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A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed non- Germline BRCA Mutated Ovarian Cancer Patients who are in Complete or Partial Response Following Platinum based Chemotherapy - OPINION -

Studio Clinico

Patologia: Tumori dell’ovaio

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: No

Fase di studio: III

Richiesta mandatoria di tessuto: No

Linee di trattamento: Mantenimento

Criteri di inclusione: 

Patients without deleterious or suspected deleterious gBRCA mutations will be included. The gBRCA status of enrolled patients will be confirmed retrospectively using a central laboratory gBRCA test.
Testing of gBRCA status should normally have been performed as part of national or institutional practice guidelines for the management of ovarian cancer, such as in the assessment of treatment options after chemotherapy.
Under exceptional circumstances, gBRCA testing of potentially eligible patients whose gBRCA status is not yet known can be considered. The gBRCA test must be completed prior to patient enrolment.
The sample may be submitted up to three months prior to the start of the screening period if it appears that the patient is likely to meet other eligibility requirements.
To facilitate early testing, these patients will be asked to sign an Informed Consent Form (ICF) specific for genotyping that will be available prior to gBRCA status testing. Study sites should also offer access to a genetic counsellor (given that this is a genetic test which may have familial implications in the case of a positive result).

For inclusion in the study patients should fulfil all of the following criteria:
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 HGSOC (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid cancer
4. Documented gBRCA1/2 mutation status
- Evidence that the patients do not have a gBRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function). gBRCA1 and/or gBRCA2 variants that are classified as “Variants of uncertain clinical significance” or “Variant of unknown significance (VUS)” are eligible, as well as “Variant, favor polymorphism” or “benign polymorphism”.
- Evidence of the absence of a somatic BRCA mutation is not required. Patients with a tumour BRCA test result only must undergo a gBRCA test to determine whether the BRCA aberration is germline or somatic in origin. If this analysis dentifies the aberration as germline the patient is not eligible
5. Patients must have completed at least 2 previous courses of platinum containing therapy:
(a) For the penultimate chemotherapy course prior to enrolment on the study:
- Treatment must have contained a platinum agent (e.g. carboplatin or cisplatin per standard clinical practice; there are no other specific requirements)
- Patient was platinum sensitive after this treatment; defined as disease progression greater than 6 months after completion of their last dose of platinum chemotherapy Maintenance treatment is allowed at the end of the penultimate platinum regimen, including  bevacizumab
(b) For the last chemotherapy course immediately prior to enrolment on the study
Patients must be, in the opinion of the investigator, in response (partial or complete radiological 
response), or may have no evidence of disease (if optimal cytoreductive surgery was conducted prior
to chemotherapy), and no evidence of a rising CA-125, as defined below, following completion of this
chemotherapy course
- Patient must have received a platinum based chemotherapy regimen (carboplatin or cisplatin) and have received at least 4 cycles of treatment
- Patients must not have received bevacizumab during this course of treatment
- Patients must not have received any investigational agent during this course of treatment
- Patients must initiate treatment within 8 weeks of their last dose of chemotherapy (last dose is the  day of the last infusion)
6. Pre-treatment CA-125 measurements must meet criterion specified below:
- If the first value is within upper limit of normal (ULN) the patient is eligible to be enrolled and a second sample is not required
- If the first value is greater than ULN a second assessment must be performed at least 7 days after the 1st. If the second assessment is ≥ 15% more than the first, the patient is not eligible
7. Patients must have normal organ and bone marrow function measured within 28 days of starting study treatment, 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
- Total bilirubin (TBL) ≤1.5 X 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 estimated using the Cockcroft-Gault equation of ≥51 mL/min: Estimated creatinine clearance (females) = [(140-age [years]) x weight (kg) x 0.85]/ serum
creatinine (mg/dL) x 72
8. ECOG performance status 0-1 (see Appendix E)
9. Patients must have a life expectancy ≥16 weeks
10. 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 any of the following:
- Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
- For women under 50 years old, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range
- Radiation-induced oophorectomy with interval of 1 year or more since last menses
- Chemotherapy-induced menopause with >1 year interval since last menses
- Surgical sterilisation (bilateral oophorectomy or hysterectomy)
11. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
12. 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 evidence of disease following a complete response to chemotherapy (with or without cytoreductive surgery)
13. An appropriately prepared tumour sample from the cancer, of sufficient quantity and quality (as specified in the 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 usually
preferred. Any exceptions to these conditions should be discussed with the Sponsor before enrollment of the patient.

Criteri di esclusione: 

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 enrolment in the present study
3. Participation in another clinical study with an investigational product (IP) during the most recent chemotherapy course
4. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to start of study treatment
5. Any previous treatment with PARP inhibitor, including olaparib
6. Patients with a germline BRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function).
7. 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
8. Concomitant use of known strong 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 olaparib is 2 weeks.
9. Concomitant use of known strong (e.g., phenobarbital, 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 olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
10. Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia
11. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
12. Patients with symptomatic uncontrolled brain metastases. 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 (SD) for 28 days
13. Major surgery within 3 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
14. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active, uncontrolled infection.
15. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
16. Currently pregnant (confirmed with a positive pregnancy test) or breastfeeding women
17. Immuno-compromised patients e.g., Human Immunodeficiency Virus (HIV) requiring treatment or active Hepatitis B or C
18. Patients with a known hypersensitivity to olaparib or any of the excipients of the product
19. Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
20. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
21. Patients having gBRCA testing should not have had whole blood transfusions in the last 30 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
22. Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely or unable to comply with study procedures, restrictions and requirements.

Numero di pazienti previsti: 

35

Schema di trattamento: 

Le pazienti riceveranno olaparib per via orale due volte al giorno (bid) a 300 mg. La dose prevista di 300 mg due volte al giorno sarà costituita da due compresse di 150 mg due volte al giorno, con compresse da 100 mg usate per gestire eventuali riduzioni della dose che potrebbero essere necessarie per le pazienti che manifestano tossicità correlate al trattamento con olaparib o in caso di utilizzo di farmaci concomitanti.

Trattamento sperimentale: 

olaparib come monoterapia di mantenimento

Trattamento di controllo: 

/

Obiettivi primari dello studio: 

Determinare l’efficacia in base alla sopravvivenza libera da progressione (PFS) (valutazioni registrate dallo sperimentatore in base alla versione modificata dei Criteri di valutazione della risposta nei tumori solidi [RECIST v1.1]) di olaparib come monoterapia di
mantenimento nel carcinoma ovarico non-gBRCAm recidivante sensibile al platino (PFS)

Centri partecipanti

Nord Italia

Azienda Spedali Civili di Brescia
Piazzale Spedali Civili 1 - 25123 Brescia - BS

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

 

PO Alessandro Manzoni
Via Dell'Eremo 9 - 23900 Lecco - LC

Riferimento: Prof. Antonio Ardizzoia
Telefono: 0341489900
Email: a.ardizzoia@asst-lecco.it

 

Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI

Riferimento: Prof.ssa Nicoletta Colombo
Telefono: 0257489543
Email: nicoletta.colombo@ieo.it

 

Istituto Oncologico Veneto IRCCS
Via Gattamelata 64 - 35128 Padova - PD

Riferimento: Dr.ssa Maria Ornella Nicoletto
Email: ornella.nicoletto@ioveneto.it

 

AO - Ordine Mauriziano
Largo Turati 62 - 10128 Torino - TO

Riferimento: Dr.ssa Annamaria Ferrero
Email: ginecologia@mauriziano.it

 

Ospedale S. Anna
Corso Spezia 60 - 10126 Torino - TO
AO Città della Salute e della Scienza

Riferimento: Prof. Paolo Zola

 

Centro Italia

Ospedale Riuniti Umberto I - Lancisi-Salesi
Via Conca 71 - 60020 Ancona - AN

Riferimento: Prof.ssa Rossana Berardi
Telefono: 0715965715
Email: r.berardi@univpm.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2017-002767-17

Data di inserimento: 26.09.2018

Promotore

AstraZeneca

CRO

NA

Principal Investigator ITALIA

Istituto Europeo di Oncologia - Divisione di Ginecologia Oncologica

Riferimento: Prof.ssa Nicoletta Colombo

Telefono: 0257489543

Email: nicoletta.colombo@ieo.it

Localita: Milano

 

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