression and censoring:


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Situation
Date of Progression or
Censoring
Outcome
No baseline tumor assessments
Randomization
Censored
Progression documented
between scheduled visits
Date of the documented
progression
Progressed
No progression
Date of last visit with adequate
assessment
Censored
Treatment discontinuation for
undocumented progression
Date of last visit with adequate
assessment
Censored
Treatment discontinuation for
toxicity or other reason
Date of last visit with adequate
assessment
Censored
New anticancer treatment
started
Date of last visit with adequate
assessment
Censored
Death between adequate
assessment visits
Date of death
Progressed
Death or progression after
more than one missed visit
Date of last visit with adequate
assessment
Censored
Once the dates of progression, survival, and censoring are derived, PFS will be calculated
as follows:
For those who died or progressed up to the end of the study,
duration of PFS (days) = date of progression or death due to any case
randomization date + 1;
for those who are censored,
duration of PFS (days) = date of censoring
randomization date + 1, with
censor indicator indicating a censor.
7.2.5
PFS: Primary Analysis
The primary analysis of PFS will be performed using the ITT population and based on the
data from the study.
Hypothesis testing between the two treatment arms will be performed using a log-rank test
with an overall two-sided 0.05 level of significance via a model including treatment
effects.
For each treatment arm the median duration of PFS and the proportion of patients alive and
progression-free at six and 12 months will be estimated using the Kaplan-Meier method.
For each estimate, a 95 % confidence interval will be reported. The hazard ratio and its
95 % confidence interval will also be reported.
7.2.6
PFS: Supportive and Sensitivity Analysis
As a supportive analysis, PFS will be analyzed based on the modified ITT and PP
populations. The same Cox models as defined for OS (see Section 7.1.3) will be made. In


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addition, PFS will be analyzed in the subset of patients from MITT that have CR, PR or
SD as best overall response.
7.2.7
Quality of Life
Change from baseline in Quality of life will be analyzed via mixed model analysis with
treatment effect, visit, its interaction, baseline quality of life score and its interaction with
visit as covariates. The treatment effect and treatment difference will be estimated and the
95 % confidence interval of the estimates will be presented.
7.2.7.1
QoL Scoring
The following sections describe the scoring algorithms used for both the QLQ-C30 and
QLQ-EN24 questionnaires.  Scoring procedures are similar for both questionnaires and can
be found in the EORTC QLQ-C30 Scoring Manual, version 3.0 (Fayers et al. 2001) and
the EN24 summary document. All scales and the single-item measures range from 0 to
100.
7.2.7.1.1
QLQ-C30
For all scales, calculate the raw score (RS) of a scale using the mean of the item scores in
the scale as follows: RS = (S1 + S2
n) / n



Use a linear transformation to standardize the raw score in order that scores will range
from 0-100:
Global Health Status/QOL = {(RS-1)/range} * 100
Functional Scales = {1- ((RS-1)/range)} * 100
Symptom Scales = {(RS-1)/range} * 100
where range for each scale is defined in Table 1.
Table 1: QLQ-C30 scales and scoring details
Number of
Items
Item
Range a
Item
Numbers
Minimum Not
Missing
Global Health Status/QOL
2
6
29,30
1
Functional Scales
Physical Functioning
5
3
1-5
3
Role Functioning
2
3
6,7
1
Emotional Functioning
4
3
21-24
2
Cognitive Functioning
2
3
20,25
1
Social Functioning
2
3
26,27
1
Symptom Scales / Items
Fatigue
3
3
10,12,18
2
Nausea / Vomiting
2
3
14,15
1


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Number of
Items
Item
Range a
Item
Numbers
Minimum Not
Missing
Pain
2
3
9,19
1
Dyspnoea
1
3
8
N/A
Insomnia
1
3
11
N/A
Appetite Loss
1
3
13
N/A
Constipation
1
3
16
N/A
Diarrhoea
1
3
17
N/A
Financial Difficulties
1
3
28
N/A
a Range is the difference between the maximum possible value of the raw score and the minimum possible
value.
QLQ-C30 scale scores range from 0 to 100 with higher scores representing a better health
state for the functional scales and lower scores representing a better health state for
symptom scores.
7.2.7.1.2
QLQ-EN24
For all scales, calculate the raw score (RS) of a scale using the mean of the item scores in
the scale as follows:
RS = (S1 + S2
n) / n
ith valid scores,
assuming the number of items with valid scores meets the minimum requirement as
specified in Table 2 or this score will be assumed missing.
Use a linear transformation to standardize the raw score in order that scores will range
from 0-100:
Functional Scales = {1- (RS-1)/range)} * 100
Symptom Scales = {(RS-1)/range)} * 100
where range for each scale is defined in Table 2.
Table 2: QLQ-EN24 scales and scoring details
Number of
Items
Item
Range a
Item
Numbers
Minimum Not
Missing
Functional Scales
Sexual Interest
1
3
49
N/A
Sexual Activity
1
3
50
N/A
Sexual Enjoyment
1
3
54
N/A
Symptom Scales / Items
Lymphoedema
2
3
31-32
1
Urological symptoms
4
3
34-37
2


