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    Summary
    EudraCT Number:2018-002262-39
    Sponsor's Protocol Code Number:131I-IPA-TLX-101-001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-03-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-002262-39
    A.3Full title of the trial
    A multi-centre, open-label, single-arm, dose-finding phase I/II study to evaluate safety, tolerability, dosing schedule, and preliminary efficacy of carrier-added 4-L-[131I]iodo-phenylalanine (131I-IPA), administered as single or repetitive injections in patients with recurrent glioblastoma multiforme (GBM), concomitantly to 2nd line external radiation therapy (XRT) - IPAX-1Study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial that is optimising 2 radioactive anti-cancer treatments to see if the combination is safe and effective for patients with a form of brain cancer known as GBM.
    A.3.2Name or abbreviated title of the trial where available
    131I-IPA + XRT in recurrent GBM
    A.4.1Sponsor's protocol code number131I-IPA-TLX-101-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTELIX International Pty Ltd
    B.1.3.4CountryAustralia
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTelix International Pty Ltd
    B.4.2CountryAustralia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationABX-CRO advanced pharmaceutical services GmbH
    B.5.2Functional name of contact pointClinical Informations
    B.5.3 Address:
    B.5.3.1Street AddressBlasewitzer Str. 78 - 80
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01307
    B.5.3.4CountryGermany
    B.5.4Telephone number0049035121 4440
    B.5.5Fax number0049035121 44415
    B.5.6E-mailinfo@abx-cro.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/06/363
    D.3 Description of the IMP
    D.3.1Product name[131I]-L-4-iodophenylalanine
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN[131I]-L-4-iodophenylalanine
    D.3.9.2Current sponsor code131 I-IPA
    D.3.10 Strength
    D.3.10.1Concentration unit GBq gigabecquerel(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product Yes
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    2nd line therapy of recurrent GBM (Glioblastoma multiforme), scheduled for repeat XRT.
    E.1.1.1Medical condition in easily understood language
    Treatment of Brain Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and tolerability of intravenous 131I-IPA administered concomitantly to 2nd line XRT in recurrent GBM
    E.2.2Secondary objectives of the trial
    1. To assess the maximum tolerated dose (MTD) of 131I -IPA administered concomitantly to 2nd line XRT in recurrent GBM
    2. To evaluate the feasibility of a fractionated administration of 131I-IPA
    3. To evaluate the radiation absorbed dose to tumour from 131I-IPA
    4. To explore the antineoplastic effect of 131I-IPA + XRT combination therapy
    5. To explore a possible influence of MGMT promoter methylation status on the biological response to 131I-IPA + XRT combination therapy
    6. To explore the occurrence and frequency of pseudo-progression (PP) in response to 131I-IPA + XRT combination therapy
    7. To explore the cognitive function before, during and after therapy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Previously confirmed histological diagnosis of GBM, with current clinical or imaging evidence for first recurrence according to modified RANO criteria (2017). History of GBM standard therapy (debulking surgery, followed by radio-chemotherapy (50–60 Gy in 2 Gy fractions, temozolomide)
    2. Interval since end of 1st line XRT ≥6 months
    3. Amino acid-based molecular imaging (preferably 18F-FET-PETor 11C-methionine, as institutionally established) indicating pathologically increased amino acid uptake inside or in the vicinity of the tumour, clearly discernible from background activity.
    4. Current indication for repeat radiation therapy as discussed at the multidisciplinary neuro-oncological tumour board meeting, planned as standard fractionated dose schedule (18*2 Gy)
    5. Gross tumour volume (GTV) of up to 4.8 cm diameter, clinical target volume (CTV) 0.5 cm margin and planning target volume (PTV) ≤0.5 cm margin
    6. Male or female ≥18 years of age.
    7. Karnofsky performance status (KPS) ≥70. Life expectancy of at least 16 weeks.
    8. Haematological, liver and renal function test results as follows:
    • WBC: >3*109/L
    • Haemoglobin >80 g/L
    • PLT >100*109/L
    • ALT, ALP, AST: ≤5 times upper international limit of normal (UILN)
    • Bilirubin ≤3 times UILN
    • Serum creatinine: within normal limits or <120 μmol/L for patients aged 60 years or older
    • Urine protein dipstick: no protein
    9. Female patients surgically sterile or postmenopausal for at least 2 years. Participants of generative potential agreeing to use effective contraception during the period of therapy and 6 months after the end of study.
    10. Written informed consent
    E.4Principal exclusion criteria
    1. Primary XRT dose >60 Gy
    2. Doses to organs at risk defined by Yasar and Tugrul (2005) exceeded or reached by prior radiation therapy; e.g. cumulative total dose on the optical chiasm >54 Gy for 2 Gy/fraction, alpha/beta =2
    3. Multifocal distant recurrence, defined as tumour lesion outside the primary XRT field, as evidenced by amino acid-based PET imaging
    4. Prior treatment with brachytherapy
    5. Prior treatment with bevacizumab
    6. History or evidence of delayed-type hypersensitivity (DTH)-dependent chronic infection (e.g. tuberculosis, systemic fungal or parasitic infection), potentially exacerbating under systemic corticoid therapy
    7. Localisation of tumour related to brain stem or axis, unless sufficient reserve capacity (e.g. remnant resection cavity, marked atrophy) to accommodate possible post–procedural tissue reactions, or pre-therapeutic consent for emergency trepanation
    8. Haemostaseologic conditions, precluding catheterisation or invasive procedures
    9. Clinically significant illness or clinically relevant trauma within 2 weeks before the administration of the investigational product
    10. Known impairment of liver or kidney function or known liver or kidney disease, such as hepatitis, cirrhosis, renal failure
    11. Known human immunodeficiency virus (HIV) positive serology or chronically active hepatitis B or C
    12. Ongoing toxicity > grade 2 NCI-CTC (version 4.03) from previous standard or investigational therapies
    13. Administration of another investigational medicinal product within 90 days prior to screening
    14. Expected non-compliance with longer-term admission at isolated nuclear medicine ward
    15. In pre-menopausal women: Pregnant as evidenced by a positive pregnancy test, or breast-feeding
    16. Patients with known phenylketonuria
    E.5 End points
    E.5.1Primary end point(s)
    a) Safety as assessed by the frequency of occurrence and severity of abnormal findings in safety investigations (physical examination, vital signs, 12-lead ECG, clinical laboratory, adverse events, concomitant medication)

