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    Clinical Trial Results:
    Translational Validation Trial-B, an add-on phase I/II study to the Clinical Research Unit (Klinische Forschergruppe) KFO179-2

    Summary
    EudraCT number
    		 2011-004228-37
    Trial protocol
    		 DE  
    Global end of trial date
    31 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TransValid-KFO179/GRCSG-B
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1132-0235
    Sponsors
    Sponsor organisation name
    Universitätsmedizin Göttingen (UMG), Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts
    Sponsor organisation address
    Robert-Koch-Straße 40, Göttingen, Germany, 37075
    Public contact
    Studienzentrum UMG, Universitätsmedizin Göttingen (UMG), +49 5513960812, sz-umg.sponsor-qm@med.uni-goettingen.de
    Scientific contact
    Prof. Dr. Torsten Liersch , Klinik für Allgemein- Viszeral- und Kinderchirurgie, Universitätsmedizin Göttingen (UMG), +49 5513963876, studiensek-chirurgie@med.uni-goettingen.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
    12 Dec 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to establish the feasibility and to receive first data on the efficacy of an innovative sequential combination of established pre-operative intensified RCT (5-FU+Oxaliplatin) with consecutively intensive but shortened preoperative FOLFOXchemotherapy (5-FU+Oxaliplatin) followed by TME-surgery. Primary Objectives: - The primary objectives for this evaluation will be toxicity and histopathologically confirmed complete tumor remission (pCR). - The data will be compared exploratively to the separate TransValid- KFO179/GRCSG-Trial-A (validation study, n=200 patients) and to expectations derived from historical data (e.g. the large CAO/AIO/ARO- 94 as well as -04 trial of the German Rectal Cancer Study Group [GRCSG] and others).
    Protection of trial subjects
    All participants underwent an exon-14-skipping-test to preclude a genetic dihydropyrimidine dehydrogenase dysfunction (DPYD*2A). This measure was intended to avoid unexpected, more severe toxicities as a result of impaired DPD enzyme function with consecutive, uncontrolled 5-FU dose escalation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 60 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    28
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were planned to enter the study at three study sites. Total recruitment was performed by only two sites, University Medical Center Göttingen and University Medical Center of Frankfurt / Main. The third site has to be deregistered caused by inactivity. The recruitment period extended from April 12, 2013 to June 30, 2017.

    Pre-assignment
    Screening details
    		 A total of 55 participants with locally advanced rectal cancer was screened for eligibility, of whom 50 patients entered the study. Five patients had to be excluded due to the inclusion/exclusion criteria of the TransValid-B study.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    As there was only one treatment regimen, the intervention was not blinded.

    Arms
    Arm title
    		 Overall Trial
    Arm description
    		 CRT: 5-FU: 250 mg/m2 civ, d1-d14 + d22-d35; OX: 50 mg/m2 2h iv d1, d8, d22 + d35. 3 applications of FOLFOX: FA: 400 mg/m2 2h iv, d1; OX: 100 mg/m2 2h iv, d1; 5-FU 2.400 mg/m2 46h civ, on d1 + d2
    Arm type
    		 Investigation of a new treatment regimen

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intraportal use
    Dosage and administration details
    CRT: 5-FU: 250 mg/m2 civ, d1-d14 + d22-d35 kCTx: 5-FU: 2.400 mg/m2 46h civ, on d1 + d2

    Investigational medicinal product name
    Folinacid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intraportal use
    Dosage and administration details
    kCTx: FA: 400 mg/m2 2h iv, d1

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intraportal use
    Dosage and administration details
    CRT: OX: 50 mg/m2 2h iv d1, d8, d22 + d35 kCTx: OX: 100 mg/m2 2h iv, d1

    Number of subjects in period 1
    		Overall Trial
    Started
    48
    Staging I
    48
    CRT
    48
    Staging II
    48
    FOLFOX-CTx
    46
    Staging III
    46
    TME-surgery
    44
    Staging IV
    44
    Follow-up
    43
    Completed
    43
    Not completed
    5
         Adverse event, serious fatal
    2
         Progression of disease
    1
         Refusal of surgery ("watch and wait")
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 Intention-to-treat-population (ITT)

