ZoptEC: Zoptarelin Doxorubicin (AEZS 108) as Second Line Therapy for Endometrial Cancer

• Sponsor: AEterna Zentaris (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01767155
• Collaborator: (none)
• Enrollment: 511
• Locations: 123
• Arms: 2
• Actual Duration (Months): 46
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Endometrial Cancer	Drug: AEZS-108 / zoptarelin doxorubicin; Drug: doxorubicin	Phase 3

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 511 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Controlled Study Comparing AEZS-108 With Doxorubicin as Second Line Therapy for Locally Advanced, Recurrent or Metastatic Endometrial Cancer.
• Actual Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Jan 30, 2017
• Actual Study Completion Date: Jan 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AEZS-108 / zoptarelin doxorubicin 267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles	Drug: AEZS-108 / zoptarelin doxorubicin; 267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles; Other Names: AEZS-108
Active Comparator: doxorubicin/ standard chemotherapy 60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles	Drug: doxorubicin; 60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles

Outcome Measures

Primary Outcome Measures

1. Compare the Overall Survival (OS) of Patients Treated With AEZS-108 to the OS of Patients Treated With Doxorubicin. [From randomization to death from any cause. During ongoing treatment: response evaluation every 3 cycles. For patients gone of treatment: re-assessment every 12 weeks.]

   Overall survival was defined as the elapsed time from randomization to death from any cause. For surviving patients, follow-up was to be censored at the date of last contact. The final analysis, which was event-based, was conducted after approximately 384 randomized patients had died. A log-rank test with an overall two sided Type I Error rate of 0.05 after taking the interim analyses into account was used to compare OS between the two treatment arms via a SAS (Statistical Analysis System) LIFETEST procedure. Kaplan Meier estimates were used to calculate median OS and the 95% confidence interval (CI) of the median OS. The proportion of patients alive at 6 and 12 months (from randomization date) and the 95% CIs for these estimated proportions were calculated.

Secondary Outcome Measures

1. Compare Efficacy Based on Objective Response Rate (ORR). [3 years]

   The ORR was defined as the sum of the Complete Response (CR) and Partial Response (PR). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) was to have a reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. All responses were confirmed at least 4 weeks after the initial response was observed. Tumor assessments occurred every 3 cycles (± 7 days) during ongoing treatment then every 3 months (± 7 days) thereafter while the patient was on study. The last assessment occurred either when progression was confirmed or when approximately 384 randomized patients had died.

2. Compare Efficacy Based on Progression-free Survival (PFS). [During ongoing treatment: response evaluation every 3 cycles. For patients gone of treatment: re-assessment every 12 weeks.]

   Progression-free survival (PFS): days between randomization and the date of documented progression or death for any cause that occurred up to the end of the study. For patients whose progression status could not be determined, their PFS data was censored for the last adequate progression assessment date that the patient was confirmed to have no progression. Response and progression were to be evaluated using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (uni-dimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes were to be used. During ongoing treatment, patients were to be re-evaluated for response every 3 cycles (i.e. every 9 weeks). A subsequent scan was obtained no earlier than 4 weeks following the initial documentation of an objective status of either complete response (CR) or partial response (PR).

3. Compare Efficacy Based on Clinical Benefit Rate (CBR). [3 years]

   Clinical benefit was defined as having stable disease (SD) or better lasting for at least 9 weeks. The CBR was analyzed using the same methods for the ORR analyses. The analysis of CBR (CR+PR+SD) was performed in the ITT (intention-to-treat) population. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) was to have a reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. All responses were confirmed at least 4 weeks after the initial response was observed. Tumor assessments occurred every 3 cycles (± 7 days) during ongoing treatment then every 3 months (± 7 days) thereafter while the patient was on study. The last assessment occurred either when progression was confirmed or when approximately 384 randomized patients had died.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Women ≥ 18 years of age

2. Histologically confirmed endometrial cancer

3. Advanced (FIGO stage III or IV), recurrent or metastatic disease.

4. Measurable or non-measurable disease that has progressed since last treatment.

5. 1. 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 (formalin-fixed and paraffin-embedded) tumor specimens for analysis of LHRH (luteinizing hormone releasing hormone) receptor expression.

Exclusion Criteria:

1. ECOG (Eastern Cooperative Oncology Group) performance status > 2.

2. Inadequate hematologic, hepatic or renal function

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 (multigated radionuclide angiography) or ECHO (echocardiography).

