E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent epithelial ovarian cancer |
Recifief epitheliaal ovarium carcinoom |
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E.1.1.1 | Medical condition in easily understood language |
recurrent ovarian cancer |
recidief eierstok kanker |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066697 |
E.1.2 | Term | Ovarian cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether the outcome of the RAD51 assay (HR proficient or HR deficient according to RECAP test) correlates with objective response rate (RR according to RECIST 1.1) of olaparib, in patients with recurrent high grade epithelial ovarian cancer. |
Vaststellen of de uitkomst of de uitslag van de RAD51 assay (RECAP test) voorspelt welke patiënten met een hooggradig recidief epitheliaal ovarium carcinoom gevoelig zijn (response rate volgens RECIT 1.1) voor behandeling met PARP-remmers |
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E.2.2 | Secondary objectives of the trial |
- Compare the descriptive 1 yr PFS of olaparib for the BRCA1 or BRCA2 mutant (germline or somatic) HR deficient group, the non BRCA mutant HR deficient group and the HR proficient group, with HR defined according to the RAD51 assay.
- Correlation of RAD51 assay outcomes with overall survival (OS).
- Determine percentage of informative RAD51 test results of RAD51 assay in tumor biopsies and/or ascites.
- Compare the outcome of the RAD51 assay with the Lynparza 15-gene HRR assay.
- Determine grade 3 / 4 toxicity.
Exploratory:
- Identify molecular markers (including genomic markers in tumor or ascites) that are associated with the outcome of the RAD51 assay.
- Explore whether these molecular markers can be measured in liquid biopsies (by analysing ctDNA in blood). |
- Vergelijk 1 jaar PFS van olaparib voor de BRCA mutante groep vs non-BRCA mutante HRD groep vs HR proficiente groep.
- Correlatie uitslag RAD51 test en totale overleving
- Bepalen van aantal informatieve RAD51 testen
- Vergelijking uitslag RAD51 test en Lynparza 15-genen panel
- Bepalen van Graad 3/4 toxiciteit
Exploratief:
- Identificatie moleculaire markers geassocieerd met de uitkomst van de RAD51 assay.
- ctDNA analyse. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with recurrent high grade serous or endometrioid EOC (> 3 months after platinum
containing chemotherapy and unwilling or ineligible for platinum based therapy) with a tumor
lesion that is amendable for biopsy or who can undergo ascites drainage prior to treatment.
treatment.
2. Diagnosis of high grade serous or endometrioid EOC confirmed by histology .
3. Provision of informed consent prior to any study specific procedures
4. Female aged >18 years
5. Patients must have normal organ and bone marrow function measured within 28 days prior to administration olaparib as defined below:
Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Platelet count ≥ 100 x 109/L
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x ULN unless liver metastases are present in which case they must be ≤ 5x ULN
Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of ≥51 mL/min:
Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a
serum creatinine (mg/dL) x 72
a where F=0.85 for females
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
7. Patients must have a life expectancy ≥ 16 weeks.
8. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.
Postmenopausal is defined as:
Amenorrhoea for > 1 year, following cessation of exogenous hormonal treatments
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
radiation-induced oophorectomy with last menses >1 year ago
chemotherapy-induced menopause with >1 year interval since last menses
surgical sterilisation (bilateral oophorectomy or hysterectomy)
9. Patients willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
10. Evaluable disease (measurable and/or non-measurable) that can be accurately assessed at baseline using RECIST 1.1 by CT or MRI and is suitable for repeated assessment (appendix B).
11. For inclusion in i) the optional exploratory genetic research and ii) the optional biomarker research, patients must fulfil the following criteria:
Provision of informed consent for genetic research
Provision of informed consent for biomarker research |
Patienten met recidief hoog gradig sereus of endometrioid EOC (> 3 maanden na platinum
bevattende chemotherapie en niet wullen of in aanmering komend voor platinum based therapie) met de mogelijkheid voor een tumor biopsue of ascites drainage voor start behandeling
2. Diagnose hoog gradig sereus of endometrioid EOC histologisch bewezen .
3. Geschreven Informed Consent
4. vrouw >/=18 jaar
5. Normale orgaan een beenmerg functie, gemweten binnen 28 dagen voor sart olaparib, gedefinieerd als:
Hb ≥ 10.0 g/dL , zonder bloedtransfusie de laatste 28 dagen
Absoluut neutrofiel getal (ANC) ≥ 1.5 x 109/L
Thrombocyten ≥ 100 x 109/L
Total bilirubine ≤ 1.5 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x ULN tenzij lever metastasen, dan ≤ 5x ULN
Creatinine klaring geschat mbv de Cockcroft-Gault equation of ≥51 mL/min
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
7. Levens verwachting≥ 16 weeks.
8. Postmenopausaal or bewijs van afwezigheid van zwangerschap voor premenopausale/vruchtbare vrouwen: negatieve urine of serum zwangerschaps test binnen 28 dagen voor start studie nedicatie en voor start van behandeling op dag 1.
