Clinical Trial Results:
CONKO-006 Additive Therapie beim R1-resezierten Pankreaskarzinom mit Gemcitabin plus Sorafenib versus Gemcitabin plus Placebo über 12 Monate - eine doppelblinde, placebokontrollierte Phase IIb Studie. A randomized double-blinded Phase IIb-Study of Additive Therapy with Gemcitabine + Sorafenib/Placebo for Patients with R1- Resection of Pancreatic cancer.

Trial information Top of page
Trial identification
Sponsor protocol code	CONKO-006
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Charité - Universitätsmedizin Berlin
Sponsor organisation address	Augustenburger Platz 1, Berlin, Germany, 13353
Public contact	Herr PD Dr. Helmut Oettle, Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie CVK, +49 450 553212, helmut.oettle@charite.de
Scientific contact	Herr PD Dr. Helmut Oettle, Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie CVK, +49 450 553212, helmut.oettle@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	15 Aug 2017
Is this the analysis of the primary completion data?	Yes
Primary completion date	15 Jul 2016
Global end of trial reached?	Yes
Global end of trial date	15 Jul 2016
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	Pancreatic cancer adjuvant therapy after R1-resectionGemcitabine plus Sorafenib vs. Gemcitabine plus Placebo is given over 12 months randomised trial, to comparate the disease free survival in both treatment groups.
Protection of trial subjects	Secondary endpoints included overall survival (defined as the time from randomization to death from any cause), safety and treatment tolerability, and the evaluation of prognostic factors.
Background therapy	CONKO-006 was designed as an investigator-initiated trial to improve survival in primarily resectable pancreatic cancer by the combination therapy of sorafenib +gemcitabine as compared to gemcitabine alone. Gemcitabine is the standard of care in this situation since 2007. The efficacy and safety profile of Gemcitabine is well known since its approval for advanced pancreatic cancer in the late 1990s.The combination therapy of gemcitabine + sorafenib was thought to be effective in metastatic pancreatic cancer in a phase I trial published in 2006 when the CONKO-006 trial was planned (Siu, CCR 2006). These data were not confirmed in subsequent phase II and III trials (Cascinu, Dig Liv Dis 2014; Goncalves, Annal Oncol 2012), but the efficacy and safety profile of sorafenib+gemcitabine is therefore well known as well.
Evidence for comparator	-
Actual start date of recruitment	15 Feb 2008
Long term follow-up planned	Yes
Long term follow-up rationale	Safety, Efficacy
Long term follow-up duration	75 Months
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Germany: 122
Worldwide total number of subjects	122
EEA total number of subjects	122
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)	98
From 65 to 84 years	24
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Pancreatic cancer patients after curatively intended surgery and R1 resection
Pre-assignment
Screening details	Main inclusion criteria • Histological confirmed diagnosis of an adenocarcinoma of the pancreas • Standardised surgery for tumor resection • Result of resection: R1 For more inclusion and exclusion criteria see attachment: Ergebnisbreicht_conko-006.pdf
Period 1
Period 1 title	48 Weeks (12 cycles) treatment (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator
Arms
Are arms mutually exclusive	Yes
Arm title	Arm A GemSorafenib
Arm description	Arm A (GemSorafenib): Sorafenib 400 mg (2 tablets à 200 mg) twice daily orally + Gemcitabine 1000 mg/m² day 1, 8,15, q 28
Arm type	Experimental
Investigational medicinal product name	Sorafenib
Investigational medicinal product code	ATC Code L01XE05
Other name	Nexavar
Pharmaceutical forms	Film-coated tablet
Routes of administration	Oral use
Dosage and administration details	Sorafenib 2x 200 mg twice daily orally (+ Gemcitabine 1000 mg/m² day 1, 8,15, q 29)
Investigational medicinal product name	Gemcitabine
Investigational medicinal product code
Other name
Pharmaceutical forms	Powder for infusion
Routes of administration	Infusion
Dosage and administration details	+ Gemcitabine 1000 mg/m² day 1, 8,15, q 28
Arm title	Arm B GemP
Arm description	Placebo 2 tablets twice orally + Gemcitabine 1000 mg/m² day 1, 8,15, q 28;
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code
Other name
Pharmaceutical forms	Film-coated tablet
Routes of administration	Oral use
Dosage and administration details	Placebo 2x 2 tablets twice daily orally
Investigational medicinal product name	Gemcitabine
Investigational medicinal product code
Other name
Pharmaceutical forms	Powder for infusion
Routes of administration	Infusion
Dosage and administration details	+ Gemcitabine 1000 mg/m² day 1, 8,15, q 28
Number of subjects in period 1 Arm A GemSorafenib Arm B GemP Started 57 65 Completed 17 15 Not completed 40 50      premature discontinuation 40 50

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Arm A GemSorafenib
Reporting group description	Arm A (GemSorafenib): Sorafenib 400 mg (2 tablets à 200 mg) twice daily orally + Gemcitabine 1000 mg/m² day 1, 8,15, q 28
Reporting group title	Arm B GemP
Reporting group description	Placebo 2 tablets twice orally + Gemcitabine 1000 mg/m² day 1, 8,15, q 28;
Reporting group values Arm A GemSorafenib Arm B GemP Total Number of subjects 57 65 122 Age categorical Units: Subjects     18-85 57 65 122 Gender categorical Units: Subjects     Female 24 27 51     Male 33 38 71 Primary tumor size Units: Subjects     T2 2 2 4     T3 54 59 113     T4 1 4 5 Nodal status Units: Subjects     N0 8 10 18     N+ 49 55 104 Grading Units: Subjects     G1 1 1 2     G2 32 32 64     G3 24 31 55     Unknown 0 1 1 Postoperative CA19-9 Arm A, Median (range): 23 (1-2823); Arm B, Median (range):40 (1-11497) Units: Subjects     <100 37 40 77     101-500 6 10 16     >500 5 4 9     missing 9 11 20 Karnofsky performance status KPS Units: Scale     median (full range (min-max)) 90 (70 to 100) 90 (60 to 100) -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Arm A GemSorafenib
Reporting group description	Arm A (GemSorafenib): Sorafenib 400 mg (2 tablets à 200 mg) twice daily orally + Gemcitabine 1000 mg/m² day 1, 8,15, q 28
Reporting group title	Arm B GemP
Reporting group description	Placebo 2 tablets twice orally + Gemcitabine 1000 mg/m² day 1, 8,15, q 28;

End points Top of page

Primary: recurrence-free survival (RFS) Top of page
End point title	recurrence-free survival (RFS)
End point description	Recurrent disease was diagnosed in 56/57 patients (98.2%) treated in GemSorafenib, and in 62/65 patients 95.3%) in GemP.
End point type	Primary
End point timeframe	75 months
End point values Arm A GemSorafenib Arm B GemP Number of subjects analysed 57 65 Units: months median (full range (min-max))     RFS 8.5 (6.6 to 10.5) 9.4 (8.3 to 10.4)
Statistical analysis title	recurrence-free survival analysis
Comparison groups	Arm A GemSorafenib v Arm B GemP
Number of subjects included in analysis	122
Analysis specification	Pre-specified
Analysis type	equivalence
P-value	= 0.73 [1]
Method	t-test, 2-sided
Confidence interval
level	95%
sides	1-sided
lower limit	-
upper limit	-
Notes [1] - all P-values are considered to be explorative, are two-sided and unadjusted for multiplicity, according to the trial protocol.

Primary: recurrence-free survival (RFS) Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	75 months
Adverse event reporting additional description	For details please find attached Report conko 006 (Table 2 (AEs maximum grade/patient), and Table 3 (SAEs)).
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	CTC AE
Dictionary version	3.0
Reporting groups
Reporting group title	Gem+Sorafenib
Reporting group description	-
Reporting group title	Gem+Placebo
Reporting group description	-
Serious adverse events Gem+Sorafenib Gem+Placebo Total subjects affected by serious adverse events      subjects affected / exposed 28 / 57 (49.12%) 26 / 65 (40.00%)      number of deaths (all causes) 3 4      number of deaths resulting from adverse events 2 0 Investigations overall Additional description: For detailed information see Table 3 (SAEs) from the attachment Report conko 006      subjects affected / exposed 28 / 57 (49.12%) 26 / 65 (40.00%)      occurrences causally related to treatment / all 11 / 33 13 / 33      deaths causally related to treatment / all 2 / 3 0 / 4
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Gem+Sorafenib Gem+Placebo Total subjects affected by non serious adverse events      subjects affected / exposed 57 / 57 (100.00%) 65 / 65 (100.00%) Investigations Overall Additional description: for detailed information see table 2 attachment Report conko 006      subjects affected / exposed 57 / 57 (100.00%) 65 / 65 (100.00%)      occurrences all number 855 917

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
09 Mar 2010	Study extension
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

More information Top of page