6. Concomitant use of prohibited therapy (specified in protocol)

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 child-bearing potential not employing adequate contraception.

13. Subjects with known hypersensitivity to peptide drugs, including LHRH agonists.

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.

17. Malignancy within last 5 years except non-melanoma skin cancer.

18. Any concomitant disease or condition which 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).

20. Lack of ability or willingness to give informed consent.

21. Anticipated non-availability for study visits/procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
2	USC Norris Hospital and LAC+USC Medical Center	Los Angeles	California	United States	90033
3	University of California, Irvine - Medical Center	Orange	California	United States	92868-3200
4	University of Colorado	Aurora	Colorado	United States	80045
5	Hartford Hospital	Hartford	Connecticut	United States	06106
6	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
7	Moffitt Cancer Center	Tampa	Florida	United States	33612
8	Northside Hospital	Atlanta	Georgia	United States	30342
9	Northwestern University	Chicago	Illinois	United States	60611
10	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
11	Women's Cancer Center	Covington	Louisiana	United States	70433
12	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
13	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
14	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
15	Washington University School of Medecine	Saint Louis	Missouri	United States	63110
16	Memorial Sloan-Kettering Cancer Institute	New York	New York	United States	10065
17	Hope Women's Cancer Centers / Mission Hospital, Inc.	Asheville	North Carolina	United States	28806
18	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
19	Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
20	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
21	Peggy and Charles Oklahoma Cancer Center	Oklahoma City	Oklahoma	United States	73104
22	Hollings Cancer Center, MUSC	Charleston	South Carolina	United States	29425
23	Sanford Research/USD	Sioux Falls	South Dakota	United States	57104
24	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-9179
25	University of Virginia	Charlottesville	Virginia	United States	22908
26	Inova Fairfax Hospitals	Falls Church	Virginia	United States	22024
27	Henrico Doctor's Hospital	Richmond	Virginia	United States	23229
28	Froedtert & The Medical College of Wisconsin, Inc.	Milwaukee	Wisconsin	United States	53226
29	Medizinische Universität Innsbruck	Innsbruck		Austria	6020
30	Alexandrov National Cancer centre of Belarus	Minsk		Belarus	223040
31	Minsk City Clinical Oncologic Dispensary	Minsk		Belarus
32	Mogilev Regional Clinical Oncologic Dispensary	Mogilev		Belarus	212018
33	Vitebsk Regional Clinical Oncologic Dispensary	Vitebsk		Belarus	210603
34	Institut Jules Bordet	Brussels		Belgium	1000
35	UZ Leuven - Campus Gasthuisberg	Leuven		Belgium
36	Hospital Centre Liege University_CHU Sart Tilman	Liege		Belgium	4000
37	CHWAPI	Tournai		Belgium	7500
38	Clinical Center Banja Luka, Oncology Clinic	Banja Luka		Bosnia and Herzegovina	78000
39	University Clinical Hospital Mostar, Oncology clinic	Mostar		Bosnia and Herzegovina	88000
40	Clinical Centre University of Sarajevo	Sarajevo		Bosnia and Herzegovina	71000
41	Specialized Hospital for Active Treatment in Obstetrics and Gynecology	Pleven		Bulgaria
42	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
43	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G 2M9
44	Hopital Notre Dame - CHUM	Montreal	Quebec	Canada	H2L 4M1
45	McGill University	Montreal	Quebec	Canada	H2W 1S6
46	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
47	Hotel Dieu de Quebec- CHUQ	Quebec		Canada	G1R 2J6
48	Masarykův onkologický ústav	Brno		Czechia	65653
49	Fakultní nemocnice Olomouc	Olomouc		Czechia	77520
50	Všeobecná fakultní nemocnice v Praze	Praha		Czechia	12851
51	Copenhagen University Hospital "Rigshospitalet"	Copenhagen		Denmark	2100
52	Herlev Hospital	Herlev		Denmark	2730
53	Kuopio University Hospital	Kuopio		Finland	70029 KYS
54	Tampere University Hospital	Tampere		Finland	33521
55	Turku University Central Hospital	Turku		Finland	20521
56	Klinikum Frankfurt Höchst	Frankfurt		Germany	65929
57	Georg-August-Universität Göttingen, Universitäts-Frauenklinik, Abteilung für Gynäkologie und Geburtshilfe	Göttingen		Germany
58	Universitätsklinik und Poliklinik für Gynäkologie Martin Luther Universität Halle-Wittenberg	Halle		Germany	06097
59	Universitätsklinikum Köln	Köln		Germany	50931
60	University Clinic Münster	Münster		Germany	48149
61	Klinik für Frauenheilkunde und Geburtshilfe der Universität Regensburg am Caritas-Krankenhaus St. Josef	Regensburg		Germany
62	Mater Misericordiae University Hospital	Dublin		Ireland	7
63	Mater Private Hospital	Dublin		Ireland	7
64	St James's Hospital	Dublin		Ireland	8
65	University Hospital Galway	Galway		Ireland
66	Waterford Regional Hospital	Waterford		Ireland
67	Barzilai Medical Center	Ashkelon		Israel	78278
68	Rambam Health Care Campus	Haifa		Israel	31096
69	Hadassah Hospital	Jerusalem		Israel	91120
70	Davidoff Center, Rabin Medical Center	Petah-Tikva		Israel	49100
71	Oncology Institute Kaplan	Rehovot		Israel	76100
72	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	64239
73	Chaim Sheba Medical Center	Tel Hashomer		Israel	52661
74	Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari	Bari		Italy	70124
75	Azienda Ospedaliero-Universitaria di Modena	Modena		Italy	41124
76	Istituto Nazionale Tumori IRCCS	Napoli		Italy	80131
77	Istituto Oncologico Veneto, IRCCS	Padova		Italy	35128
78	Azienda Ospedaliera Ospedali Riuniti Marche Nord	Pesaro		Italy	61122
79	Policlinico A. Gemelli	Rome		Italy	00168
80	Academic Medical Center	Amsterdam		Netherlands	1105
81	Maastricht University Medical Center (UMC)	Maastricht		Netherlands	6229 HX
82	Haukeland University Hospital	Bergen		Norway	5021
83	The Norwegian Radium Hospital	Oslo		Norway	0310
84	Helse Stavanger HF, Stavanger Universitetssjukhus	Stavanger		Norway	NO-4068
85	Bialostockie Centrum Onkologii	Bialystok		Poland	15-027
86	I Klinika Ginekologii Onkologicznej i Ginekologii	Lublin		Poland	20-081
87	Wojewodzki Szpital Specjalistyczny	Olsztyn		Poland	10-561
88	NZOZ Magodent, Szpital Onkologiczny	Warszawa		Poland	03-291
89	Centrum Terapii Współczesnej ul.	Łódź		Poland	90-242
90	Oncolab	Craiova	Dolj County	Romania	200385
91	Spitalul Clinic Judetean Mures	Targu Mures	Mures County	Romania	540072
92	Oncology Institute "Prof. Dr. I. Chiricuta"	Cluj Npaoca		Romania	400015
93	Centru de Oncologie Sf. Nectarie	Craiova		Romania
94	Spitalul Clinic Judetean de Urgenta "Sf. Ioan cel Nou"	Suceava		Romania	720237
95	Oncomed	Timisoara		Romania	300239
96	GAUZ "Republican Clinical Oncology Center"	Kazan	Republic Of Tatarstan	Russian Federation	420029
97	FGBU "RONC n.a. N.N. Blokhin"	Moscow		Russian Federation	115478
98	Nizhny Novgorod Regional Oncology Dispensary	Nizhny Novgorod		Russian Federation	603081
99	Pyatigorsk Regional Oncology Dispensary	Pyatigorsk		Russian Federation
100	FGBU "NIIO n.a. N.N. Petrov"	Saint-Petersburg		Russian Federation
101	Budget Institution of Health / Leningrad Regional Oncological Dispensary	St. Petersburg		Russian Federation	191014
102	Saint-Petersburg State Budgetary Institution Healthcare "City Clinical Oncology Center"	St. Petersburg		Russian Federation	198255
103	Republican Clinical Oncology Dispensary	Ufa		Russian Federation	450071
104	Volgograd Regional Oncology Dispensary #3	Volzhskiy		Russian Federation
105	Hospital Vall d´Hebron	Barcelona		Spain
106	MD Anderson cáncer center	Madrid		Spain	28033
107	Ramon Y Cajal Hospital	Madrid		Spain	28034
108	Hospital Clínico San Carlos	Madrid		Spain	28040
109	Hospital Universitario 12 de Octubre	Madrid		Spain	28045
110	Instituto Valenciano de Oncologia	Valencia		Spain	46009
111	Zina Memorial Cancer Hospital (LISSOD)	Plyuty	Kiev Region	Ukraine	08720
112	Municipal institution "Dnipropetrovsk City Multidisciplinary Clinical Hospital No. 4"	Dnepropetrovsk		Ukraine	49102
113	CCMP I Donetsk Regional Anticancer Center	Donetsk		Ukraine	83092
114	Public health enterprise "Kharkov regional Clinical Oncological Center"	Kharkov		Ukraine	61070
115	Kiev City Clinical Oncology Center	Kiev		Ukraine	03115
116	Zakarpatskyi Regional Clinical Oncology Dispensary	Uzhgorod		Ukraine	88014
117	Vinnitsa Regional Clinical Oncology Dispensary	Vinnitsa		Ukraine	21029
118	The Royal Marsden Hospital NHS Foundation Trust	Sutton	Surrey	United Kingdom	SM2 5PT
119	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Wirral	United Kingdom	CH63 4JY
120	University Hospitals Coventry and Warwickshire NHS Trust	Coventry		United Kingdom	CV2 2DX
121	St James's University Hospital	Leeds		United Kingdom	LS9 7TF
122	Imperial college Healthcare NHS Trust	London		United Kingdom
123	Nottingham City Hospital NHS Trust	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

• AEterna Zentaris

Investigators

• Principal Investigator: David S Miller, MD, University of Texas Southwestern Medical Center, Dallas, USA
• Principal Investigator: Hani Gabra, MD, Imperial College London Hammersmith Campus, London, UK

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 10, 2017
• Study Protocol - Sep 12, 2014

More Information

Publications

None provided.

• Responsible Party: AEterna Zentaris
• ClinicalTrials.gov Identifier: NCT01767155
• Other Study ID Numbers: AEZS-108-050
• First Posted: Jan 14, 2013
• Last Update Posted: Jul 31, 2018
• Last Verified: Jan 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Endometrial Neoplasms; Doxorubicin; Liposomal doxorubicin

Study Results

Participant Flow

Arm/Group Title	AEZS-108 / Zoptarelin Doxorubicin	Doxorubicin/ Standard Chemotherapy
Arm/Group Description	267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles	60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles
Period Title: Overall Study
STARTED	256	255
Modified ITT (mITT)	252	249
Safety Population (SAF)	252	249
COMPLETED	243	240
NOT COMPLETED	13	15

Baseline Characteristics

Arm/Group Title	AEZS-108 / Zoptarelin Doxorubicin	Doxorubicin/ Standard Chemotherapy	Total
Arm/Group Description	267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles	60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles	Total of all reporting groups
Overall Participants	256	255	511
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	130 50.8%	136 53.3%	266 52.1%
>=65 years	126 49.2%	119 46.7%	245 47.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.7 (8.63)	63.8 (8.81)	63.7 (8.71)
Sex: Female, Male (Count of Participants)
Female	256 100%	255 100%	511 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	237 92.6%	240 94.1%	477 93.3%
Black or African American	10 3.9%	7 2.7%	17 3.3%
Asian	6 2.3%	5 2%	11 2.2%
Native Hawaiian or Other Pacific Islander	1 0.4%	1 0.4%	2 0.4%
Other	1 0.4%	2 0.8%	3 0.6%
Unknown	1 0.4%	0 0%	1 0.2%
ECOG (Eastern Cooperative Oncology Group) PS (Performance Status) (Count of Participants)
0	120 46.9%	125 49%	245 47.9%
1	121 47.3%	118 46.3%	239 46.8%
2	15 5.9%	11 4.3%	26 5.1%
unknown	0 0%	1 0.4%	1 0.2%
Stage of endometrial cancer at study entry (Count of Participants)
Advanced (FIGO III or IV)	99 38.7%	94 36.9%	193 37.8%
Metastatic	86 33.6%	90 35.3%	176 34.4%
Recurrent	71 27.7%	71 27.8%	142 27.8%

Outcome Measures

1. Primary Outcome

Title	Compare the Overall Survival (OS) of Patients Treated With AEZS-108 to the OS of Patients Treated With Doxorubicin.
Description	Overall survival was defined as the elapsed time from randomization to death from any cause. For surviving patients, follow-up was to be censored at the date of last contact. The final analysis, which was event-based, was conducted after approximately 384 randomized patients had died. A log-rank test with an overall two sided Type I Error rate of 0.05 after taking the interim analyses into account was used to compare OS between the two treatment arms via a SAS (Statistical Analysis System) LIFETEST procedure. Kaplan Meier estimates were used to calculate median OS and the 95% confidence interval (CI) of the median OS. The proportion of patients alive at 6 and 12 months (from randomization date) and the 95% CIs for these estimated proportions were calculated.
Time Frame	From randomization to death from any cause. During ongoing treatment: response evaluation every 3 cycles. For patients gone of treatment: re-assessment every 12 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AEZS-108 / Zoptarelin Doxorubicin	Doxorubicin/ Standard Chemotherapy
Arm/Group Description	267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles	60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles
Measure Participants	256	255
Death Events	196 76.6%	188 73.7%
Censored	60 23.4%	67 26.3%
Survivors at 6 months	171 66.8%	174 68.2%
Survivors at 12 months	111 43.4%	106 41.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 6 months
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	69.8
	Confidence Interval	(2-Sided) 95%; 63.6 to 75.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 12 months
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	45.8
	Confidence Interval	(2-Sided) 95%; 39.5 to 52.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin/ Standard Chemotherapy
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 6 months
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	72.1
	Confidence Interval	(2-Sided) 95%; 66.0 to 77.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin/ Standard Chemotherapy
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 12 months
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	44.6
	Confidence Interval	(2-Sided) 95%; 38.2 to 50.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin, Doxorubicin/ Standard Chemotherapy
	Comments	A Cox model with treatment effects was used to estimate the hazard ratio and perform hypothesis testing. The estimated hazard ratio and the 95% CI of the hazard ratio were presented.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5441
	Comments
	Method	Log Rank
	Comments	2-sided
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Compare Efficacy Based on Objective Response Rate (ORR).
Description	The ORR was defined as the sum of the Complete Response (CR) and Partial Response (PR). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) was to have a reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. All responses were confirmed at least 4 weeks after the initial response was observed. Tumor assessments occurred every 3 cycles (± 7 days) during ongoing treatment then every 3 months (± 7 days) thereafter while the patient was on study. The last assessment occurred either when progression was confirmed or when approximately 384 randomized patients had died.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AEZS-108 / Zoptarelin Doxorubicin	Doxorubicin/ Standard Chemotherapy
Arm/Group Description	267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles	60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles
Measure Participants	256	255
CR	6 2.3%	5 2%
PR	26 10.2%	31 12.2%
ORR	32 12.5%	36 14.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin, Doxorubicin/ Standard Chemotherapy
	Comments	Hypothesis testing between the two treatment arms was performed using a Mantel Haenszel test. The odds ratio and 95% CI of the odds ratio were presented.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5907
	Comments
	Method	Mantel Haenszel
	Comments	2-sided test
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Compare Efficacy Based on Progression-free Survival (PFS).
Description	Progression-free survival (PFS): days between randomization and the date of documented progression or death for any cause that occurred up to the end of the study. For patients whose progression status could not be determined, their PFS data was censored for the last adequate progression assessment date that the patient was confirmed to have no progression. Response and progression were to be evaluated using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (uni-dimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes were to be used. During ongoing treatment, patients were to be re-evaluated for response every 3 cycles (i.e. every 9 weeks). A subsequent scan was obtained no earlier than 4 weeks following the initial documentation of an objective status of either complete response (CR) or partial response (PR).
Time Frame	During ongoing treatment: response evaluation every 3 cycles. For patients gone of treatment: re-assessment every 12 weeks.

Outcome Measure Data

Analysis Population Description

The population analyzed is the mITT. PFS was analyzed in the subset of patients from mITT that have CR, PR or stable disease (SD) as best overall response.

Arm/Group Title	AEZS-108 / Zoptarelin Doxorubicin	Doxorubicin/ Standard Chemotherapy
Arm/Group Description	267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles	60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles
Measure Participants	252	249
PFS events	166 64.8%	148 58%
Censored	90 35.2%	107 42%
Progression Free Survivors at 6 months	69 27%	51 20%
Progression Free Survivors at 12 months	28 10.9%	12 4.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 6 months.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	46.7
	Confidence Interval	(2-Sided) 95%; 39.5 to 53.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 12 months
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	20.6
	Confidence Interval	(2-Sided) 95%; 14.6 to 27.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin/ Standard Chemotherapy
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 6 months
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	47.5
	Confidence Interval	(2-Sided) 95%; 40.0 to 54.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin/ Standard Chemotherapy
	Comments	Kaplan-Meier log-log transformed estimates: survivors at 12 months
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	12.3
	Confidence Interval	(2-Sided) 95%; 6.9 to 19.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin, Doxorubicin/ Standard Chemotherapy
	Comments	Hypothesis testing between the two treatment arms was performed using a log rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3089
	Comments
	Method	Log Rank
	Comments	2-sided
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Compare Efficacy Based on Clinical Benefit Rate (CBR).
Description	Clinical benefit was defined as having stable disease (SD) or better lasting for at least 9 weeks. The CBR was analyzed using the same methods for the ORR analyses. The analysis of CBR (CR+PR+SD) was performed in the ITT (intention-to-treat) population. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) was to have a reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. All responses were confirmed at least 4 weeks after the initial response was observed. Tumor assessments occurred every 3 cycles (± 7 days) during ongoing treatment then every 3 months (± 7 days) thereafter while the patient was on study. The last assessment occurred either when progression was confirmed or when approximately 384 randomized patients had died.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AEZS-108 / Zoptarelin Doxorubicin	Doxorubicin/ Standard Chemotherapy
Arm/Group Description	267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles	60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles
Measure Participants	256	255
CR	6 2.3%	5 2%
PR	26 10.2%	31 12.2%
SD	106 41.4%	102 40%
Progressive Disease (PD)	65 25.4%	67 26.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AEZS-108 / Zoptarelin Doxorubicin, Doxorubicin/ Standard Chemotherapy
	Comments	Hypothesis testing between the two treatment arms was performed using a Mantel Haenszel test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6924
	Comments
	Method	Mantel Haenszel
	Comments	2-sided
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Approx. over 3 years, during the whole duration of the trial.
Adverse Event Reporting Description	The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 4.03 or subsequent ones) were to be used for the grading of severity of symptoms and abnormal findings.
Arm/Group Title	AEZS-108 / Zoptarelin Doxorubicin		Doxorubicin/ Standard Chemotherapy
Arm/Group Description	267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles		60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles
All Cause Mortality
	AEZS-108 / Zoptarelin Doxorubicin		Doxorubicin/ Standard Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	196/252 (77.8%)		188/249 (75.5%)
Serious Adverse Events
	AEZS-108 / Zoptarelin Doxorubicin		Doxorubicin/ Standard Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	92/252 (36.5%)		75/249 (30.1%)
Blood and lymphatic system disorders
Neutropenia	21/252 (8.3%)		15/249 (6%)
Anemia	16/252 (6.3%)		9/249 (3.6%)
Febrile neutropenia	17/252 (6.7%)		8/249 (3.2%)
Thrombocytopenia	8/252 (3.2%)		3/249 (1.2%)
Leukopenia	4/252 (1.6%)		6/249 (2.4%)
Gastrointestinal disorders
Nause	11/252 (4.4%)		8/249 (3.2%)
Vomiting	7/252 (2.8%)		9/249 (3.6%)
Intestinal obstruction	6/252 (2.4%)		2/249 (0.8%)
Abdominal pain	5/252 (2%)		3/249 (1.2%)
Small intestinal obstruction	3/252 (1.2%)		4/249 (1.6%)
Metabolism and nutrition disorders
Dehydratation	8/252 (3.2%)		2/249 (0.8%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	7/252 (2.8%)		5/249 (2%)
Dyspnoe	6/252 (2.4%)		1/249 (0.4%)
Other (Not Including Serious) Adverse Events
	AEZS-108 / Zoptarelin Doxorubicin		Doxorubicin/ Standard Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	239/252 (94.8%)		240/249 (96.4%)
Blood and lymphatic system disorders
Neutropenia	132/252 (52.4%)		126/249 (50.6%)
Aneamia	107/252 (42.5%)		101/249 (40.6%)
Gastrointestinal disorders
Nausea	120/252 (47.6%)		125/249 (50.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

According to the study protocol, "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." In addition, the definitions per individual trial site agreement did apply.