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 48 48
    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)
    		 29 29
        From 65-84 years
    		 19 19
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.77 ( 9.41 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 38 38
    ECOG-Status
    Units: Subjects
        ECOG-0
    		 40 40
        ECOG-1
    		 8 8
    BMI (grouped)
    Units: Subjects
        underweight
    		 2 2
        normal weigth
    		 20 20
        overweight
    		 16 16
        obese
    		 8 8
        missing
    		 2 2
    Grading
    Units: Subjects
        G1
    		 1 1
        G2
    		 44 44
        G3
    		 3 3
    Tumor location
    Classification: low (< 6 cm); mid (6-11 cm)
    Units: Subjects
        lower rectum
    		 16 16
        mid rectum
    		 32 32
    Clinical (c) UICC-stages
    rES, MRI and CT findings were summarized.
    Units: Subjects
        cUICC-III
    		 42 42
        cUICC-IV
    		 6 6
    Body height (cm)
    Units: cm
        arithmetic mean (standard deviation)
    		 174.30 ( 7.29 ) -
    Body weigth (kg)
    Units: kg
        arithmetic mean (standard deviation)
    		 78.64 ( 13.16 ) -
    Body-Mass-Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 25.77 ( 4.31 ) -
    Tumormarker - CEA
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 8.88 ( 12.93 ) -
    Tumormarker - CA 19-9
    Units: U/ml
        arithmetic mean (standard deviation)
    		 26.97 ( 55.86 ) -
    Tumor location
    Distance between the anal verge (av) and the inferior tumor margin.
    Units: cm
        arithmetic mean (standard deviation)
    		 6.73 ( 3.08 ) -

    End points

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    End points reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 CRT: 5-FU: 250 mg/m2 civ, d1-d14 + d22-d35; OX: 50 mg/m2 2h iv d1, d8, d22 + d35. 3 applications of FOLFOX: FA: 400 mg/m2 2h iv, d1; OX: 100 mg/m2 2h iv, d1; 5-FU 2.400 mg/m2 46h civ, on d1 + d2

    Primary: Acute toxicity

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    End point title
    		 Acute toxicity [1]
    End point description
    Acute toxicity grading (according to NCI-CTC-AE, Vs. 4.0) included the proportion of patients with at least one toxicity event.
    End point type
    Primary
    End point timeframe
    Acute toxicity assessment during TNT and 4 weeks postoperatively.
    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: Acute toxicity (grading according to National Cancer Institute Common Terminology Criteria for Adverse Events, NCI-CTC-AE, Vs 4.03) and the proportion of patients with atleast one CTC event < 4 weeks after TNT. We hypothesized that TNT-associated toxicity, esp. AEs grade ≥ 3, will not reach 35%as shown in the adjuvant setting of the CAO/ARO/AIO-04 trial (Hofheinz et al. 2018).
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 0-5
        grade 1
    341
        grade 2
    119
        grade 3
    52
        grade 4
    2
        grade 5
    1
    No statistical analyses for this end point

    Primary: Complete tumor remission

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    End point title
    		 Complete tumor remission [2]
    End point description
    The histopathological confirmed complete LARC remission (CR) was defined as ypT0 and ypN0 status or as ypUICC stage 0. Near CR (nCR) was defined as ypT1/T2 and ypN0 or ypUICC stage I. Comparison with the clinically determined CR/nCR (defined as no endoluminal visible and/or palpable cancer formation without any radiological findings or rES signs for residual cancer after TNT) for assessment of the accuracy.
    End point type
    Primary
    End point timeframe
    After TNT and TME within the histopathological analyses.
    Notes
    [2] - 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: We hypothesized that TNT could enhance the CR rate up to 20%, whereas this CR rate was approximately achieved in 8% - 15% after MMT in the CAO/ARO/AIO-94 and -04 trials (Sauer et al. 2004, 2012; Rödel et al. 2012, 2015).
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 0-1
        CR
    7
        nCR
    10
        not
    31
    No statistical analyses for this end point

    Primary: Recurrence-free-survival (RFS)

