Clinical Trial Results:
Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR) Topotecan plus Carboplatin im Vergleich zur Standardtherapie (Paclitaxel plus Carboplatin oder Gemcitabin plus Carboplatin oder pegyliertes liposomales Doxorubicin plus Carboplatin) in der Therapie von Patientinnen mit Platin-sensitivem rezidivierten epithelialen Ovarialkarzinom, Peritonealkarzinom oder Tubenkarzinom HECTOR (Hycamtin plus Carboplatin versus Established Regimens for the Treatment of Ovarian Cancer Relapse)

Trial information Top of page
Trial identification
Sponsor protocol code	HECTOR_PhaseIII_2006
Additional study identifiers
ISRCTN number	-
US NCT number	NCT00170677
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Charité - Universitätsmedizin Berlin
Sponsor organisation address	Charitéplatz 1, Berlin, Germany, 10117
Public contact	Prof. Jalid Sehouli, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Charité University Medicine Berlin, Department of Gynecology, European Competence Center for Ovaria, +49 30 450564002, jalid.sehouli@charite.de
Scientific contact	Prof. Jalid Sehouli, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Charité University Medicine Berlin, Department of Gynecology, European Competence Center for Ovaria, +49 30 450564002, jalid.sehouli@charite.de
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	30 Jun 2015
Is this the analysis of the primary completion data?	Yes
Primary completion date	30 Jun 2015
Global end of trial reached?	Yes
Global end of trial date	30 Jun 2015
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	Vergleich der progressionsfreien Überlebensrate nach 12 Monaten Nachbeobachtungszeit
Protection of trial subjects	This study was approved by the local ethics committee and carried out in accordance with local laws and regulations, and the guidelines on Good Clinical Practice and the Declaration of Helsinki.
Background therapy	The aim of this multicenter randomized phase III trial was to compare the efficacy and the clinical outcome of topotecan and carboplatin (TC) compared with established standard platinum based combinations. The North-Eastern German Society of Gynecological Oncology(NOGGO) has carried out a multicenter phase I/II trial with a 3-day schedule of topotecan in combination with carboplatin which demonstrated the feasibility of this combination and reported promising response rate of 67%. - Topotecan ( Hycamtin)is an inhibitor of DNA topoisomerase I, an enzyme that allows for relaxation of DNA torsional strain by cleaving and then resealing the DNA molecule. Topotecan is primarily used in the treatment of ovarian cancer and lung cancer. - Carboplatin or cis-diammine (1,1-cyclobutane dicarboxylate) platinum(II) is administered intravenously.Carboplatin Paraplatin® (AUC 4) is a ‘second generation’ platinum compound, with a different and usually improved toxicity profile. - Gemcitabine (GEM) is a widely used chemotherapeutic agent for the treatment of various cancers. - Pegylated liposomal doxorubicin (Caelyx/Doxil). Pegylated liposomes (diameter about 70–100 nm) and liposomal daunorubicin (diameter 45 nm) are small enough to pass intact through defective blood vessels that supply tumors.
Evidence for comparator	-
Actual start date of recruitment	01 Mar 2007
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Spain: 37
Country: Number of subjects enrolled	Austria: 276
Country: Number of subjects enrolled	Germany: 237
Worldwide total number of subjects	550
EEA total number of subjects	550
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	275
From 65 to 84 years	275
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	The trial was conducted at 62 center in Germany , at 12 center in Spain and at 9 center in Austria.
Pre-assignment
Screening details	591 female patients with histologically-confirmed ovarian cancer, relapse within 6 month after primary therapy and primary therapy with platin and taxan were screened, from whom 41 patients were excluded . 550 patients were randomly assigned to the experimental and the standard treatment arm in a 1:1 ratio.
Period 1
Period 1 title	Overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Single blind
Roles blinded	Subject
Arms
Are arms mutually exclusive	Yes
Arm title	TC arm
Arm description	patients received topotecan 0.75mg/m2/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks
Arm type	Experimental
Investigational medicinal product name	TOPOTECAN
Investigational medicinal product code	123948878
Other name	Hycamtin
Pharmaceutical forms	Powder and solvent for solution for infusion
Routes of administration	Infusion
Dosage and administration details	0.75 mg/m2) on days 1 to 3 plus carboplatin equating an area under the curve (AUC) of 5 on day 3 after infusion of topotecan, repeated every 21 days. Both study drugs were infused over 30 min in 250 ml of 0.9% saline solution.
Investigational medicinal product name	CARBOPLATIN
Investigational medicinal product code	41575944
Other name	Carboplat 50-Lösung; AUC 5
Pharmaceutical forms	Powder for solution for infusion
Routes of administration	Infusion
Dosage and administration details	Topotecan 0.75 mg/m2 /day on days 1–3 and carboplatin AUC 5 on day 3 after topotecan, every 3 weeks. Drugs were infused over 30 min in 250 ml of 0.9% saline solution.
Arm title	standard arm
Arm description	There were three different treatment possibilities in the standard arm: - (PC) paclitaxel 175 mg/m2/day on day 1, and carboplatin AUC 5 on day 1, every 3 weeks; (n= 191) - (GC) gemcitabine 1000 mg/m2/day on day 1 and 8 and carboplatin AUC 4 on day 1, every 3 weeks; (n= 79) - (PLDC) carboplatin AUC 4 and doxorubicin on day 1, every 3 weeks (n=5)
Arm type	Active comparator
Investigational medicinal product name	CARBOPLATIN
Investigational medicinal product code	41575944
Other name	Carboplat 50/150/450-Lösung; Paraplatin® (AUC 4); AUC 5
Pharmaceutical forms	Powder for solution for injection/infusion
Routes of administration	Infusion
Dosage and administration details	carboplatin AUC 4 or AUC 5 on day 1, every 3 weeks.
Investigational medicinal product name	PACLITAXEL
Investigational medicinal product code	33069624
Other name	TAXOL
Pharmaceutical forms	Powder for solution for infusion
Routes of administration	Infusion
Dosage and administration details	paclitaxel 175 mg/m2 /day on day 1 and carboplatin AUC 5 on day 1
Investigational medicinal product name	GEMCITABINE
Investigational medicinal product code	95058814
Other name	Gemzar
Pharmaceutical forms	Powder for solution for infusion
Routes of administration	Infusion
Dosage and administration details	gemcitabine 1000 mg/m2 /day on day 1 and 8 and carboplatin AUC 4 on day 1, every 3 weeks.
Investigational medicinal product name	Pegyliertes liposomales Doxorubicin
Investigational medicinal product code	25316-40-9
Other name	Doxorubicin Hydrochlorid, CAELYX
Pharmaceutical forms	Powder for solution for infusion
Routes of administration	Infusion
Dosage and administration details	Doxorubicin 2 mg/m2/dayon day 1 carboplatin AUC 4 on day 1, every 3 weeks.
Number of subjects in period 1 TC arm standard arm Started 275 275 Completed 275 275

