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    Summary
    EudraCT Number:2017-001755-31
    Sponsor's Protocol Code Number:NCT-2017-0417
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-22
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-001755-31
    A.3Full title of the trial
    Randomized Phase-II Study of Trabectedin/Olaparib Compared to Physician’s Choice in Subjects with Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies
    Randomisierte Phase 2-Studie mit Trabectedin/Olaparib im Vergleich zu einer Behand-lung gemäß aktuellen onkologischen Therapieleitlinien bei Patienten mit bereits behandelten, lokal fortgeschrittenen oder wiederkehrenden metastasierten soliden Organtumoren bei molekulargenetisch nachgewiesener Störung der DNA-Reparatur
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Compare a Treatment with Trabectedin and Olaparib to Physician’s Choice in Subjects with Previously Treated Solid Tumors Having a Special lack of Cellular Repair Mechanism
    Studie zu einer Behandlung mit Trabectedin und Olaparib im Vergleich zu Standardbehandlung nach ärztlichem Ermessen bei Patienten mit soliden Tumoren, die eine gestörte Zellreparatur haben.
    A.3.2Name or abbreviated title of the trial where available
    NCT-PMO1603 TOP-ART
    A.4.1Sponsor's protocol code numberNCT-2017-0417
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03127215
    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 SponsorRuprecht-Karls-Universität Heidelberg, Medical Faculty
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDKFZ Heidelberg
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportAstraZeneca GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportPharma Mar S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHeidelberg University Medical School
    B.5.2Functional name of contact pointMedical Oncology
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 460
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number+496221563521
    B.5.5Fax number+496221565389
    B.5.6E-mailrichard.schlenk@nct-heidelberg.de
    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 Yes
    D.2.1.1.1Trade name Yondelis
    D.2.1.1.2Name of the Marketing Authorisation holderPharmaMar
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTrabectedin
    D.3.2Product code ET-743
    D.3.4Pharmaceutical form Powder for concentrate for solution for 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 INNTRABECTEDIN
    D.3.9.1CAS number 114899-77-3
    D.3.9.4EV Substance CodeSUB20756
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 No
    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.IMP: 2
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOlaparib
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOlaparib
    D.3.9.1CAS number 763113-22-0
    D.3.9.2Current sponsor codeAZD2281
    D.3.9.3Other descriptive nameOLAPARIB
    D.3.9.4EV Substance CodeSUB32234
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 No
    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
    Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies
    Patienten mit lokal fortgeschrittenen bzw. metastasierten soliden Organtumoren bei molekulargenetisch nachgewiesenen Störungen im DNA-Reparaturweg
    E.1.1.1Medical condition in easily understood language
    Previously Treated Advanced Tumors
    Fortgeschrittene Krebserkrankung, die bereits behandelt wurde
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess clinical activity of combination therapy with trabectedin and olaparib in adult patients with advanced or recurrent solid tumors harboring DNA repair deficiency. Clinical efficacy is determined by disease control rate (DCR) at week 16
    E.2.2Secondary objectives of the trial
    • To assess progression-free survival (PFS) of combination therapy with trabectedin and olaparib in comparison to treatment as per physician’s choice
    • To assess overall survival (OS)
    • To assess Tumor Response Rate (TRR) including CR and PR according RECIST v1.1 criteria after 16 weeks
    • Safety/tolerability of combination therapy with trabectedin and olaparib
    • Quality of life
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of a written informed consent
    2. Patients is able to understand and comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
    3. Progressive locally advanced or metastatic malignancy as determined by local investigator.
    4. At least one measurable lesion that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment
    5. Prior administration of at least one standard treatment for primary and/or relapsed malignancy according to current guidelines
    6. Eastern Cooperative Oncology Group Performance Status ≤ 1
    7. Patients with central venous access device in place (central venous catheter or port-a-cath)
    8. Male or female patient aged ≥ 18 and ≤ 70 years
    9. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential: negative urine or serum pregnancy test within 14 days prior to study treatment and highly effective forms of contraception in place thereafter as well as confirmed negative urine or serum pregnancy test prior to treatment on day 1 of every cycle
    Postmenopausal or evidence of non-childbearing status is defined as:
    o Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
    o Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50 except in patients with a history of surgical sterilisation (bilateral oophorectomy or hysterectomy)
    o Radiation-induced oophorectomy with last menses >1 year ago
    o Chemotherapy-induced menopause with >1 year interval since last menses
    o Surgical sterilisation (bilateral oophorectomy or hysterectomy)
    10. Female patients of child bearing potential and male patients with partners of child bearing potential, who are sexually active, must agree to the use of highly effective forms of contraception. This should be started from the signing of the informed consent and continue throughout period of taking study treatment and for 1 month (female patients) / 3 months (male patients) after last dose of study drug.