    b) Tolerability as assessed by Health-Related Quality of Life (HRQOL) total scores on European Organisation for Research and Treatment of Cancer – EORTC QLQ-C30 and EORTC-BN20 questionnaires (Aaronson et al. 1993; Osoba et al. 1996)
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 monthly scans for 12 months.
    E.5.2Secondary end point(s)
    Whole body biodistribution and dosimetry (safety dosimetry)
    a) Residence times for discernible organs (MBq*h)
    b) Organ and whole body absorbed radiation doses (µGy/MBq)

    Tumour dosimetry of 131I-IPA following systemic administration (therapeutic dosimetry)
    a) Cmax (maximum activity concentration in tumour Bq/cm³)
    b) tmax (time point of maximum activity concentration in tumour)
    c) TAC (time activity curve) for metabolic tumour volume (MTV) defined by BL 18F-FET PET and 131I-IPA SPECT
    d) Tumour absorbed radiation dose (µGy/MBq)

    Efficacy
    a) Radiological and clinical response according to the current RANO criteria
    b) Metabolic tumour response: SUVmax, SUVmean, MTV
    c) Survival: PFS, OS

    Dosing schedule
    a) Proportion of subjects (%) with reduction morphological, contrast, and metabolic tumour volume reduction, analysed by dose level and dosing schedule
    b) Extent of morphological, contrast, and metabolic tumour volume reduction (mL), analysed by dose level and dosing schedule
    c) Duration (months) of morphological, contrast, and metabolic tumour volume reduction, analysed by dose level and dosing schedule

    E.5.2.1Timepoint(s) of evaluation of this end point
    Endpoint 1: Evaluated on Patient by Patient Basis by an analysis of Adverse events
    Endpoint 2: Evaluated on Patient by Patient Basis by an analysis of Adverse events
    Endpoint 3: conducted by Imaging, four images to evaluate uptake excretion to determine the radiation absorbed dose in the Tumor
    Endpoint 4: Analyzing functional and metabolic response based on the 3 monthly image aqquisition
    Endpoint 5: Remote analysis after end of study
    Endpoint 6: Analyzing functional and metabolic response based on the 3 monthly image aqquisition
    Endpoint 7: Quarterly analysis of Patient completed and physician completed Quality of Life documents
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Netherlands
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 34
    F.4.2.2In the whole clinical trial 44
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following completion of this study, the patients will be treated according to clinical practice at the discretion of the investigator. This includes treatment of the tumour disease as well as any conditions that may arise during the trial. No limitaion is placed on any form of therapy.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-05-31
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