Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   38003   clinical trials with a EudraCT protocol, of which   6235   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma or leukemia

    Summary
    EudraCT number
    2007-005537-11
    Trial protocol
    DE  
    Global end of trial date
    24 Mar 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Feb 2019
    First version publication date
    01 Feb 2019
    Other versions
    Summary report(s)
    Vorinostat_CTR

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    NCT-2007-11-02-1004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01422499
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Heidelberg
    Sponsor organisation address
    Im Neuenheimer Feld 672, Heidelberg, Germany, 69120
    Public contact
    Commercial Director Mrs. Irmtraut Gürkan, University of Heidelberg, Irmtraut.Guerkan@uni-heidelberg.de
    Scientific contact
    Clinical Trial Unit, Hopp-Kindertumorzentrum Heidelberg (KiTZ) , 06221 567294, ruth.witt@kitz-heidelberg.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
    27 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To determine a safe dose recommended (SDR) for the routine application of oral vorinostat (involving dose escalation) in children and adolescents (3-18 years) with relapsed/refractory solid tumor, lymphoma or leukemia. A SDR is defined as the highest dose with no ≥ grade 3 toxicity according to CTC criteria in no more than 1/50 patient in this study (for details refer chapter 2.1). Secondary: To determine the  -pharmacokinetics and the distribution of individual maximum tolerated doses (MTD), which is the maximum dose with no grade 3 or 4 toxicity according to CTC criteria.  -antitumor effectiveness of vorinostat as measured by treatment response rate. Response will be evaluated in each patient three months after start of treatment with the individual MTD. - association of the histone deacetylase (HDAC)-inhibiting activity with the dose administered, toxicity, and treatment response.  -feasibility and safety - duration of response in responding patients.
    Protection of trial subjects
    Continuous risk assessment: The toxicity associated with the starting dose chosen in this study will be continuously monitored using a Bayesian criterion with a noninformative prior and a binomial-beta model for the toxicity rate r. If, for the second and following patients, the posterior probability that r>10% is 90% or higher, the starting dose used for the following patients will be lowered by 50mg/m2. This decision process is repeated, i.e., it is applied to the lowered starting dose in an analogous way.
    Background therapy
    During vorinostat dose escalation and 3 months maintenance treatment at individual MTD, patients will receive a routine pediatric physical examination including vital signs, body weight, concomitant treatment and AEs once per week. Blood will be taken once per week for full blood counting including differential, serum electrolytes, glucose, AST, ALT, protein, bilirubin, LDH and creatinine. An ECG will be done at day 8 and 15 of vorinostat treatment and when the MTD is reached, to rule out QT-changes. Collection of blood and cerebrospinal fluid for pharmacokinetic evaluation will be done after 1 week of vorinostat treatment and at the time when individual MTD is established. This material will be sent to the reference pharmacokinetic laboratory. 3 months after start of vorinostat treatment at MTD, response will be evaluated by MRI imaging using the RECIST criteria and bone marrow cytology if indicated. In patients with neuroblastoma, a MIBG scan will also be performed and response additionally evaluated according to the International Neuroblastoma Response Critera (INRC). Furthermore, full blood counting including differential, serum electrolytes, glucose, AST, ALT, protein, bilirubin, LDH, creatinine, and tumor marker (if indicated). Biomarker (IL-6, IL-10, BMP4) will be determined at month 1 and 3 of MTD. Patients showing CR, PR, or SD on response evaluation will continue with vorinostat treatment for a maximum of 9 months or until disease progression. In these patients, tumor manifestations (MRI, tumor markers, bone marrow if indicated, MIBG) will be determined every three months until end of treatment (EOT). During this time, patients will receive routine pediatric oncological care including physical examination including body weight, full blood counting including differential, serum electrolytes, glucose, AST, ALT, protein, bilirubin, LDH and creatinine every 2 weeks.
    Evidence for comparator
    no comparator
    Actual start date of recruitment
    11 May 2012
    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
    Germany: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    26
    Adolescents (12-17 years)
    23
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Recruitment of patients started in October 2011 and was continue until 50 patients will be enrolled.

    Pre-assignment
    Screening details
    After obtaining patient informed consent, screening evaluations and procedures must be performed within 14 days prior to initiating study drug treatment.

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

    Arms
    Arm title
    single-arm
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Vorinostat study
    Investigational medicinal product code
    0006-0568-40
    Other name
    Pharmaceutical forms
    Capsule, Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose will be 180 mg/m²/d in children ≥ 3 years. The drug is provided as suspension of 50mg/ml or as capsules of 100 mg vorinostat and will be centrally distributed by the Department of Pharmacy, University of Heidelberg. A dosing schedule of vorinostat suspension or 100mg capsules based on body surface area is provided in the appendix section of the protocol.