Postmenopausaal is alsvolgt gedefineerd:
Amenorrhoea > 1 year, na staken endocriene therapie
Luteinizing hormone (LH) en Follicle stimulating hormone (FSH) waarden in de post menopausale range voor vrouwen onder 50 jaar
radiatie-geinduceerde oophorectomy en laatste menstruatie >1 jaar
chemotherapy-geinduceerde menopause en laatste menstriuatie >1 jaar
chirurgische sterilisatie (bilateral oophorectomy of hysterectomy)
9. Patients compliant willen en kunnen zijn.
10. Evalueerbare ziekte (meetbaar en/of niet-meetbaar) als beoordeeld bij baseline middels RECIST 1.1 mbv CT of MRI.
11. Voor inclusie in i) optioneel genetische ondezoek en ii) optioneel biomarker onderzoek, dienen patienten te voldoen aan de volgende criteria:
Geschreven informed consent voor genetisch onderzoek
Geschreven informed consent voor biomarker onderzoek |
|
E.4 | Principal exclusion criteria |
Participation in another clinical study with an investigational product during the last months
13. Any previous treatment with PARP inhibitor, including olaparib.
14. *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 breast cancer and lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥3 years.
15. Patients receiving radiotherapy y within 3 weeks prior to study treatment.
16. 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 2 weeks.
17. Concomitant use of known strong (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 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
18. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) >-grade 2) caused by previous cancer therapy, excluding alopecia.
19. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
20. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
21. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
22. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
23. Breast feeding women.
24. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
25. Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
26. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
27. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
28. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
29. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable outside of 28 days prior to treatment.
30. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
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Deelname in een andere studie met een onderzoeksmiddel gedurende de afgelopen maand.
13. Eerdere behandeling met PARP remmer, inclusief olaparib.
14. *andere maligniteit de afgelopen 5 jaar, muv: adequaat behandelde non-melanoom huidkanker, curatief behandeldein situ cancer, stadium 1 en graad 1 endometrial carcinoom, of andere solide tumoren incusief mammacarcinoom en lymfoom (zonder beenmerg betrokkenheid) curatief behendeld zonder aanwijzimg voor ziekte voor ≥3 years.
15. Radiotherapy binnen 3 weken voor studie behandeling.
16. Gelijktijdig gebruik van sterke CYP3A remmers (bv. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) of gemiddel sterke CYP3A remmers (bv. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). De benodigde washout periode voor start olaparib is 2 weken.
17. Gelijktijdig gebruik vann sterke (bv. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) of gemiddelde CYP3A inducers (eg. bosentan, efavirenz, modafinil). De benodigde washout periode voor start olaparib 5 weken voor enzalutamide of phenobarbital en 3 weken voor de overige middelen.
18. Persisterende toxiciteit (Common Terminology Criteria for Adverse Event (CTCAE) >-grade 2) tgv eerdere antitumor therapie, exclusief alopecia.
19. Symptomatische ongecontroleerde hersen metastasen. stabiele dosering corticosteroiden is toegestaan indien deze minimaal 4 weken zijn gestart voor start olaparib. Patienten met spinal cord compressie tenzij ze hiervoor behandeld zijn en klinisch stabiel gedurende 28 days.
20. Grote chirurgie binnen 2 weken en patienten dienen te zijn hersteld van elk effect van enige eerdere chirurgie.
21. Patienten met medisch risico obv een serieus ungecontroleerde medische aandoening of infectie. Voorbeelden inclderen, maar zijn niet gelimiteerd tot, ongecontroleerde ventriculaire aritmie, recent (binnen 3 maanden) hart infarct, ongecontroleerd CVA, onstabiel of dreigende dwarslesie, vena cava superior syndroom, extensieve interstitiele long ziekte of enige psychiatrische ziekte dat het informed concent belemmert.
22. Patienten die geen orale medicatie kunnen innemen of met een verminderde orale absorptie.
23. patienten die borstvoeding geven.
24. Immuun gecompromiteerde patienten.
25. Bekende hypersensitiviteit van olaparib of bestanddelen van het product.
26. Bekende actieve hepatitis (bv Hepatitis B of C)
27. Eerdere allogene beenmerg of navestreng transplantatie.
28. Bekend myelodysplastisch syndroome / acute myeloide leukaemie of kenmerken suggestief voor MDS/AML.
29. Bloed transfusie in de afgelopen 120 dagen en trombocyten transfusie in de afgelopen 28 dagen vor start behandelng.
30. Rust ECG met QTc > 470 msec op 2 of meer tijdspunten binnen 24 hr of familie geschiedenis met een lang QT syndrome.
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E.5 End points |
E.5.1 | Primary end point(s) |
response rate according to RECIST 1.1
outcome RAD51 test |
response rate volgens RECIST 1.1
Uitkomst van de RAD51 test |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
response rate according to RECIST 1.1: every 12 weeks
outcome RAD51 test: baseline |
response rate volgens RECIST 1.1: elke 12 weken
Uitkomst van de RAD51 test: baseline |
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E.5.2 | Secondary end point(s) |
Overall survival
Toxicity according to NCI-CTC v4.03 criteria
|
Overleving
Toxiciteit volgens NCI CTC v4.03 criteria |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival: end of study
Toxicity according to NCI-CTC v4.03 criteria: every 4 weeks
|
Overleving: studie einde
Toxiciteit volgens NCI CTC v4.03 criteria: elke 4 weken |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
|
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |