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

Randomized Controlled Study Comparing AEZS-108 With Doxorubicin as Second Line Therapy for Locally Advanced, Recurrent or Metastatic Endometrial Cancer.

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

Study Overview

• Status: Completed
• Conditions: Endometrial Cancer
• Intervention / Treatment: Drug: AEZS-108 / zoptarelin doxorubicin; Drug: doxorubicin

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 511
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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. 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 (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare the Overall Survival (OS) of Patients Treated With AEZS-108 to the OS of Patients Treated With Doxorubicin.	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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare Efficacy Based on Objective Response Rate (ORR).	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.	3 years
Compare Efficacy Based on Progression-free Survival (PFS).	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).	During ongoing treatment: response evaluation every 3 cycles. For patients gone of treatment: re-assessment every 12 weeks.
Compare Efficacy Based on Clinical Benefit Rate (CBR).	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.	3 years

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• Mathews C, Lorusso D, Coleman RL, Boklage S, Garside J. An Indirect Comparison of the Efficacy and Safety of Dostarlimab and Doxorubicin for the Treatment of Advanced and Recurrent Endometrial Cancer. Oncologist. 2022 Sep 16:oyac188. doi: 10.1093/oncolo/oyac188. Online ahead of print. Erratum In: Oncologist. 2022 Nov 18;:

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2013
• Primary Completion (Actual): January 30, 2017
• Study Completion (Actual): January 30, 2017

Study Registration Dates

• First Submitted: January 9, 2013
• First Submitted That Met QC Criteria: January 11, 2013
• First Posted (Estimate): January 14, 2013

Study Record Updates

• Last Update Posted (Actual): July 31, 2018
• Last Update Submitted That Met QC Criteria: July 5, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Endometrial Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: AEZS-108-050

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No