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    Clinical Trial Results:
    A multicentre randomised phase II clinical study of UFT/leucovorin (LV), radiotherapy with or without cetuximab following induction gemcitabine plus capecitabine in patients with locally advanced pancreatic cancer

    Summary
    EudraCT number
    		 2008-000517-30
    Trial protocol
    		 GB  
    Global end of trial date
    20 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Aug 2016
    First version publication date
    07 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3065
    Additional study identifiers
    ISRCTN number
    		 ISRCTN65518365
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Royal Marsden NHS Foundation Trust
    Sponsor organisation address
    Downs Road, Sutton, London, United Kingdom,
    Public contact
    Khurum Khan, Royal Marsden NHS Foundation Trust, 0208 661 3279, khurum.khan@rmh.nhs.uk
    Scientific contact
    Dr Khurum Khan, Dr Chiara Braconi, 0208 661 3279, jacqui.oates@rmh.nhs.uk
    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
    20 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    One-year overall survival rate
    Protection of trial subjects
    Regular IDMC
    Background therapy
    		 Despite the recent advancements in diagnosis and management of solid malignancies, pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease, with mortality to incidence ratio of nearly one and 5-year survival of 6% (1). Only 10-20% of patients with PDAC present with potentially resectable disease while the remaining either present with locally advanced unresectable (40-50%) or metastatic disease (40%) (2). Management of Locally advanced Pancreatic Cancer (LAPC) remains largely under-researched with lack of evidence both in terms of optimal treatment approach and biomarkers that could inform such an approach (3). Although previously conducted studies failed to demonstrate any definite survival advantage of chemo-radiotherapy (CRT) over chemotherapy (CT) alone (4, 5), retrospective analysis of 4 phase II-III studies demonstrated that patients without disease progression after 3 months of CT, followed by CRT had a longer survival than those continuing on CT alone (6). Moreover, a pooled meta-analysis of SAKK and UK studies showed survival advantage with gemcitabine and capecitabine (GEM-CAP) combination (HR 0.86, 95% CI 0.75-0.98, p=0.02) (7, 8); suggesting this could be considered as useful neo-adjuvant chemotherapy (NACT) approach. Recent evidence suggests that addition of epidermal growth factor receptor (EGFR) inhibition to CRT is feasible and promising in terms of efficacy (9). Furthermore, EGFR is known to be expressed or upregulated in up to 69-95% of advanced pancreatic cancer (10, 11) and the EGFR tyrosine kinase inhibitor (TKI), erlotinib combined with gemcitabine demonstrated modest survival benefit over gemcitabine alone (12). However, currently there are no convincing data on the combination of TKI and radiotherapy, whilst cetuximab, an anti-EGFR antibody has been safely combined with chemotherapy and radiotherapy in patients with LAPC and with other cancers (13-15).
    Evidence for comparator
    		 References: 1. Siegel R et al,Cancer statistics, 2014. PubMed PMID: 24399786. 2. Willett CG et al,2005. PubMed PMID: 16002845. 3. Yip D et al, 2006 (3):CD002093. PubMed PMID: 16855985. 4. Sultana A, et al. 2007 Apr 23;96(8):1183-90. PubMed PMID: 17406358. 5. Chauffert B,et al. 2008 Sep;19(9):1592-9. PubMed PMID: 18467316. 6. Huguet F, 2007 Jan 20;25(3):326-31. PubMed PMID: 17235048. 7. Herrmann R,et al. 2007 Jun 1;25(16):2212-7. PubMed PMID: 17538165 8. Cunningham D, et al. 2009 Nov 20;27(33):5513-8. PubMed PMID: 19858379. 9. Van Zweeden AA, et al. 2015 Jun 8. PubMed PMID: 26056353. 10. Xiong HQ, et al. 2004 Jul 1;22(13):2610-6. PubMed PMID: 15226328. 11. Bloomston M, 2006;23(1-2):74-9. PubMed PMID: 16717472. 12. Moore MJ, et al. 2007 May 20;25(15):1960-6. PubMed PMID: 17452677. 13. Crane CH, et al.011 Aug 1;29(22):3037-43. PubMed PMID: 21709185. 14. Bonner JA, et al. 2006 Feb 9;354(6):567-78. PubMed PMID: 16467544. 15. Hofheinz RD, et al. 2006 Dec 1;66(5):1384-90. PubMed PMID: 16979839.
    Actual start date of recruitment
    17 Dec 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    9
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients screened according to the following includion criteria:Inclusion criteria: • Histologically or cytologically proven adenocarcinoma or poorly differentiated carcinoma of pancreas • Considered to be unresectable based on one of the following: • extensive peri-pancreatic lymph node involvement • encasement or occlusion of the superior me