    11. Identification of defective DNA repair via Homologous Recombination, as determined by molecular analysis within NCT/DKTK MASTER (Heidelberg Ethics Committee Reference No.: S-206/2011). Eligibility for the study is defined by the molecular tumorboard of NCT on the basis of whole-exome/genome sequencing and the presence of genomic markers for “BRCAness”.
    12. Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:
    o Hemoglobin ≥ 10 g/dl
    o Neutrophil count ≥ 1,500/mm3
    o Platelet count ≥ 100,000/µl
    o Bilirubin ≤ 1.0 x upper limit of normal (ULN)
    o ALT and AST ≤ 2.5 x ULN
    o Alkaline phosphatase ≤ 2.5 x ULN
    o PT-INR/PTT ≤ 1.5 x ULN
    o Albumin ≥ 25 g/l
    o Creatine kinase ≤ 2.5 x ULN
    o Serum creatinine  1.5 mg/dl or creatinine clearance  51 ml/min (calculation according to Crockroft-Gault)

    E.4Principal exclusion criteria
    1. Hematological malignancies and primary brain tumors. Patients with known progressive brain metastases determined by serial imaging or declining neurologic function in the opinion of the treating physician are not eligible. Patients with symptomatic uncontrolled brain metastases and patients with symptomatic uncontrolled spinal cord compression are not eligible. Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the three months prior to enrollment. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month, both prior to study enrollment
    2. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years
    3. Concurrent or previous treatment within 4 weeks in another interventional clinical trial
    4. Treated with an investigational anticancer therapy less than 4 weeks prior to study treatment. Inclusion may be possible after > five half-lifes of previous treatment after consultation with the coordinating investigator on a case by case decision.
    5. Prior treatment with PARP inhibitors
    6. Patients with platinum-refractory disease, defined as progressive disease during or immediately after treatment with platinum based chemotherapy
    7. Persistent toxicity (≥Grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia
    8. Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0)
    9. History of HIV infection and immunocompromised patients
    10. Viral active or chronic hepatitis (HBV or HCV)
    11. Dementia or significant impairment of cognitive state
    12. Epilepsy requiring pharmacologic treatment
    13. Pregnancy and breast feeding (women)
    14. Inability to take oral medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
    15. Major surgery within 4 weeks of starting study treatment. Patients must have reco-vered from any effects of any major surgery.
    16. Patients receiving any systemic chemotherapy or radiotherapy within 2 weeks prior to study treatment or a longer period depending on the defined characteristics of the agents used
    17. Known hypersensitivity to any of the study drugs or other ingredients of the investigational medicinal products
    18. Resting ECG with QTc > 450 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
    19. Abnormal left ventricular ejection fraction, defined as ejection fraction of <50% on echocardiography
    20. Heart failure NYHA III/IV
    21. Severe obstructive or restrictive ventilation disorder
    22. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is at least five half-lifes.
    23. Concomitant use of known strong CYP3A inducers (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is at least five half-lifes (e.g. 5 weeks for enzalutamide or phenobarbital)
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint is the disease control rate (DCR) at week 16
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 16 after five 21-days cycles of treatment in the experimental arm and either also after five 21-days cycles or alternatively four 28-days cycles in the physician’s choice arm
    E.5.2Secondary end point(s)
    - Tumor response rate
    - Survival analysis: Progression Free Survival, Overall Survival
    - Safety analysis: frequency of adverse events
    - Patient reportet outcomes including quality of life analysis
    E.5.2.1Timepoint(s) of evaluation of this end point
    After treatment period (week 16) plus (optional) extended treatment period (until progression or End of Study) and safety follow-up (28 days).
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 Yes
    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 Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    Last patient first visit plus 20 weeks
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months34
    E.8.9.1In the Member State concerned days
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 state108
    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)
    None
    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 Decision2018-07-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-31
    P. End of Trial
    P.End of Trial StatusOngoing
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