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    End point title
    		 Recurrence-free-survival (RFS) [3]
    End point description
    Time from surgery to detection of an event (LR, FM or death from any cause; second cancers were ignored; loss of contact was censored). Showing the survival in patients with UICC stages ≤ II, II and ≥ III after TNT. The Kaplan Meier estimated survival curves are shown in a chart. The 3-y and 5-y RFS rates were 73.9% (95%-CI: 61.8%; 88.5%) and 71.0% (95%-CI: 58.3%; 86.4%).
    End point type
    Primary
    End point timeframe
    Recurrence-free-survival (RFS) estimation after 36 and 60 months after TME-surgery as determined during follow-up.
    Notes
    [3] - 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: The clinical aim of this proof-of-concept study was to achieve higher rates of recurrence-free survival (RFS, > 75% at 3-y / > 70% at 5-y) compared to the recently published trials CAO/ARO/AIO-94-, -04-, -12- and PETACC-6 (Sauer et al. 2004, 2012; Rödel et al. 2010, 2012, 2015; Fokas et al. 2019, 2022; Schmoll et al. 2013, 2021). The endpoints, methods and analyses of the Trans-Valid-B-trial had been given in the statistical analysis plan (SAP Vs 1.2/ 2022-03-24).
    End point values
    		 Overall Trial
    Number of subjects analysed
    43
    Units: Patients at risk
        day: 0
    43
        day: 1000
    30
        day: 2000
    6
        day: 3000
    0
    Attachments
    		 RFS (R0, 60 months follow-up) after TME-surgery
    No statistical analyses for this end point

    Secondary: Cumulative incidence of local recurrence

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    End point title
    		 Cumulative incidence of local recurrence
    End point description
    Local-recurrence (LR) estimation measured as a cumulative incidence. The LR is defined as locoregional failure within 5 cm of the anastomotic region (after LAR) or in the pelvic or perineal area (after APR).
    End point type
    Secondary
    End point timeframe
    Timeperiod from surgery to detection of a local recurrence.
    End point values
    		 Overall Trial
    Number of subjects analysed
    44
    Units: Number of local recurrences
    1
    No statistical analyses for this end point

    Secondary: Cumulative incidence of distant metastases

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    End point title
    		 Cumulative incidence of distant metastases
    End point description
    Distant metastases (DM) estimation measured as a cumulative incidence. The DM is defined as radiological / pathological event of the same cancer.
    End point type
    Secondary
    End point timeframe
    Timeperiod from surgery to detection of a distant metastases.
    End point values
    		 Overall Trial
    Number of subjects analysed
    44
    Units: Number of distant metastases
    12
    No statistical analyses for this end point

    Secondary: Circumferential resection margin (CRM)

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    End point title
    		 Circumferential resection margin (CRM)
    End point description
    Proportion of patients with circumferential resection margin (CRM: < 1 mm vs ≥ 1 mm; CRM: < 2 mm vs ≥ 2 mm (according to Nagtegaal et al. 2005, Wittekind et al. 2009).
    End point type
    Secondary
    End point timeframe
    After TNT, within histopathological examinations.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 0-2
        <1 mm
    2
        ≥ 1 mm
    38
        < 2 mm
    4
        ≥ 2 mm
    36
    No statistical analyses for this end point

    Secondary: Tumor regression grading (TRG)

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    End point title
    		 Tumor regression grading (TRG)
    End point description
    Proportion of patients with tumor regression grades (TRG 0 to 4, Dworak et al. 1997).
    End point type
    Secondary
    End point timeframe
    After TNT, within histopathological examinations.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 0;1;2;3;4
        TRG 0
    1
        TRG 1
    5
        TRG 2
    19
        TRG 3
    11
        TRG 4
    8
    No statistical analyses for this end point

    Secondary: Residual lymph node status

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    End point title
    		 Residual lymph node status
    End point description
    Proportion of patients with nodal status (ypN0 to ypN2) and subgroups (ypN1 a-c, ypN2 a-b); number of lymph nodes (LN) and lymph node metastases (LNM) in total and per specimen; the quotient (ratio) of total LNM/LN and of LNM/LN per specimen.
    End point type
    Secondary
    End point timeframe
    After TNT, within histopathological examinations.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 0;1
        ypN0
    31
        ypN1a
    6
        ypN1b
    3
        ypN2x
    1
        ypN2a
    1
        ypN2b
    2
    No statistical analyses for this end point