    Number of subjects in period 1
    single-arm
    Started
    50
    Completed
    7
    Not completed
    43
         Death
    20
         other reasons
    3
         Adverse event, serious fatal
    1
         occurence of exclusion criterion
    12
         Consent withdrawn by subject
    4
         Lost to follow-up
    3

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Reporting group values
    overall trial Total
    Number of subjects
    50 50
    Age categorical
    Units: Subjects
        Children (2-11 years)
    26 26
        Adolescents (12-17 years)
    23 23
        Adults (18-64 years)
    1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.9 ± 4.13 -
    Gender categorical
    Units: Subjects
        Female
    22 22
        Male
    28 28

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    single-arm
    Reporting group description
    -

    Primary: Dose Limiting Toxicity

    Close Top of page
    End point title
    Dose Limiting Toxicity [1]
    End point description
    Number of Patients with DLT N at respective dose of Vorinostat (mg/m2/day) (N=50) Number of Patients with at least one DLT observed
    End point type
    Primary
    End point timeframe
    dose escalation scheme was changed from 2 weekly to weekly
    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: The primary endpoint was the determination of a safe dose recommended (SDR) for the routine application of oral Vorinostat in children and adolescents. SDR was defined as the highest dose with no DLT (Dose Limiting Toxicity) in no more than 1/50 patient. According to this definition the SDR was 130 mg/m2/day. Disorders related to the Blood and lymphatic system were the most frequently reported DLTs.
    End point values
    single-arm
    Number of subjects analysed
    50
    Units: Number of Patient
    number (not applicable)
        130 mg/m²/day
    1
        180 mg/m²/day
    10
        230 mg/m²/day
    14
        280 mg/m²/day
    15
        330 mg/m²/day
    10
        380 mg/m²/day
    5
        430 mg/m²/day
    6
        480 mg/m²/day
    4
        530 mg/m²/day
    4
        580 mg/m²/day
    5
    Attachments
    Dose Limiting Toxicity(Preferred Terms) by Dosage
    DLT observed by Dosage - Safety Set
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    All AEs reported by the subject or detected by the investigator, will be collected during the trial and must be documented on the appropriate pages of the CRF. AEs must also be documented until the completion of the trial
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Serious adverse events
    overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 50 (38.00%)
         number of deaths (all causes)
    20
         number of deaths resulting from adverse events
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Platelet count decreased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 20
    Weight decreased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 20
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 20
    Dyspnoea
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Pleural effusion
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Thrombocytopenia
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 20
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Ataxia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 20
    Depressed level of consciousness
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Headache
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 20
    Hydrocephalus
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Seizure
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 20
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 20
    General physical health deterioration
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Pain
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Pyrexia
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 20
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 20
    Skin and subcutaneous tissue disorders
    Swelling face
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 20
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Herpes zoster
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 20
    Rhinitis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Tooth infection
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    Wound abscess
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 20
    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
    36 / 50 (72.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    5
    Blood creatine increased
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    5
    Platelet count decreased
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    6
    Weight decreased
         subjects affected / exposed
    10 / 50 (20.00%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 50 (24.00%)
         occurrences all number
    12
    Leukopenia
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    8
    Thrombocytopenia
         subjects affected / exposed
    31 / 50 (62.00%)
         occurrences all number
    31
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 50 (38.00%)
         occurrences all number
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 50 (40.00%)
         occurrences all number
    20
    General physical health deterioration
         subjects affected / exposed
    9 / 50 (18.00%)
         occurrences all number
    9
    Pain
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    15 / 50 (30.00%)
         occurrences all number
    15
    Nausea
         subjects affected / exposed
    20 / 50 (40.00%)
         occurrences all number
    20
    Vomiting
         subjects affected / exposed
    14 / 50 (28.00%)
         occurrences all number
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    9 / 50 (18.00%)
         occurrences all number
    9
    Dry skin
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    8
    Infections and infestations
    Infection
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    5
    Rhinitis
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    5

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2013
    The patient cohort enrolled in this trial turned out to have progressive disease under first/secondline therapy predominantly. These patients require immediate onset of vorinostat treatment in order to increase the likelihood of therapy response before fatal outcome of the disease. Other pediatric relapse protocols (i.e. HIT REZ 2005 trial) therefore have two week time interval to previous treatment as inclusion criterion. Changing the inclusion criterion “1 months interval from previous treatment” to two weeks has a safety and an efficacy response evaluation aspect. Safety: A 2 week interval is sufficiently long enough to ensure wash out of previous drug treatment, which in the case of valproic acid will additionally be ensured by determination of plasma drug levels. Also, the inclusion criteria “sufficient bone marrow, liver, kidney function etc.” ensures patient safety by enrolling only patients that show recovered organ functions from previous treatments. Efficacy: Disease progression under previous treatment already proofs non-efficacy of previous treatment modality ensuring that response assessment of the study drug does not interfere with effects from previous treatments.
    12 Jun 2014
    Up to now we have included 35 patients into the trial and observed 3 responses. All responses occurred at very high doses (530 and 580mg/d/m²) and no responses at lower doses. The almost exclusive dose limiting toxicity (DLT) observed were reversible thrombocytopenia. After discontinuation of treatment, all side effects and symptoms (thrombocytopenia and other changes in blood counts, gastrointestinal symptoms, fatigue) completely resolved within 1 week which corresponds with observations in the literature (see protocol p. 21). In addition, preliminary PK analyses in the present trial demonstrate no accumulation of vorinostat in plasma and rapid clearance of the drug within 8h also at higher doses. Most patients haven’t reached higher dosage due to disease progression or DLT. Importantly, the occurrence of toxicities showed no correlation with the dose received. To give patients with poor life expectancy a chance to reach effective doses in a shorter time period without additional risk, dose escalation scheme was changed from 2 weekly to weekly.

    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/22915450
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA