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A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study of Olaparib Maintenance Retreatment in Patients with Epithelial Ovarian Cancer Previously Treated With a PARPi and Responding to Repeat Platinum Chemotherapy (OReO)

Studio Clinico

Patologia: Tumori dell’ovaio

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: 

Fase di studio: III

Richiesta mandatoria di tessuto: 

Linee di trattamento: Mantenimento

Criteri di inclusione: 

1. Provision of informed consent prior to any study specific procedures
2. Patients must be ≥18 years of age
3. Female patients with histologically diagnosed relapsed non-mucinous EOC (including primary peritoneal and/or fallopian tube cancer)
4. Documented BRCA1/2 status
- To be regarded as BRCA1/2 (+ve), the patient must have a mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function)
5. Patients must have received one prior PARPi therapy or blinded treatment in a trial with a PARPi as the experimental arm
- PARPi therapy includes any agent (including Olaparib) used in a maintenance
setting
- For the BRCA1/2 (+ve) cohort, the duration of first PARPi exposure must have been ≥18 months following a first line of chemotherapy or ≥12 months following a second or subsequent line of chemotherapy
- For the BRCA1/2 (-ve) cohort, the duration of first PARPi exposure must have been ≥12 months following a first line of chemotherapy or ≥6 months following a second or subsequent line of chemotherapy
For the last chemotherapy course immediately prior to randomisation on the study
- Patients must have received a platinum-based chemotherapy regimen (carboplatin or cisplatin) and have received at least 4 cycles of treatment
- Patients must be in partial or complete radiological response following completion of this chemotherapy course as evaluated by the Investigator
- Patients must not have received bevacizumab during this course of treatment. Bevacizumab use as part of an earlier line of chemotherapy is permitted
- Patients must not have received any investigational agent during this course of treatment
- Patients must be randomised within 8 weeks of their last dose of chemotherapy (last dose is the day of the last infusion)
6. Patients must have normal organ and bone marrow function measured within 28 days of randomisation, as defined below. In the event of minor deviations from these values which would lead to screen failure, repeat testing within the 28-day screening period (limited to the tests listed below) is allowed before the patient is declared a screen failure.
- 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 with no platelet transfusion in the last 14 days
- Total bilirubin (TBL) ≤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 institutional ULN, unless liver metastases are present in which case they must be ≤5 X ULN
- Patients must have creatinine clearance (CrCl) estimated using the Cockcroft-Gault equation of ≥51 mL/min:

Estimated CrCl = (140-age [years]) X weight (kg) (X F)a
                         serum creatinine (mg/dL) X 72
a where F=0.85 for females
7. ECOG performance status 0-1
8. Patients must have a life expectancy ≥16 weeks
9. 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 1Postmenopausal is defined as:
- Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
- Luteinizing hormone and follicle stimulating hormone levels in the postmenopausal 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).
10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
11. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment
OR
No measurable disease following a complete response to chemotherapy
12. A formalin fixed, paraffin embedded (FFPE) tumour sample from the cancer of sufficient quantity and quality (as specified in the Covance Central Laboratory Services Manual) must be available for future central testing of tumour genetic status. If a recent biopsied sample is provided, the biopsied tumour should not be assessed as target lesions as part of the RECIST assessments if there are other lesions available, and the biopsy should be taken after the baseline scan has been performed. Archival tissue samples may be from the primary tumour or metastatic tumour deposits. Archival bone metastases are not acceptable. Provision of blocks is preferred. Alternatively pre-cut 5μm thick, unstained sections from the FFPE block may be provided. Any exceptions to these conditions should be discussed with the Sponsor before randomisation of the patient.
13. For inclusion in the optional biomarker research, patients must fulfil the following criteria:
- Provision of informed consent for biomarker research.
If a patient declines to participate in the optional biomarker research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.

Criteri di esclusione: 

Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2. Previous randomisation in the present study
3. Participation in another clinical study with an investigational product during the chemotherapy course immediately prior to randomisation.
4. 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. Patients with history of primary breast cancer may be eligible provided they completed their definitive anticancer treatment more than 3 years ago and they remain breast cancer disease free prior to start of study treatment
5. Resting electrocardiogram (ECG) with corrected QT interval (QTc) >470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
6. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative radiotherapy) within 3 weeks prior to study treatment
7. Concomitant use of known strong cytochrome P450 (CYP) subfamily 3A (CYP3A) inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir,
telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks
8. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required
washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
9. Persistent toxicities (Common Terminology Criteria for Adverse Event [CTCAE] grade 2 or higher) caused by previous cancer therapy, excluding alopecia
10. Patients with current or previous myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
11. 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
12. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
13. 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
14. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
15. Breast feeding women
16. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)
17. Patients with a known hypersensitivity to Olaparib or any of the excipients of the product
18. Patients with known active hepatitis (i.e., Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
19. Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
20. Whole blood transfusions in the last 120 days prior to randomisation to the study (packed red blood cells and platelet transfusions are acceptable).

Schema di trattamento: 

Patients will be administered study treatment orally bd at 300 mg bd continually, or lower if 300 mg is not tolerated on initial PARPi treatment. Two x 150 mg Olaparib (or placebo) study treatment tablets should be taken at the same time each day, approximately 12 hours

Trattamento sperimentale: 

Olaparib

Trattamento di controllo: 

Placebo

Obiettivi primari dello studio: 

To determine the efficacy of Olaparib maintenance retreatment compared to matching placebo by assessment of progression-free survival (PFS)

Obiettivi secondari dello studio: 

- To determine the efficacy of Olaparib maintenance retreatment compared to matching placebo by assessment of overall survival (OS)
- To determine the efficacy of Olaparib maintenance retreatment compared to matching placebo by assessment of time to progression by Gynecologic Cancer Intergroup (GCIG) criteria
- To determine the efficacy of Olaparib maintenance retreatment compared to matching placebo by assessment of the use of subsequent therapies and study treatment discontinuation
- To determine the HRQoL of Olaparib maintenance retreatment compared to matching placebo as measured by the Functional Assessment of Cancer Therapy – Ovarian (FACT-O) Trial Outcome Index (TOI)

Centri partecipanti

Nord Italia

Ospedale S.Orsola Malpighi, Università di Bologna
Via Pietro Albertoni 15 - 40138 Bologna - BO
SSD Oncologia medica Addarii-Zamagni - Via Massarenti 9

Riferimento: Prof. Claudio Zamagni
Email: claudio.zamagni@aosp.bo.it

 

Azienda Spedali Civili di Brescia
Piazzale Spedali Civili 1 - 25123 Brescia - BS
U.O. Ostetricia e Ginecologia 2

Riferimento: Dr.ssa Germana Tognon
Email: gine2@spedalicivili.brescia.it

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI
S.C. Oncologia Ginecologica

Riferimento: Dr.ssa Domenica Lorusso
Email: domenica.lorusso@istitutotumori.mi.it

 

Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI
Divisione di Ginecologia Oncologica

Riferimento: Prof.ssa Nicoletta Colombo
Email: nicoletta.colombo@ieo.it

 

Ospedale San Raffaele di Milano
Via Olgettina 60 - 20132 Milano - MI
UO Ginecologia, Oncologia Ginecologica

Riferimento: Dr.ssa Giorgia Mangili
Email: mangili.giorgia@hsr.it

 

Istituto Oncologico Veneto IRCCS
Via Gattamelata 64 - 35128 Padova - PD
Ginecologia Medica 2

Riferimento: Prof. Pierfranco Conte
Telefono: 0498215290
Email: pierfranco.conte@unipd.it

 

Ospedale di S. Maria Nuova - Reggio Emilia
Viale Risorgimento 80 - 42100 Reggio nell'Emilia - RE
U.O. Oncologia

Riferimento: Dr.ssa Alessandra Bologna
Telefono: 0522296620
Email: bologna.alessandra@ausl.re.it

 

IRCCS Candiolo (TO)
St.Provinciale Km 3,95 SP142 - 10060 Candiolo - TO
Oncologia Medica

Riferimento: Dr. Giorgio Valabrega
Telefono: 0119933250
Email: giorgio.valabrega@ircc.it

 

AO - Ordine Mauriziano
Largo Turati 62 - 10128 Torino - TO
Presidio Ospedaliero Umberto I - S.C.D.U. Ostetricia e Ginecologia - Via Magellano 1

Riferimento: Dr.ssa Annamaria Ferrero

 

Ospedale S. Anna
Corso Spezia 60 - 10126 Torino - TO
Ginecologia e Ostetricia 2: Via Ventimiglia 3

Riferimento: Prof. Paolo Zola

 

Centro Italia

Fondazione Policlinico A. Gemelli
Largo Agostino Gemelli 8 - 00168 Roma - RM
U.O. Ginecologia Oncologica

Riferimento: Prof. Giovanni Scambia
Telefono: 0630156134
Email: giovanni.scambia@unicatt.it

 

Sud Italia e isole

Azienda Ospedaliera Universitaria Federico II
Via Sergio Pansini 5 - 80131 Napoli - NA
Dipartimento di Medicina clinica e Chirurgia

Riferimento: Prof. Sabino De Placido
Email: deplacid@unina.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2016-003346-90

Data di inserimento: 28.08.2018

Promotore

AstraZeneca

Principal Investigator ITALIA

Fondazione Policlinico Universitario A.Gemelli

Riferimento: Prof. Giovanni Scambia

Telefono: 0630156134

Email: giovanni.scambia@unicatt.it

Localita: Roma

 

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