    Secondary: Postoperative 30 d and 60 d mortality

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    End point title
    		 Postoperative 30 d and 60 d mortality
    End point description
    The 30d mortality rate was 2.3% and and consequently the 30 d and 60 d postsurgical survival rates amounted 97.7%.
    End point type
    Secondary
    End point timeframe
    After TNT, within 30 and 60 days.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 0;1
    1
    No statistical analyses for this end point

    Secondary: Postsurgical morbidity

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    End point title
    		 Postsurgical morbidity
    End point description
    Postsurgical complications within 4 weeks after TME-surgery (e.g. anastomotic leaks, wound healing disorders). Late complications > 4 weeks after qTME (diarrhea, defacation problems, late anastomotic leaks or stenoses, loss of sphincter function, need for a diverting stoma, low anterior resection syndrome (LARS)). Events will categorized according to the NCI-CTC-AE Vs. 4.0 and/or Dindo-Clavien-classification. Correlation of the acute peri-/postsurgical complications with the patients` ASA-score.
    End point type
    Secondary
    End point timeframe
    Postoperatively
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: grade 1 - 5
        peri-/postop. CTCAE ≥ 2
    31
        peri-/postop. CTCAE ≥ 3
    15
        late CTCAE ≥ 2
    104
        late CTCAE ≥ 3
    49
    Attachments
    		 Peri-/postoperative CTC-AEs associated to TME-surg
    Patients with late CTC-AEs during follow-up (1-5)
    Correlation between ASA score and postsurgical com
    No statistical analyses for this end point

    Secondary: Quality of TME surgery

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    End point title
    		 Quality of TME surgery
    End point description
    Peri- and postoperative assessment of TME according to MERCURY-criteria (Quirke et al. 2009).
    End point type
    Secondary
    End point timeframe
    Peri- and postoperatively, assessed by surgeon and histopathologist.
    End point values
    		 Overall Trial
    Number of subjects analysed
    44
    Units: poor, moderate, optimal
        poor - periop.
    0
        moderate - periop.
    4
        optimal - periop.
    36
        missing - periop.
    4
        poor - postop.
    1
        moderate - postop.
    3
        optimal - postop.
    40
        missing - postop.
    0
    Attachments
    		 Quality of TME-surgery and interrater reliability
    No statistical analyses for this end point

    Secondary: Disease-free survival (DFS)

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    End point title
    		 Disease-free survival (DFS)
    End point description
    Time from surgery to detection of an event (LR, FM, second cancer or death from any cause; loss of contact was censored).
    End point type
    Secondary
    End point timeframe
    Disease-free survival (DFS) estimation after 36 and 60 months after TME-surgery as determined during follow-up.
    End point values
    		 Overall Trial
    Number of subjects analysed
    43
    Units: Patients at risk
        day: 0
    43
        day: 1000
    30
        day: 2000
    5
        day: 3000
    0
    Attachments
    		 DFS (R0, 60 months follow-up) after qTME
    No statistical analyses for this end point

    Secondary: Cancer-specific survival (CSS)

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    End point title
    		 Cancer-specific survival (CSS)
    End point description
    Time from surgery to detection of an event (death from cancer; LR, FM, second cancers, death from any cause than cancer were ignored; loss of contact was censored). Including competing risk to non-cancer specific death. Cancer-specific survival (CSS) and competing risk to non-cancer specific death during 60 months follow-up. CSS was defined as the time interval between study entry and the date of death caused by the same cancer and/or progression. Patients who died by any other cause had been regarded as competing risks. During follow-up 1 patient suffered an urothel-carcinoma (pat_5535) 20 months after qTME of the LARC. Later, LM of this secondary cancer occurred and led to death. Another patient (pat_5603) died 5 days after qTME due to heart failure and massive cerebral bleeding. The plot shows the estimates of the non-parametric Aalen-Johansen estimate of the cumulative incidence functions (competing risks data); other: pat_5603 with death not due to cancer or toxicity
    End point type
    Secondary
    End point timeframe
    Cancer-specific survival (CSS) estimation after 36 and 60 months after TME-surgery as determined during follow-up.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: Patients at risk
        detection of an event
    2
    Attachments
    		 Cancer-specific survival (CSS) with competing risk
    No statistical analyses for this end point

