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    Clinical Trial Results:
    OSSII-TTP Evaluation chez l’enfant et l’adulte présentant une rechute d’ostéosarcome de l’efficacité et de la tolérance d’un traitement adjuvant par Thiotépa® haute dose associé à une chimiothérapie conventionnelle OSII-TTP A multicentric randomized phase II clinical trial evaluating high-dose thiotepa as adjuvant treatment to standard chemotherapy in patients with resectable relapsed osteosarcoma

    Summary
    EudraCT number
    		 2009-009899-12
    Trial protocol
    		 FR  
    Global end of trial date
    23 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Mar 2021
    First version publication date
    13 Mar 2021
    Other versions
    Summary report(s)
    		 Publication OSII-TTP

    Trial information

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    Trial identification
    Sponsor protocol code
    ET2008-044
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00978471
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre Léon Bérard
    Sponsor organisation address
    28 rue Laennec, LYON, France, 69008
    Public contact
    Dr Perrine MAREC-BERARD, Centre Léon Bérard, 33 478782828, DRCIreglementaire@lyon.unicancer.fr
    Scientific contact
    Dr Perrine MAREC-BERARD, Centre Léon Bérard, 33 478782828, DRCIreglementaire@lyon.unicancer.fr
    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
    23 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary endpoint was overall survival (OS), defined as the time from randomisation until death from any cause
    Protection of trial subjects
    follow-up will be performed at the end of the 2nd and 4th courses of conventional chemotherapy, following the administration of thiotepa (if applicable), 8 weeks after the end of the therapeutic program, 3 months and 6 months after the end of the treatment, then every 6 months until the end of the study (3 years after inclusion of the last patient). Beyond this period, monitoring will be carried out according to the habits of each center.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Sep 2009
    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
    France: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    10
    Adolescents (12-17 years)
    20
    Adults (18-64 years)
    14
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomization will be carried out following the second course of conventional chemotherapy, after the radiological evaluation of the targets scheduled between D14 and D21 after the 2nd course. It will be stratified on the criterion "single lesion" "multiple lesions" at the time of the relapse.

    Pre-assignment
    Screening details
    		 Inclusion will be made at the time of diagnosis of the relapse, after operability has been confirmed (immediate or delayed).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental
    Arm description
    		 4 courses of conventional chemotherapy followed by high-dose chemotherapy with thiotepa associated with autologous PSC. Resection surgery of all tumor locations will be performed as soon as it is deemed possible.
    Arm type
    		 Experimental

    Investigational medicinal product name
    THIOTEPA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    The reconstituted solution is hypotonic and must be diluted before administration in 500 ml of 9 mg / ml (0.9%) sodium chloride solution for injections. In the experimental arm, thiotepa will be administered 3 to 4 weeks after the last course of conventional chemotherapy (within a period of 8 weeks maximum), 3 days in a row, by an intravenous infusion over two hours at a dose of 300 mg/ m²/day, i.e. a total dose of 900 mg/m² for one treatment.

    Arm title
    		 Conventional chemotherapy
    Arm description
    		 4 courses of conventional chemotherapy. Surgery resection of all tumor locations will be performed as soon as it is deemed possible.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Adriamycin, ifosfamide, cisplatin, etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    It will include 4 courses spaced 21 days apart, according to a scheme therapy optimized according to the first-line treatment protocol and the histological response to the initial treatment. This optimization will make it possible to maintain the cumulative doses of A, I, P and E at 450 mg, 120 g, 600 mg and 3000 mg, respectively. The regimens proposed below are recommended depending on the 1st line treatments, but each investigator can adapt this treatment on a case-by-case basis, respecting the number of cures, the interval between each course and the maximum cumulative doses.

    Number of subjects in period 1
    		Experimental Conventional chemotherapy
    Started
    22
    22
    Completed
    22
    22

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 4 courses of conventional chemotherapy followed by high-dose chemotherapy with thiotepa associated with autologous PSC. Resection surgery of all tumor locations will be performed as soon as it is deemed possible.

    Reporting group title
    Conventional chemotherapy
    Reporting group description
    		 4 courses of conventional chemotherapy. Surgery resection of all tumor locations will be performed as soon as it is deemed possible.

    Primary: Primary end point

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    End point title
    		 Primary end point [1]
    End point description
    The primary endpoint was overall survival (OS), defined as the time from randomisation until death from any cause.
    End point type
    Primary
    End point timeframe
    Month
    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: OS, PFS, and PR-S were estimated with the KaplaneMeier method and were described in terms of median and survival rates (at 1- and 2-year) in each arm, along with the associated two-sided 95% confidence intervals (CIs) for the estimates. Survival distributions were compared between the two study arms using a logank test, supported by a Cox regression to estimate the HR and its 95% CIs. Median follow-up (minemax) was calculated using the reverse KaplaneMeier method.
    End point values
    		 Experimental Conventional chemotherapy
    Number of subjects analysed
    22
    22
    Units: Month
    22
    22
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The investigator collects (spontaneous patient report or questionning) and immediately notifies the sponsor of all SAEs, in a written report, wether or not theay are deemed to be attributable to research and wich occur during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    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: The majority of patients in both treatment arms experienced AEs (17 [77.3%] patients in arm A; 19 [86.4%] patients in arm B), including at least one grade>3 AE (A: 16 [72.7%]; B: 18 [81.8%]). Nine patients experienced serious AEs (A:5; B:4). To note, several unexpected serious adverse events occurred in Arm A in one patient (pancytopenia grade 4, gastrointestinal disorders, including stomatitis grade 3, oesophagitis grade 3, anal inflammation grade 4); no toxic death was observed.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jun 2009
    Modification of 2 inclusion and randomization criteria
    08 Feb 2011
    Collection of intercurrent AEs and SAEs at randomization and those occurring following randomization Collection only of AEs of grade ≥2 according to NCI-CTCAE V4
    12 Sep 2011
    Extension of the duration of inclusions by 24 months

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Nov 2011
    Temporary stop of inclusions following the withdrawal of Thiotépa from the market on 13/10/11. Awaiting new lots.
    26 Oct 2012

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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