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Number of
Items
Item
Range a
Item
Numbers
Minimum Not
Missing
Gastrointestinal symptoms
5
3
38-42
3
Poor body image
2
3
47 48
1
Sexual/vaginal problems
3
3
51 53
2
Pain in back and pelvis
1
3
33
N/A
Tingling/numbness
1
3
43
N/A
Muscular pain
1
3
44
N/A
Hair loss
1
3
45
N/A
Taste change
1
3
46
N/A
a Range is the difference between the maximum possible value of the raw score and the minimum possible
value.
A high score for the functional scales represents a high level of functioning, while a high
score for the symptom scales represents a high level of symptoms or problems. Symptoms
related to sexual/vaginal problems (including items 51-53) are optional.
7.2.7.1.3
Missing items
The method used for both health-related quality of life (HRQL) instruments requires that
for multi-item scales, at least half of the items from the scale have been answered. The
missing items are imputed based on the average of those items that are answered. None of
the single item measures can be imputed using this method of imputation. In the event of
missing full assessments, none of the subscales will be scored or imputed. Tables 1 and 2
detail the number of required items for the QLQ-C30 subscales and QLQ-EN24 subscales
respectively.
7.2.7.2
Mixed Model Analysis
7.2.7.2.1
Hypothesis
The hypothesis for the HRQL endpoint
change over time in the QLQ-C30 GHS/QOL is
as follows:
H0:
There is no difference in health-related quality of life based on the EORTC
QLQ C-30 GHS/QOL scale between AEZS-108 and doxorubicin treated
subjects.
Ha:
Treatment with AEZS-108 is associated with better health-related quality of
life based on the EORTC QLQ C-30 GHS/QOL scale as compared to
treatment with doxorubicin.
The same set of hypotheses holds for QLQ-EN24.
HRQL assessments are performed at the following visits:


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Screening, end of cycles 3 and 6, end of therapy (3-5 weeks after last dose) and at
post therapy follow-up (every 3 months).
7.2.7.2.2
Missingness
Missingness can be classified in terms of missing items (i.e. specific item(s) not completed
on an otherwise completed form) or missing forms (i.e. entire form not completed).
Furthermore, missing forms can be classified in terms of intermittent missing (i.e. missing
assessment(s) between two non-missing assessments) or monotone missing (i.e. missing all
assessments after a certain time point possibly due to subject dropout or treatment
discontinuation).
In this study, as the HRQL data capture is scheduled up to the end of therapy and post
therapy visits and subjects are expected to experience certain disease- or treatment-related
morbidity that will lead to discontinuation of study treatment, missing assessments are
inevitable. Also missing full assessments even for the subjects still on treatment can occur
despite the best effort to minimize those.
The underlying reasons for missing data are
unknown but, in general, 3 different missing data mechanisms are considered (Rubin 1976;
Little and Rubin, 1987; Fairclough, 2002).
Missing Completely at Random (MCAR)
Missingness is assumed to be completely unrelated to the HRQL scores. In general,
this assumption is not plausible in oncology studies and will therefore not be assumed
for the analyses.
Missing at Random (MAR)
Missingness depends only on observed data (e.g. prior observed HRQL scores or
observed covariates). This is the assumption underlying the mixed modelling approach
described here.
Missing Not at Random (MNAR)
Missingness depends on the HRQL scores that are missing.  Since we have not
observed the missing HRQL scores, it is not possible to test if the missingness of
HRQL data depends on the value they would have had if not missing. However, the
possibility of missing not at random may not be completely ruled out.
7.2.7.2.3
Description of mixed model with assumptions
Changes over time in QLQ-C30 Global Health Status/QOL scores and in QLQ-EN24
scores will be compared between treatment groups using a restricted maximum likelihood-
based mixed model for repeated measures (MMRM) data under the missing at random
(MAR) assumption (Mallinckrodt et al, 2008).
The dependent variable of this model will be the change of QLQ-C30 Global Health
Status/QOL score or the QLQ-EN24 score measured at the end of cycles 3 and 6, at the
end of therapy and at post therapy follow-up as compared to baseline (denoted by HRQL).
The model will include the fixed, categorical effects of treatment (trt), visit (visit), and
treatment-by-visit interaction (trt*visit). As there is only a limited amount of time points
per subject and given the possibility that not all time points are equally spaced in time,
time is entered into the model as the categorical variable visit. The random subject effects


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are not explicitly formulated in the model form, but will be modelled as part of the within-
subject error correlation structure. For this purpose, an unstructured covariance matrix will
be used, allowing for different variances / covariances across subjects. If the analysis
using the unstructured covariance matrix fails to converge, the following covariance
structures will be tested: heterogeneous Toeplitz, heterogeneous compound symmetry,
Toeplitz and compound symmetry. The covariance structure converging to the best fit, as
. The
Kenward-Roger approximation will be used to estimate denominator degrees of freedom.
The least square means for each treatment group and the treatment difference will be
presented together with the 95% confidence interval and p-value.
The pseudo SAS code of the primary model is as follows:
proc mixed data = HRQLdataset method = reml;
class PatID trt visit;
model HRQL = trt visit trt*visit baseline baseline*visit / noint ddfm = kr;
repeated r / subject = PatID type=un;
run;
where PatID represents the individual subject id.
The mixed model will provide estimates of the treatment effect and of the treatment
difference at each visit until end of treatment, together with their 95% confidence intervals.
7.3
Interim Analyses
The Data and Safety Monitoring Board (DSMB) will review data periodically throughout
the trial. The DSMB may recommend stopping the trial for safety at any time or for
futility at the interim looks. Two planned interim analyses will be conducted, one for
futility only and one for both safety and efficacy. The first for a futility analysis only will
be conducted at 1/3 of information time (i.e., approximately at 128 death event time). The
interim efficacy/safety analysis is planned at 50 % of information time (when
approximately 192 death events take place).
In the interim efficacy/safety analysis, OS, the primary efficacy outcome of the study, will
be analyzed using a two-sided log-rank test. The Lan-DeMets implementation of the
0.05. The nominal p-values for the planned second interim and the final analyses will be
0.003051 and 0.049002, respectively.
The interim analysis may not be binding. However, if the interim analysis results
demonstrate strong evidence of efficacy, the DSMB may request a meeting with the FDA
to discuss potential early termination of the study.
7.4
Adjustments for Multiplicity
One non-binding efficacy interim analysis is planned for this study. Lan-DeMets
-Fleming alpha-spending function will be used to control


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the overall Type I error rate at 0.05. The study has one primary efficacy endpoint; no p-
value adjustment for multiple endpoints is required.
Two key secondary efficacy variables, PFS and ORR will also be analyzed for potential
labeling claims. Hierarchical testing procedures will be used to control the Type I Error at
the 0.05 level. Specifically, the superiority of the active treatment will be tested at a two-
sided significance level of 0.05 for OS first, then for PFS, and then for ORR. The
superiority claim for an efficacy outcome can be made only if all previous claims are
successfully made.
7.5
Power and Sample Size Justification
Approximately 384 events of deaths will be required to achieve 80 % power to detect a
treatment difference at the overall two-sided 0.05 significance level after taking the
planned efficacy/safety interim look into account. It is expected that approximately
500 patients will be enrolled during an estimated 24-month recruitment period and will
then be followed for 12 months to observe a total of approximately 384 death events. In
the sample size calculation, it is assumed that the median OS is 12 months for the group
with investigational treatment (AEZS-108) and 9 months for the control group
(doxorubicin). The sample size calculation has taken the interim analyses into
consideration.
Based on published data on the pharmacokinetics of doxorubicin, a sample size of
20 patients for each arm is proposed, to provide a more detailed description than is
currently available for the key pharmacokinetic parameters of AEZS-108, doxorubicin, and
doxorubicinol. Based on preliminary pharmacokinetic data available from an ongoing
study in bladder cancer patients, a variability of AEZS-108 similar to that for doxorubicin
may be expected. Since collection of only a limited number of samples over a limited
period (about 2-3 terminal elimination half-lives) is feasible within this sub-study, the
comparison of the metabolite profiles will be orienting / exploratory / descriptive in nature.
8
PHARMACOKINETICS
A PK sub-study at selected sites and sparse PK sampling at all sites is performed to assess
the pharmacokinetics and exposure-response relationships of AEZS-108, doxorubicin and
doxorubicinol. A SAP supplement contains all details of non-compartmental analysis that
will be performed on the PK sub-study samples and is not part of this main SAP. All
details of population PK analysis (using all available PK samples) will be described in a
second SAP supplement that is also no part of this main SAP.
9
SUMMARIES OF MEASURES OF SAFETY
Safety analyses will be performed for the safety population. Safety evaluations will be
based on the incidence, intensity, and type of adverse events, as well as on clinically
laboratory results. Safety variables will be tabulated and presented by study drug actually
received.


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Because there is no pre-specified safety outcome defined in terms of AEs, clinically
relevant laboratory parameters, or vital signs, any formal comparisons between the
treatment arms with respect to specific safety parameters will be post-hoc.
9.1
Adverse Events
Each AE and SAE term recorded on the case report forms (CRFs) will be mapped to a
preferred term (PT) using the MedDRA dictionary. The investigator will classify the
severity of AEs and SAEs using the NCI CTCAE v4.0 and will assess the relationship of
each event to the study treatment.
All AEs and SAEs occurring on study will be listed by treatment drug, center, and patient.
Four additional listings will be made: listing of AEs associated with dropout (i.e. Drug
withdrawn on CRF page), listing of AEs leading to dose reduction (i.e. Dose reduced on
CRF page), listing of AEs with fatal outcome and listing of deaths. AE listings will contain
(not limited to): last dose before event (mg/m2), time on treatment (date of last dose before
AE onset
C1D1) and time since last dose (start date of AE
date of last dose before AE
onset). The listing of deaths will include for each death case: overall survival (duration),
reason for end of treatment, time on treatment (C1D1
date of last dose), time since last
dose (start date
date of last dose) and best response.
The frequency and percentages of patients with treatment-emergent adverse events
(TEAEs) will be tabulated by system organ class (SOC) and PT, where treatment-emergent
is defined as any AE that;
occurs after randomization and through the end of the study or up through 30 days
after the last dose of study treatment,
is considered treatment-related (i.e., considered at least possibly related to the study
treatment) regardless of the start date of the event, or
is present before randomization but worsens in intensity or the investigator
subsequently considers treatment-related (i.e., considered at least possibly related to
any component of the study treatment).
For the purpose of calculating treatment emergence and inclusion in summary tables,
incomplete onset dates will be imputed as detailed in Appendix D. If treatment-relatedness
is missing, AE will be considered as RELATED. Summaries will display incidence by
study drug (AEZS-108 or doxorubicin) received and total incidence, and PTs within each
SOC will appear in decreasing order of total incidence. At each level of summarization, a
patient will be counted only once for each AE, SOC, or PT experienced within that level.
Related TEAEs, serious TEAEs, Grade 3 or higher TEAEs, Grade 3/4 serious TEAEs,
Grade 5 serious TEAEs, related serious TEAEs, related Grade 3 or higher TEAEs, and
TEAEs resulting in discontinuation or dose modification of study treatment will be
similarly summarized. Summaries of TEAEs by relationship to each of the study
treatments will also be prepared.
At each level of summarization, a patient will be counted only once for each AE, SOC, or
PT experienced within that level. In the summation for AE severity, within each level of
AE, SOC, or PT experienced, the one with the highest severity will be included. In the


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experienced, the one with the closest relationship to the study drug will be included.
Several TEAE tables with AEs sorted by PT (>= certain cut-off) by decreasing frequency
(in the AEZS-108 arm), irrespective of SOC, will be made in addition (see Appendix E
List of Tables/Graphs and Listings).
9.2
Laboratory Assessments
Laboratory data for hematology and serum chemistry tests will be reported in International
Units. Individual values outside the central laboratory reference ranges will be identified
each patient.
9.2.1
Variables
The following Hematology, Chemistries, Urinalysis laboratory evaluations will be
performed:
Panel name
Laboratory parameters included
Hematology
leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes
(platelets); differential white blood cell count (neutrophils, lymphocytes,
monocytes, basophils, eosinophils)
Chemistries
- Enzymes
AST/SGOT, ALT/SGPT, gamma-GT, alkaline phosphatase, LDH
- Substrates
total protein, total bilirubin, creatinine, urea, uric acid
- Electrolytes
sodium, potassium, calcium
Urinalysis
glucose*, protein*, microalbumin**
Hormones
luteinizing hormone (LH), follicle stimulating hormone (FSH)
Pregnancy test
ß-HCG (in serum; for women of childbearing potential only)
* In case there is no possibility for evaluation of the parameters provided above semiquantitative
dipstick analysis will be accepted.
** In cases where 24-hour urine is not available to determine microalbumin, the
microalbumin/creatinine ratio may be used instead.
9.2.2
Statistical Analysis
Continuous laboratory test results will be summarized descriptively by study drug received
for actual values and for changes from baseline. Visits to be summarized include all
scheduled post-Cycle 1 Day 1 visits. Unscheduled visit data is not captured in summary
statistics.
Shift from baseline tables for laboratory parameters will be presented. Categories will be
based on CTCAE grade (where applicable) or by high/low flags (where CTCAE grades are
not defined). Data will be analyzed at all post-Cycle 1 Day 1 visits, by worst grade post-
Cycle 1 Day 1. Laboratory tests that have high and low abnormalities will be summarized
separately for each direction (e.g., hypocalcemia and hypercalcemia). Worst post-baseline


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values also include unscheduled visits. For WBC, neutrophils (absolute value) and
thrombocytes extra shift table only considering cycle 1 lab results will be made in addition.
Abnormalities in laboratory tests that the investigator considered clinically significant
(relevant) were to be recorded and summarized as AEs.
9.3
Vital Signs
9.3.1
Variables
The following vital signs will be summarized:
Blood pressure (systolic and diastolic, mmHg)
Oral temperature (Celsius)
Pulse rate (beats/min)
Respiration rate (breaths/min)
Body weight (kg)
9.3.2
Statistical Analysis
Summary tables of vital signs and change from baseline will be presented for all scheduled
visits where vital signs were assessed. All recorded vital sign data will be listed.
9.4
Physical Examination
Physical examination data will be presented in a data listing.
9.5
Cardiac Assessments
9.5.1
Left Ventricular Ejection Fraction (LVEF)
LVEF (ECHO or MUGA) data (raw values and change from baseline) will be summarized
descriptively (arithmetic mean, standard deviation, median, range interquartile values) by
treatment at all available timepoints. In case only a range is specified for an LVEF
measurement: use the mid-point (arithmetic mean) of the specified range as the substitute
for the not-available point-
Moreover, a shift table will be made analyzing the data at all scheduled post-Cycle 1 Day 1
visits, by worst value post Cycle 1 Day 1 until end of study treatment (EOT) visit, and until
end of post therapy follow-up. The following categories will be considered: FROM (%)
50-55,    55-60,    60-65,    65-70,   70-75   and >75 to <35, 40-35, 45-40, 50-55, 55-60, 60-
65, 65-70, 70-75, >75. For LVEF-values specified by range the mid-point of the range
should be used for the assignment. In addition, at the end of C3, C6, C7, C8, end of
treatment and at post-therapy follow-up, number of subjects (and percentage) with absolute
decline from baseline of 10% or more or absolute value of LVEF <50%, will be presented.
Moreover, cumulatively at any time after C1D1, the following will be assessed: (number of
subjects and percentage of):
Absolute decline by 10% or more,
Absolute decline by 15% or more,


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Absolute value of LVEF <50,
Absolute value of LVEF <45%,
Absolute decline from baseline of 10% or more or absolute value of LVEF <50%,
Absolute decline from baseline of 15% or more or absolute value of LVEF <45%
A plot with mean LVEF (mean of raw LVEFE values) evolution over time by treatment
arm (including indication of number of patients present at each time point) will also be
made.
9.5.2
Electrocardiogram (ECG)
For all 12-ECGs recorded as part of the core study, the global classification of clinically
significant (relevant) abnormalities will be summarized. For all continuous ECG variables,
descriptive statistics (arithmetic mean, standard deviation, median, range interquartile
values) will be used for summaries of all continuous ECG variables and their changes from
baseline.
Categorical analysis will be performed (by means of frequency tables, worst post-cycle 1
day 1 until post-therapy FU result) with respect to QTcF and other cardiac intervals for the
following categories:
Absolute values:
QTc
450 ms
QTc > 450 ms and
480 ms
QTc > 480 ms and
500 ms
QTc > 500 ms
PR > 220 ms
QRS > 110 ms
Change from baseline in cardiac intervals:
QTc increase
30 ms
QTc increase > 30 ms and
60 ms
QTc increase > 60 ms
PR > 25%
QRS > 25%
The heart rate corrected QTc interval will be calculated according to
la (QTcB =
),
),
where QTc is the QT interval corrected for rate, and RR is the interval from the onset of
one QRS complex to the onset of the next QRS complex, measured in miliseconds.
RR interval (sec) = 60 / HR; with Heart Rate (HR) in beats per minute.


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For patients participating in the PK sub-study, descriptive analyses of results and changes
from baseline will be performed. More details can be found in the SAP supplement for the
PK/QTc sub-study.
9.6
ECOG Performance Status
ECOG Performance Status will be summarized as shift from baseline tables by visit using
frequencies and percentages at all scheduled visits where performance status was assessed.
10
IDENTIFICATION AND SUMMARY OF PROTOCOL
DEVIATIONS
All protocol deviations will be classified as major or minor. All protocol deviations that
can be extracted from numeric or coded study data as well as treatment compliance will be
summarized. Protocol deviation classification will be determined and documented prior to
data base lock.
10.1
Data Quality Assurance
Accurate and reliable data collection will be ensured by verification and cross check of the
verification) and by the maintenance of a drug-dispensing log by the investigator.
Collected data will be entered into a computer database and subject to electronic and
manual quality assurance procedures.
11
REFERENCES
Fairclough, DL. Design and analysis of quality of life studies in clinical trials. Chapman
& Hall/CRC. 2002.
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of
the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition).
Published by: European Organisation for Research and Treatment of Cancer, Brussels
2001.
Lan K.K.G., D.D., Discrete sequential boundaries for clinical trials. Biometrika, 1883.
70: p.659-63.
Little, RJA and Rubin, DB. Statistical Analysis with Missing Data. New York: Wiley.
1987.
Mallinckrodt, C.H., Lane, P.W., Schnell, D., Peng Y, and Mancuso, J.P.
Recommendations for the primary analysis of continuous endpoints in longitudinal clinical
trials.  Drug Information Journal, Vol. 42, pp.303-319, 2008.
Rubin, DB. Inference and missing data. Biometrika 63:581-592, 1976.


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12
APPENDICES
12.1
Appendix A - Time and Events Schedule
Procedures
Screen
Cycle 1
Cycle 2 to 9
End of
therapy
Post
Therapy
Follow up
Visit / Cycle Day
1)
Within
4 wks
before
C1 D1
2)
D1
D8 + D15
(+D22 + D29
if retreatment
delayed)
3)
4)
3-5 weeks
after last
dose
5)
Every 3
months
6)
Informed consent
X
Demographics
X
Medical history
X
Physical examination
X
Interval history and
symptom-directed exams
X
D1
X
Clinical assessments:
Height (screen only), Weight
X
X
D1
X
ECOG performance status
X
X
D1
X
X (until PD)
Blood pressure, pulse
X
X
X
D1
X
X (until PD)
Adverse events
Cumulative recording 7)
(whenever observed/applicable)
X9)
Concomitant treatments
X
X
D1
X
X10)
Clinical laboratory tests
Hematology, Chemistries,
and Urinalysis
X
X
X11)
D1 4)
X
LH, FSH
X
D1
X
Pregnancy test (ß-HCG)
X 8)
Tumor tissue specimens
collection
X 14)
Pharmacokinetics (sub-study)
X12)
D2+D312)
Cardiac function test
LVEF (ECHO or MUGA)
X 2A)
End of
C3 , C6, C7,
C816)
X
X 9)
ECG (12-lead)
X
D1
X
X 9)


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Procedures
Screen
Cycle 1
Cycle 2 to 9
End of
therapy
Post
Therapy
Follow up
Tumor imaging/evaluation
X 2B)
End of
C3 + C6
X
X
Quality of Life questionnaire
X
End of
C3 + C6
X
X
Survival follow-up
X
Patient registration
X
Eligibility criteria review
X
X15)
Randomization13)
D-1 to
D-413)
Study treatment
X
D1
1) A window of +/- 3 days will be allowed for scheduled visits/actions, +/- 7 days for 3 monthly follow-ups.
If a procedure or visit falls on a public holiday, the patient should be scheduled for the next working day.
2) Pre-study evaluations dating back more than 2 weeks prior to treatment start are acceptable.
2A) LVEF: In absence of intercurrent chemotherapy or cardiac medical history, results dating back up to
8 weeks will be acceptable.
2B) Tumor imaging: Assessments of indicator lesions up to 4 weeks prior to treatment start (C1D1) will
be considered valid for baseline evaluation.
3) Patients who have not recovered sufficiently from treatment-related adverse events within 3 weeks may
have their retreatment delayed by up to 2 weeks; patients who cannot be retreated 5 weeks after previous
dose, will not receive further study treatment but will still be followed for outcome.
4) Start of a new cycle is planned every 3 weeks unless treatment delay is required due to residual toxicity.
Per footnote 1, a window of up to 3 days is allowed to schedule tests prior to the anticipated day of
retreatment, to assure sufficient recovery from treatment-related adverse events ('toxicity') prior to dosing.
5) A full End-of-Therapy assessment will be also required whenever a patient is being withdrawn from the
study. The reason(s) for discontinuation will be documented.
6) Patients discontinuing study treatment for reasons other than disease progression will be reassessed at
3-month intervals to assess the time to treatment failure (progression / death).
Follow-up until progression will be suspended in patients in whom a new cancer treatment has been
started without prior documentation of progressive disease.
Information on survival status may be captured by telephone if no follow-up visit is scheduled for other
reasons.
7) If treatment was discontinued because of a drug-related adverse event (i.e., causality at least possibly
related), the patient will be followed up as clinically indicated to assess and document the outcome.
8) Only required in women of child-bearing potential
9) Only a patient developing signs of cardiac failure during post-treatment follow-up will have LVEF and
ECG evaluated; a left ventricular dysfunction of CTCAE grade 4 will be reported as an SAE.
10) Only anticancer treatments that a patient received during post treatment follow-up for survival will be
recorded.


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11) For tests performed by a laboratory not affiliated to study site (e.g. mid-
home doctor) copies of the external laboratory reports will be provided to the sponsor and results
recorded in the CRF.
12) The pharmacokinetic sub-study will be conducted at selected investigational sites. Procedures are
described in Appendix 7 of the protocol.
13) Every effort should be made to start treatment within 4 days of randomization.
14) Specimens from FFPE fresh biopsies if FFPE archival tumor specimens are not available.
15) Except for Day 1 clinical laboratory tests
16) Recommended to be conducted also at end of Cycle 7 and 8 (i.e., before start of Cycle 8 and Cycle 9,
respectively) for both arms. Results are to be captured on the eCRF if there is an abnormal finding.
12.2
Appendix B - Progressive Disease and Response Algorithm
12.2.1
Introduction
This algorithm is designed to determine the following:
The censoring date for patients whose disease never progressed
12.2.2
Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Details can be found in Protocol Section 7.1.
12.2.3
Date of Progression or Censoring
The date of death is the documented date of death. The date of progression (non death)
will be determined as follows:


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Progression is first observed based on
Date of progression
Unscheduled test prescribed by the investigator
based on patients clinical presentation
The date the test is performed
Scheduled assessment per protocol
Assessment done on scheduled visit date + 7
days (Visit Window)
The date of the assessment
Assessment done > 7 days after
scheduled visit date (Note: this case is
not relevant for this trial.)
The date of the next scheduled assessment date
after the date of last test indicating no
progression. For example, if a patient has an
assessment done at Jth scheduled assessment
visit with a result no progression and has the
next assessment done at (J+4)th scheduled
assessment visit (i.e., skipping 4 scheduled
assessment visit) with a result showing
progression, the date of progression will be the
date of (J+1)st scheduled assessment visit.
12.3
Appendix C - ECOG Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity. Fully active,
able to carry on all pre-disease
performance without restriction.
100
Normal, no complaints, no evidence
of disease.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
1
Symptoms, but ambulatory.
Restricted in physically strenuous
activity, but ambulatory and able
to carry out work of a light or
sedentary nature (e.g., light
housework, office work).
80
Normal activity with effort; some
signs or symptoms of disease.
70
Cares for self, unable to carry on
normal activity or to do active work.
2
In bed <50 % of the time.
Ambulatory and capable of all
self-care, but unable to carry out
any work activities. Up and
about more than 50 % of waking
hours.
60
Requires occasional assistance, but is
able to care for most of his/her needs.
50
Requires considerable assistance and
frequent medical care.
3
In bed >50 % of the time.
Capable of only limited self-care,
confined to bed or chair more
than 50 % of waking hours.
40
Disabled, requires special care and
assistance.
30
Severely disabled, hospitalization
indicated. Death not imminent.
4
100 % bedridden. Completely
disabled. Cannot carry on any
self-care. Totally confined to bed
or chair.
20
Very sick, hospitalization indicated.
Death not imminent.
10
Moribund, fatal processes progressing
rapidly.


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5
Dead.
0
Dead.


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12.4
Appendix D - Imputation Rules for Missing Dates
Terminology in this appendix: first dose = first administration of either AEZS-108
(Arm A) or doxorubicin (Arm B).
The date of event (death/progression) is the documented date of event. The missing date
will be handled as follows:
What is missing in event date
Imputed value is
Year
If year is missing or cannot be
confirmed to be earlier than the month
of last assessment
the year of last assessment
If, without considering year, the date of
the event is confirmed to be earlier than
the date of the last assessment (e.g.,
January vs. November or May 15 vs.
May 1)
the year of last assessment+1
Month
If month of the event is missing or is
confirmed to be the same as the year of
the last assessment
Month of the last assessment unless the day of
death is earlier than the day of the last
assessment (5th vs. 10th). In this case the
month will be imputed as the month after the
month of the last assessment
If month of the event is confirmed to be
after the year of the last assessment
January
Day
1, unless the resulting imputed date is earlier
than the last assessment date. In this case the
imputed day is the day of the last assessment

Adverse Event
If onset date is completely missing, onset date is set to date of first dose.
If (year is present and month and day are missing) or (year and day are present and
month is missing):
o If year = year of first dose, then set month and day to month and day of first dose.
o If year < year of first dose, then set month and day to December 31st.
o If year > year of first dose, then set month and day to January 1st.


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If month and year are present and day is missing:
o
If year = year of first dose and
if month = month of first dose then set day to day of first dose date.
if month < month of first dose then set day to last day of month.
if month > month of first dose then set day to 1st day of month.
o
If year < year of first dose then set day to last day of month.
o
If year > year of first dose then set day to 1st day of month.
For all other cases, set onset date to date of first dose.
Concomitant Medications/Medical History
If start date is completely missing, start date will not be imputed.
If (year is present and month and day are missing) or (year and day are present and
month is missing), set month and day to January 1.
If year and month are present and day is missing, set day to 1st day of month.
If end date is completely missing, end date will not be imputed.
If (year is present and month and day are missing) or (year and day are present and
month is missing), set month and day to December 31.
If year and month are present and day is missing, set day to last day of the month.


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12.5
Appendix E
List of Tables/Graphs and Listings
List of Statistical Tables
Number
Description
CODE: GREEN = topline; needed first
Table 14.1.1.1
Patient disposition
Table 14.1.1.2
Patient disposition by investigational site
Table 14.1.1.3
Patient disposition by territory
Table 14.1.2
Major protocol deviations
Table 14.1.3.1
Patients demographics and baseline characteristics (ITT)
Table 14.1.3.2
Patients demographics and baseline characteristics (safety)
Table 14.1.4.1
History of endometrial cancer (ITT)
Table 14.1.4.2
History of endometrial cancer (safety)
Table 14.1.5
Prior treatment for endometrial cancer
Table 14.1.6.1
Prior medications
Table 14.1.6.2
Concomitant medications
Table 14.1.7.1
Treatment exposure (ITT)
Table 14.1.7.2
Treatment exposure (safety)
Table 14.1.7.3
Treatment
mode of administration (ITT)
Table 14.1.8.1
Treatment modifications (ITT)
Table 14.1.8.2
Treatment modifications (safety)
Table 14.1.9
Post-study treatment anticancer therapy
Table 14.2.1
Overall survival: primary analysis (ITT)
Table 14.2.2
Overall survival: sensitivity analysis 1 (PP)
Table 14.2.3
Overall survival: sensitivity analysis 2 (MITT)


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Table 14.2.4
Overall survival: sensitivity analysis 3 (ITT, censoring at time subject
drops out due to AE)
Table 14.2.5.1
Overall survival: sensitivity analysis 4: part 1 (Cox models for treatment
and each covarariate separately)
Table 14.2.5.1
Overall survival: sensitivity analysis 4: part 2 (multivariate Cox model)
Table 14.2.6
Overall response rate: primary analysis
Table 14.2.7
Overall response rate: sensitivity analysis 1 (PP)
Table 14.2.8
Overall response rate: sensitivity analysis 2 (MITT)
Table 14.2.9.1
Overall response rate: sensitivity analysis 3: part 1 (logistic regression
models for treatment and each covarariate separately)
Table 14.2.9.2
Overall response rate: sensitivity analysis 3: part 2 (multivariate logistic
regression model)
Table 14.2.10
Duration of overall response
Table 14.2.11
Duration of stable disease
Table 14.2.12
Duration of follow-up
Table 14.2.13
Progression-free survival: primary analysis
Table 14.2.14
Progression-free survival: sensitivity analysis 1 (PP)
Table 14.2.15
Progression-free survival: sensitivity analysis 2 (MITT)
Table 14.2.16
Progression-free survival: sensitivity analysis 3 (MITT
selection of
patients with CR, PR or SD as best overall response)
Table 14.2.17.1
Progression-free survival: sensitivity analysis 4: part 1 (Cox models for
treatment and each covarariate separately)
Table 14.2.17.2
Progression-free survival: sensitivity analysis 4: part 2 (multivariate Cox
model)
Table 14.2.18.1
Quality of Life: C30 scores raw data summaries
Table 14.2.18.2
Quality of Life: EN24 scores raw data summaries
Table 14.2.18.3
Quality of Life: individual questions C30 raw data summaries


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Table 14.2.18.4
Quality of Life: individual questions EN 24 raw data summaries
Table 14.2.19.1
Quality of Life: C30 scores change from baseline summaries
Table 14.2.19.2
Quality of Life: EN24 scores change from baseline summaries
Table 14.2.19.3
Quality of Life: individual questions C30 change from baseline
summaries
Table 14.2.19.4
Quality of Life: individual questions EN 24 change from baseline
summaries
Table 14.2.20.1
Quality of Life: mixed model analysis on C30 scores change from
baseline
Table 14.2.20.2
Quality of Life: mixed model analysis on EN24 scores change from
baseline
Table 14.3.1.1
Summary of occurrence of treatment emergent adverse events (TEAE)
Table 14.3.1.2
Treatment emergent adverse events (TEAE)
by SOC and PT
Table 14.3.1.3
Treatment emergent adverse events (TEAE) (showing PT >= 5%)
by
PT
Table 14.3.1.4
Treatment emergent adverse events (TEAE)
by SOC, PT and severity
Table 14.3.1.5
Related treatment emergent adverse events (TEAE)
by SOC and PT
Table 14.3.1.6
Related treatment emergent adverse events (TEAE) (showing PT >= 5%)
by PT
Table 14.3.1.7
Summary of TEAEs by relationship to each study treatment by SOC
and PT
Table 14.3.1.8
Summary of TEAEs by combined relationship to each study treatment
by SOC and PT
Table 14.3.1.9
Serious treatment emergent adverse events (TEAE)
by SOC and PT
Table 14.3.1.10
Serious treatment emergent adverse events (TEAE) (showing PT >= 2%)
by PT
Table 14.3.1.11
Serious treatment emergent adverse events (TEAE)
by SOC, PT and
severity
Table 14.3.1.12
Related serious treatment emergent adverse events (TEAE)
by SOC