    Secondary: Sphincter-sparing surgery

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    End point title
    		 Sphincter-sparing surgery
    End point description
    Rate of spincter-sparing surgery: among patients for whom sphincter preservation was deemed feasible at baseline; in patients who were able to preserve the sphincter muscle after completion of TNT; Accuracy of staging (III) and repeated judgement about feasibility of sphincter preservation as a result of TNT induced longitudinal tumor shrinkage and / or infiltration depth (ypT-status).
    End point type
    Secondary
    End point timeframe
    Pre- and postoperative assessment of sphincter preservation
    End point values
    		 Overall Trial
    Number of subjects analysed
    44 [4]
    Units: 0-1
        baseline ssTME - yes
    37
        baseline ssTME - no
    7
        actual ssTME - yes
    32
        actual ssTME - no
    10
    Attachments
    		 Sphincter-saving TME-surgery
    Notes
    [4] - PP patients` cohort
    No statistical analyses for this end point

    Secondary: Proportion of ypUICC-stages

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    End point title
    		 Proportion of ypUICC-stages
    End point description
    Comparison of ypUICC-stages 0-IV (including subgroups II a-c, III a-c, IV a-b); Number of patients with confirmed ypUICC <= I + <= II.
    End point type
    Secondary
    End point timeframe
    Postoperative examination of the histopathological parameters.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 1;0
        ypUICC-0
    6
        ypUICC-I
    9
        ypUICC-II
    14
        ypUICC-III
    10
        ypUICC-IV
    5
        ypUICC ≤ I
    15
        ypUICC ≥ III
    15
    No statistical analyses for this end point

    Secondary: Compliance to TNT

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    End point title
    		 Compliance to TNT
    End point description
    Patient`s compliance to TNT was measured as the number of patients willing to complete the treatment sequence CRT ► CTx ► TME-surgery.
    End point type
    Secondary
    End point timeframe
    Examination postoperative.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 1;0
        TNT complete
    45
    No statistical analyses for this end point

    Secondary: Adherence to preoperative treatment

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    End point title
    		 Adherence to preoperative treatment
    End point description
    The adherence to the treatment sequence CRT ► CTx was measured as number of completely applied irradiation and CTx per patient.
    End point type
    Secondary
    End point timeframe
    Examination after TNT.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: 1;0
        Adherence number
    42
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Time from surgery to detection of an event (death from any cause; LR, FM, second cancers were ignored; loss of contact was censored).
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) estimation after 36 and 60 months after TME-surgery as determined during follow-up.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: Patients at risk
        day: 0
    48
        day: 1000
    43
        day: 2000
    11
        day: 3000
    0
    Attachments
    		 Overall survival (OS)
    No statistical analyses for this end point

    Secondary: Time-to-treatment-failure (TTF)

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    End point title
    		 Time-to-treatment-failure (TTF)
    End point description
    Time-to-treatment-failure (TTF) was defined as the interval between study entry and any signs of progressive disease (PD) for patients in UICC stage IV or of any local regrowth in patients with refusal of TME or in patients after TNT with any local or metastatic event related to rectal cancer.
    End point type
    Secondary
    End point timeframe
    Measured from study entry.
    End point values
    		 Overall Trial
    Number of subjects analysed
    48
    Units: Patients at risk
        day: 0
    48
        day: 1000
    36
        day: 2000
    8
        day: 3000
    0
    Attachments
    		 Time-to-treatment failure (TTF) and survival
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events have been monitored during 2 cycles of CRT, 3 applications of FOLFOX-CTx, in between CRT and CTx and during follow-up.
    Adverse event reporting additional description
    Acute and late toxicity of the preoperative CRT and preoperative FOLFOX-CTx were classified according to the NCI-CTC-AE (vs 4.0).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTC-AE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Included 48 participants.

    Serious adverse events
    		 Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 48 (31.25%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Deterioration general health status / tumor perforation
    Additional description: Event occurred during CRT; SUSAR. Outcome fatal. During the first period of CRT a patient (pat_5505, f, 53-y, cUICC III) died due to septic shock and tumor-toxic cardiovascular failure. ((y)pUICC-II or (y)pT4b N0 (0/43 LN) L/V/Pn0 G2, TRG 2).
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiovascular arrest
    Additional description: Event occurred postoperatively. Outcome fatal.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Portdysfunction
    Additional description: Event occurred between CRT and CTx; resolved with sequelae. Patient received portimplantation.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Port needle dislocation
    Additional description: Event occurred during CRT; resolved without sequelae.
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Soft-tissue infection (area of the port)
    Additional description: Event occurred during CRT; resolved without sequelae.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Deterioration of persistent anastomotic leakage
    Additional description: Event occurred postoperatively; resolved with sequelae. Event ended with additional surgical intervention (Hartmann-Situation).
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
    Additional description: Patient 1: Event occurred between informed consent and start of therapy. Resolved without sequelae. Patient 2: Event occurred during CRT; resolved without sequelae. Patient was withdrawn due to peritoneal-carcinosis (drop-out).
         subjects affected / exposed
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
    Additional description: Event occurred during CTx; resolved without sequelae.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
    Additional description: Event occurred postoperatively; resolved without sequelae.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Coprostasis
    Additional description: Event occurred postoperatively; resolved without sequelae.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anastomotic leakage
    Additional description: Event occurred postoperatively; ongoing, no therapy. Patient refuses recommended surgical intervention.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Sacral wound healing disorder
    Additional description: Event occurred postoperatively; ongoing, no therapy. Patient refuses recommended surgical intervention.
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 48 (100.00%)
    Investigations
    Creatinine increased
    Additional description: Acute adverse event occured during TNT; 9x grade 1, 1x grade 2; ≥ grade 2: 1x
         subjects affected / exposed
    10 / 48 (20.83%)
         occurrences all number
    10
    White blood cell count decreased
    Additional description: Acute adverse event occured during TNT; 17x grade 1, 11x grade 2, 4x grade 3; ≥ grade 2: 15x, ≥ grade 3: 4x
         subjects affected / exposed
    32 / 48 (66.67%)
         occurrences all number
    32
    Neutrophil count decreased
    Additional description: Acute adverse event occured during TNT; 3x grade 1, 3x grade 2, 1x grade 3; ≥ grade 2: 4x, ≥ grade 3: 1x
         subjects affected / exposed
    7 / 48 (14.58%)
         occurrences all number
    7
    Platelet count decreased
    Additional description: Acute adverse event occured during TNT; 25x grade 1, 1x grade 2; ≥ grade 2: 1x
         subjects affected / exposed
    26 / 48 (54.17%)
         occurrences all number
    26
    Injury, poisoning and procedural complications
    RT-related dermatitis
    Additional description: Acute adverse event occured during TNT; 17x grade 1, 8x grade 2, 2x grade 3; ≥ grade 2: 19x, ≥ grade 3: 2x
         subjects affected / exposed
    27 / 48 (56.25%)
         occurrences all number
    27
    Nervous system disorders
    Erectile dysfunction
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 3x grade 1, 10x grade 2, 3x grade 3; ≥ grade 2: 13x, ≥ grade 3: 3x
         subjects affected / exposed
    16 / 48 (33.33%)
         occurrences all number
    16
    Oxaliplatin induced neurotoxicity (chronic)