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	TC arm
Reporting group description	patients received topotecan 0.75mg/m2/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks
Reporting group title	standard arm
Reporting group description	There were three different treatment possibilities in the standard arm: - (PC) paclitaxel 175 mg/m2/day on day 1, and carboplatin AUC 5 on day 1, every 3 weeks; (n= 191) - (GC) gemcitabine 1000 mg/m2/day on day 1 and 8 and carboplatin AUC 4 on day 1, every 3 weeks; (n= 79) - (PLDC) carboplatin AUC 4 and doxorubicin on day 1, every 3 weeks (n=5)
Reporting group values TC arm standard arm Total Number of subjects 275 275 550 Age categorical Units: Subjects     In utero 0     Preterm newborn infants (gestational age < 37 wks) 0     Newborns (0-27 days) 0     Infants and toddlers (28 days-23 months) 0     Children (2-11 years) 0     Adolescents (12-17 years) 0     Adults (18-64 years) 0     From 65-84 years 0     85 years and over 0 Age continuous Units: years     median (full range (min-max)) 61 (29 to 84) 61 (24 to 80) - Gender categorical Units: Subjects     Female 275 275 550     Male 0 0 0 ECOG performance status Units: Subjects     status 0 127 154 281     status 1 131 109 240     status 2 15 12 27     not known 2 0 2 FIGO stage at initial diagnosis Units: Subjects     stage I 21 16 37     stage II 22 17 39     stage III 204 202 406     stage IV 25 39 64     not known 3 1 4 Histology Units: Subjects     serous-papillary 210 210 420     endometrioid 22 18 40     mucinous 4 5 9     undifferentiated 7 13 20     other (i.e. clear sell, transitional) 32 29 61

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	TC arm
Reporting group description	patients received topotecan 0.75mg/m2/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks
Reporting group title	standard arm
Reporting group description	There were three different treatment possibilities in the standard arm: - (PC) paclitaxel 175 mg/m2/day on day 1, and carboplatin AUC 5 on day 1, every 3 weeks; (n= 191) - (GC) gemcitabine 1000 mg/m2/day on day 1 and 8 and carboplatin AUC 4 on day 1, every 3 weeks; (n= 79) - (PLDC) carboplatin AUC 4 and doxorubicin on day 1, every 3 weeks (n=5)

End points Top of page

Primary: progression-free survival (PFS) after 12 months Top of page
End point title	progression-free survival (PFS) after 12 months [1]
End point description	The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470).
End point type	Primary
End point timeframe	from baseline up to 12 months
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: more details described in manuscript posted http://www.ncbi.nlm.nih.gov/pubmed/27789470
End point values TC arm standard arm Number of subjects analysed 275 275 Units: subjects     median (confidence interval 95%) 10.0 (9.17 to 10.83) 11 (10.1 to 11.9)
No statistical analyses for this end point

Primary: progression-free survival (PFS) after 12 months Top of page

Adverse events Top of page
Adverse events information [1]
Timeframe for reporting adverse events	overall study , 0–52 months
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	12
Frequency threshold for reporting non-serious adverse events: 5%
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Overall survival (OS), response rate, toxicity, were defined as secondary end points. Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia. More information see secondary endpoints

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported
Online references
http://www.ncbi.nlm.nih.gov/pubmed/27789470

More information Top of page