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and PT
Table 14.3.1.13
Related serious treatment emergent adverse events (TEAE) (showing PT
>= 1.8%)
by PT
Table 14.3.1.14
Grade 3 or 4 serious treatment emergent adverse events (TEAE)
by
SOC and PT
Table 14.3.1.15
Grade 5 serious treatment emergent adverse events (TEAE)
by SOC
and PT
Table 14.3.1.16
Grade 3 or higher treatment emergent adverse events (TEAE)
by SOC
and PT
Table 14.3.1.17
Grade 3 or higher treatment emergent adverse events (TEAE) (showing
PT >= 2%)
by PT
Table 14.3.1.18
Related grade 3 or higher treatment emergent adverse events (TEAE)
by SOC and PT
Table 14.3.1.19
Related grade 3 or higher treatment emergent adverse events (TEAE)
(showing PT >= 1.8%)
by PT
Table 14.3.1.20
Treatment emergent adverse events (TEAE) resulting in discontinuation
of study treatment
by SOC and PT
Table 14.3.1.21
Treatment emergent adverse events (TEAE) resulting in dose reduction
of study treatment
by SOC and PT
Table 14.3.1.22
Treatment emergent adverse events (TEAE) resulting in interruption of
study treatment administration
by SOC and PT
Table 14.3.2.5
Deaths
Table 14.3.2.6
Deaths on study treatment (within 30 days after last dose of study
treatment)
Table 14.3.4.1
Quantitative laboratory test results in SI units, hematology
Table 14.3.4.2
Shift from baseline, hematology
Table 14.3.4.3
Cycle 1 WBC, neutrophiles, and thrombocytes, shift from baseline,
CTCAE grades
Table 14.3.4.4
Quantitative laboratory test results in SI units, serum chemistry
Table 14.3.4.5
Shift from baseline, serum chemistry


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Table 14.3.4.6
Quantitative laboratory test results in SI units, urinalysis
Table 14.3.4.7
Shift from baseline (quantitative), urinalysis
Table 14.3.4.8
Dipstick test results, urinalysis
Table 14.3.4.9
Quantitative laboratory test results in SI units, hormones
Table 14.3.4.10
Shift from baseline, hormones
Table 14.3.4.11
Pregnancy test results
Table 14.3.4.12
Vital signs
Table 14.3.4.13
LVEF summaries
Table 14.3.4.14
LVEF shift from baseline
part 1
Table 14.3.4.15
LVEF shift from baseline
part 2
Table 14.3.4.16
Interpretation of 12 lead ECG results
Table 14.3.4.17
ECG summaries
Table 14.3.4.18
ECG categorical analysis
Table 14.3.4.19
ECOG performance status shift from baseline


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List of Graphs
Number
Description
Figure 14.2.1
Kaplan Meier curve for OS: primary analysis
Figure 14.2.2
Kaplan Meier curve for OS: sensitivity analysis 1 (PP population)
Figure 14.2.3
Kaplan Meier curve for OS: sensitivity analysis 2 (MITT population)
Figure 14.2.4
Kaplan Meier curve for OS: sensitivity analysis 3 (ITT population
censoring at time subject drops out due to AE)
Figure 14.2.5
Kaplan Meier curve for PFS: primary analysis
Figure 14.2.6
Kaplan Meier curve for PFS: sensitivity analysis 1 (PP population)
Figure 14.2.7
Kaplan Meier curve for PFS: sensitivity analysis 2 (MITT population)
Figure 14.2.8
Kaplan Meier curve for PFS: sensitivity analysis 3 (MITT
selection of
patients with CR, PR or SD as best overall response)
Figure 14.3.1
LVEF evolution over time


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List of Listings
Number
Description
Listing 16.2.1.1
Patient disposition
Listing 16.2.2
Major protocol deviations
Listing 16.2.4.1
Patients demographics
Listing 16.2.4.2
Patients baseline characteristics
Listing 16.2.4.3
History of endometrial cancer
Listing 16.2.4.4
Prior treatment for endometrial cancer
Listing 16.2.4.5
Prior medications
Listing 16.2.4.6
Concomitant medications
Listing 16.2.5
Treatment exposure (including modifications)
Listing 16.2.6.1
OS: time to event
Listing 16.2.6.2
Overall response rate
Listing 16.2.6.3
PFS: time to event
Listing 16.2.6.4.1
Quality of Life: C30 individual questions
Listing 16.2.6.4.2
Quality of Life: C30 scores
Listing 16.2.6.4.3
Quality of Life: EN24 individual questions
Listing 16.2.6.4.4
Quality of Life: EN24 scores
Listing 16.2.7
Adverse events
Listing 16.2.7.3
AEs associated with dropout
Listing 16.2.7.4
AEs leading to dose reduction
Listing 16.2.7.7
AEs with fatal outcome
Listing 16.2.7.8
Deaths


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Listing 16.2.8.1
Laboratory test results: hematology
Listing 16.2.8.2
Laboratory test results: serum chemistry
Listing 16.2.8.3
Laboratory test results: urinalysis
Listing 16.2.8.4
Vital signs
Listing 16.2.8.5
LVEF
Listing 16.2.8.6
ECG
Listing 16.2.8.7
ECOG performance status