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 2x grade 2, 1x grade 2, 24x grade 3; ≥ grade 2: 25x, ≥ grade 3: 24x
    alternative dictionary used: Wassermann-Score 1
         subjects affected / exposed
    27 / 48 (56.25%)
         occurrences all number
    27
    Peripheral sensory neuropathy (chronic)
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 14x grade 1, 13x grade 2, 2x grade 3; ≥ grade 2: 15x, ≥ grade 3: 2x
         subjects affected / exposed
    29 / 48 (60.42%)
         occurrences all number
    29
    Oxaliplatin induced neurotoxicity (acute)
    Additional description: Acute adverse event occured during TNT; 18 grade 1, 5x grade 2, 17x grade 3; ≥ grade 2: 22x, ≥ grade 3: 17x
    alternative dictionary used: Wassermann-Score 1
         subjects affected / exposed
    30 / 48 (62.50%)
         occurrences all number
    30
    Peripheral sensory neuropathy (acute)
    Additional description: Acute adverse event occured during TNT; 28x grade 1, 11x grade 2; ≥ grade 2: 11x
         subjects affected / exposed
    39 / 48 (81.25%)
         occurrences all number
    39
    General disorders and administration site conditions
    Fatigue
    Additional description: Acute adverse event occured during TNT; 30x grade 1, 1x grade 2
         subjects affected / exposed
    31 / 48 (64.58%)
         occurrences all number
    31
    Fever
    Additional description: Acute adverse event occured during TNT; 3x grade 1, 1 grade 2; ≥ grade 2: 1x
         subjects affected / exposed
    4 / 48 (8.33%)
         occurrences all number
    4
    Pain
    Additional description: Acute adverse event occured during TNT; 13x grade 1, 15x grade 2
         subjects affected / exposed
    28 / 48 (58.33%)
         occurrences all number
    28
    Other AEs postoperative (free text)
    Additional description: postoperative; 6x grade 2, 3x grade 3, 1x grade 5; ≥ grade 2: 10x, ≥ grade 3: 4x
         subjects affected / exposed
    10 / 48 (20.83%)
         occurrences all number
    10
    Other AEs acute (free text)
    Additional description: Acute adverse event occured during TNT: 4x grade 1, 6x grade 2, 5x grade 3, 1x grade 4; ≥ grade 2: 12x, ≥ grade 3: 6x
         subjects affected / exposed
    16 / 48 (33.33%)
         occurrences all number
    16
    Other AEs chronic (free text)
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up): 6x grade 1, 8x grade 2, 9x grade 3; ≥ grade 2: 17x, ≥ grade 3: 9x
         subjects affected / exposed
    23 / 48 (47.92%)
         occurrences all number
    23
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Acute adverse event occured during TNT; 39x grade 1, 4x grade 2; ≥ grade 2: 4x
         subjects affected / exposed
    43 / 48 (89.58%)
         occurrences all number
    43
    Immune system disorders
    Allergic reaction
    Additional description: Acute adverse event occured during TNT; 3x grade 1
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    Gastrointestinal disorders
    Anastomotic leak
    Additional description: Postoperative; 1x grade 2, 5x grade 3; ≥ grade 2: 6x, ≥ grade 3: 5x
         subjects affected / exposed
    6 / 48 (12.50%)
         occurrences all number
    6
    Ileus
    Additional description: Postoperative; 3x grade 2; 1x grade 4; ≥ grade 2: 4x, ≥ grade 3: 1x
         subjects affected / exposed
    4 / 48 (8.33%)
         occurrences all number
    4
    Anastomotic stenosis
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 3x grade 1, 1x grade 2, 2x grade 3; ≥ grade 2: 3x, ≥ grade 3: 2x
         subjects affected / exposed
    6 / 48 (12.50%)
         occurrences all number
    6
    Diarrhoea (chronic)
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 8x grade 1, 9x grade 2, 7x grade 3; ≥ grade 2: 16x, ≥ grade 3: 7x
         subjects affected / exposed
    24 / 48 (50.00%)
         occurrences all number
    24
    Proctitis (chronic)
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 6x grade 1
         subjects affected / exposed
    6 / 48 (12.50%)
         occurrences all number
    6
    Faecal incontinence
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 10x grade 1, 6x grade 2, 1x grade 3; ≥ grade 2: 7x, ≥ grade 3: 1x
         subjects affected / exposed
    17 / 48 (35.42%)
         occurrences all number
    17
    Diarrhoea (acute)