    Period 1
    Period 1 title
    Registration
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Patients
    Arm description
    		 all patients recieved GEM-CAP prior to randmisation
    Arm type
    		 GEM-CAP

    Investigational medicinal product name
    GEM-CAP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GEM-CAP × 4 cycles Gemcitabine 1000mg/m2 Days 1, 8 + 15 Capecitabine 1660mg/m2/day Days 1-21 q 4 weeks

    Number of subjects in period 1
    		All Patients
    Started
    17
    Completed
    13
    Not completed
    4
         Patients ineligible for randomisation
    4
    Period 2
    Period 2 title
    Randomisation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RT alone
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 RT + Cetux
    Arm description
    		 Radiotherapy plus cetuximab
    Arm type
    		 Experimental

    Investigational medicinal product name
    CETUXIMAB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Cetuximab 400mg/m2 week 1, thereafter 250mg/m2 weeks 2-6

    Number of subjects in period 2
    		RT alone RT + Cetux
    Started
    7
    6
    Completed
    4
    5
    Not completed
    3
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    -
         Lack of efficacy
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Registration
    Reporting group description
    		 -

    Reporting group values
    		 Registration Total
    Number of subjects
    		 17 17
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 8 8
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    All Patients
    Reporting group description
    		 all patients recieved GEM-CAP prior to randmisation
    Reporting group title
    RT alone
    Reporting group description
    		 -

    Reporting group title
    RT + Cetux
    Reporting group description
    		 Radiotherapy plus cetuximab

    Primary: 1 year Overall Survival

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    End point title
    		 1 year Overall Survival
    End point description
    Overall survival at 1 year as defined as time from registration to death, or censored at last follow-up if still alive at time of analysis.
    End point type
    Primary
    End point timeframe
    1 year post last patient registered
    End point values
    		 RT alone RT + Cetux
    Number of subjects analysed
    7
    6
    Units: survival percent alive
        number (confidence interval 95%)
    100 (100 to 100)
    66.7 (29.1 to 100)
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    Overall survival was calculated using Kaplan Meier methods.
    Comparison groups
    RT alone v RT + Cetux
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.801
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 3.92

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to 30 days post last treatment
    Adverse event reporting additional description
    Grade 3 - 5 only
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No dictionary
    Dictionary version
    0
    Reporting groups
    Reporting group title
    RT alone
    Reporting group description
    		 -

    Reporting group title
    RT + Cetux
    Reporting group description
    		 -

    Serious adverse events
    		 RT alone RT + Cetux
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    5
    6
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Allergic Reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIBCAGE AND UPPER ABDO PAIN
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Non Neutropenic infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RT alone RT + Cetux
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 7 (71.43%)
    5 / 6 (83.33%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Neutropenia
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 6 (83.33%)
         occurrences all number
    2
    7
    Gastrointestinal disorders
    MALAENA
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hand Foot Syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2013
    Emergent data from the LAP-07 study failed to demonstrate any meaningful survival advantage (either progression free survival or overall survival) with the use of chemo-radiotherapy following first-line chemotherapy in locally advanced pancreatic cancer. These results were presented at the ASCO 2013 annual meeting and thus the study was closed on recommendation of IDMC.

    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.
    The study closed prematurely resulting in recruitment of only 17 patients, therefore data obtained from the study need to be interprested with caution. The molceular data obtained form the study on utility of micro-RNA21 is however extremely valuable

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26862857
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