    Additional description: Acute adverse event occured during TNT; 12x grade 1, 8x grade 2, 3x grade 3; ≥ grade 2: 11x, ≥ grade 3: 3x
         subjects affected / exposed
    23 / 48 (47.92%)
         occurrences all number
    23
    Vomiting
    Additional description: Acute adverse event occured during TNT; 8x grade 1
         subjects affected / exposed
    8 / 48 (16.67%)
         occurrences all number
    8
    Mucositis oral
    Additional description: Acute adverse event occured during TNT; 11x grade 1, 2x grade 2; ≥ grade 2: 2x
         subjects affected / exposed
    13 / 48 (27.08%)
         occurrences all number
    13
    Constipation
    Additional description: Acute adverse event occured during TNT; 7x grade 1, 1x grade 2; ≥ grade 2: 1x
         subjects affected / exposed
    8 / 48 (16.67%)
         occurrences all number
    8
    Proctitis (acute)
    Additional description: Acute adverse event occured during TNT; 21x grade 1, 13x grade 2, 4x grade 3; ≥ grade 2: 17x, ≥ grade 3: 4x
         subjects affected / exposed
    38 / 48 (79.17%)
         occurrences all number
    38
    Nausea
    Additional description: Acute adverse event occured during TNT; 20x grade 1, 3x grade 2; ≥ grade 2: 3x
         subjects affected / exposed
    23 / 48 (47.92%)
         occurrences all number
    23
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    Additional description: Acute adverse event occured during TNT; 2x grade 1, 1x grade 2, 1x grade 3, 1x grade 4; ≥ grade 2: 3x, ≥ grade 3: 2x
         subjects affected / exposed
    5 / 48 (10.42%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Wound healing disorder abdominal
    Additional description: Postoperative; 3x grade 3
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    Wound healing disorder sacral
    Additional description: Postoperative; 4x grade 1; 1x grade 2; 1x grade 3; ≥ grade 2: 2x, ≥ grade 3: 1x
         subjects affected / exposed
    6 / 48 (12.50%)
         occurrences all number
    6
    Dermatitis radiation
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 3x grade 1
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    Renal and urinary disorders
    Bladder voiding disorder (postoperative)
    Additional description: Postoperative; 1x grade 1; 5x grade 2; 4x grade 3; ≥ grade 2: 9x, ≥ grade 3: 4x
         subjects affected / exposed
    10 / 48 (20.83%)
         occurrences all number
    10
    Bladder voiding disorder (chronic)
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 8x grade 1, 6x grade 2, 1x grade 3; ≥ grade 2: 7x, ≥ grade 3: 1x
         subjects affected / exposed
    15 / 48 (31.25%)
         occurrences all number
    15
    Cystitis (non-infectious) (chronic)
    Additional description: Chronic toxicity (> 4 weeks postop during follow-up); 3x grade 1, 1x grade 2; ≥ grade 2: 1x
         subjects affected / exposed
    4 / 48 (8.33%)
         occurrences all number
    4
    Cystitis (non-infectious) (acute)
    Additional description: Acute adverse event occured during TNT; 15x grade 1, 3x grade 2; ≥ grade 2: 3x
         subjects affected / exposed
    18 / 48 (37.50%)
         occurrences all number
    18
    Urinary frequency
    Additional description: Acute adverse event occured during TNT; 25x grade 1, 3x grade 2; ≥ grade 2: 3x
         subjects affected / exposed
    28 / 48 (58.33%)
         occurrences all number
    28
    Infections and infestations
    Infection
    Additional description: Acute adverse event occured during TNT; 3x grade 1, 2x grade 2, 1x grade 3; ≥ grade 2: 3x, ≥ grade 3: 1x
         subjects affected / exposed
    6 / 48 (12.50%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2014
    Amendment by Ethiccomission; Patients Informed Consent Vs 1.4
    25 Apr 2016
    Amendment by Ethiccomission; temporary change of the PI (LKP).
    12 Jul 2016
    Amendment by BfArM; temporary change of the PI, Protocol Version 1.3
    21 Jul 2016
    Amendment by Ethiccomission; Document customization
    25 Jun 2019
    Amendment by Ethiccomission; change of the interim PI and return of the former PI (TL); change of the CRO, Protocol Vs 1.4
    12 Jul 2019
    Amendment by BfArM; change of the interim PI and return of the former PI (TL); change of the CRO, Protocol Vs 1.4

    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
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