Etude : VIOLETTE /

ATTENTION : pour chaque essai clinique, les éléments affichés ci-dessous ne sont pas exhaustifs, et le protocole fourni par le promoteur reste l’unique document à consulter pour mener à bien un essai clinique sur centre. Pour plus d'informations, contactez le référent du territoire concerné.

Acronyme / Nom
Situation thérapeutique
Cadre réglementaire
Présentation de l'étude
Acronyme / Nom : VIOLETTE

Situation thérapeutique : Métastatique ou localement avancé

Traitement :

Cadre réglementaire : RIPH1

Dernière MÀJ : 30/04/2021
CIM10 - Localisation(s)
Informations principales
Titre : Étude de phase II, ouverte, randomisée, multicentrique visant à évaluer la sécurité d'emploi et l'efficacité d'agents ciblant la réparation des dommages à l'ADN en combinaison avec l'olaparib par rapport à l'olaparib en monothérapie dans le traitement de patients atteints de cancer du sein triple négatif métastatique stratifiées en fonction des altérations des gènes impliqués dans la réparation par recombinaison homologue (HRR) (y compris BRCA1/2)

Spécialité : Seins, organes génitaux de la femme
Localisation : C50 - Tumeur maligne du sein
Informations complémentaires
Schéma : This is a prospective, open label, randomised, multi-centre Phase 2 study that will assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (AZD6738) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (AZD1775) in second or third line setting in patients with TNBC prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the HRR pathway.
Eligible patients will be randomised by a ratio 1:1:1 to olaparib monotherapy, AZD6738 & olaparib or AZD1775 & olaparib combinations.
The actual treatment given to individual patients will be determined by a randomisation scheme that has been loaded into the Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) database.
Treatment arms included:
- Arm 1: olaparib continuous in a 28-day cycle.
- Arm 2: AZD6738 Days 1-7 with olaparib continuous in a 28-day cycle.
- Arm 3: AZD1775 Days 1-3 and 8-10 with olaparib continuous in a 21-day cycle (CLOSED)
The study subject population will be divided into Stratum A (patients with tumour mutations in, BRCA1 or BRCA2 (Breast cancer susceptible gene mutation (BRCAm)), Stratum B (patients with tumour mutations in any of the other genes involved in the HRR pathway and no mutation in BRCA1 and no mutation in BRCA2), and Stratum C (patients with no detected tumour mutations in any of the HRR genes).
Within each stratum A, B and C, there will be further stratification by whether the patient received prior platinum-based therapy (yes/no).
In the olaparib monotherapy treatment arm as well as in the AZD6738+olaparib treatment arm, patients will be administered olaparib bd at 300 mg continually. Two (2) 150 mg olaparib tablets will be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL).
In the AZD1775+olaparib treatment arm, patients will be given olaparib 200 mg bd (2 x 100 mg tablets twice a day). AZD6738 will be supplied as 20 mg, 80 mg, or 100 mg film coated tablets. Patients will be administered AZD6738 od at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle. A total of 160 mg of AZD6738 tablets will be taken at the same time on each day of dosing with approximately 250 mL of water. AZD1775 will be supplied as capsules containing 25 mg, 50 mg, 75 mg, 100 mg, or 200 mg of drug substance. AZD1775 will be taken with approximately 250 mL of water approximately 2 hours before or 2 hours after food. Olaparib, AZD6738 and AZD1775 will be provided by AstraZeneca.
Primary outcome measures (progression free survival [PFS]) will be analysed for the 3 patient populations BRCAm, Non BRCAm HRRm (Homologous Recombination Repair gene mutation) and Non HRRm. Secondary outcome measures will be analysed in 2 patient populations HRRm and All for PFS, Objective response rate (ORR) and overall survival (OS) will be analysed in all 5 patient populations. DoR, and tumour change will be analysed in BRCAm, Non BRCAm HRRm, and Non HRRm patient populations. Tumour and germline mutation status, which will be analysed only for the All patient population. PK outcome measures, which will be analysed only for the all patient population. Blinded Independent Central Review (BICR) of radiological imaging data will be carried out using RECIST version 1.1 and Investigator assessments will also be analysed for sensitivity purposes.

Phase : II

Stade : Métastatique

2, 3
Critères d'inclusion
Critères de non-inclusion
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1.Provision of informed consent prior to any study specific procedures
2.Patients must be male or female ≥18 years of age.
3.Progressive cancer at the time of study entry with a life expectancy of ≥16 weeks
4.Histologically or cytologically confirmed TNBC with evidence of metastatic disease as per ASCO-CAP HER2 guideline recommendations 2013
5.Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic setting.
6.Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.
7.At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
8.Patients must have normal organ and bone marrow function measured within 28 days prior to randomisation as defined by protocol
9.ECOG PS 0-1 within 28 days of randomisation.
10.Patients must be willing to comply with the protocol requirements

Critères de non-inclusion : 1. Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment.
2. More than 2 prior lines of cytotoxic chemotherapy for metastatic disease.
3. Previous randomisation in the present study.
4. Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor (unless treatment was for less than 3 weeks duration and at least 12 months have elapsed between the last dose and randomisation. Patients that did not tolerate prior treatment are excluded).
5. Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to randomisation.The minimum washout period for immunotherapy shall be 42 days.
6. Patients with MDS/AML or with features suggestive of MDS/AML.
7. Patients with second primary cancer, EXCEPTIONS: 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 curatively treated with no evidence of disease for ≥ 5 years prior to study entry.
8. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470 msec/female patients and >450 msec for male patients or congenital long QT syndrome.
9. Any of the protocol specified cardiac diseases currently or within the last 6 months defined by New York Heart Association (NYHA) ≥ Class 2:
10. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors or use of known strong or moderate CYP3A inducers.
11. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
12. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
13. Immunocompromised patients, eg,human immunodeficiency virus (HIV) patients.
14. Patients with known active hepatitis (B or C).
15. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease or active, uncontrolled infection.
16. Patients with symptomatic uncontrolled brain metastases.
17. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
18. Patients with a known hypersensitivity to olaparib, AZD1775, AZD6738, or any of the excipients of the products.
19. Pregnant or breast feeding women.
Informations relatives au promoteur
Promoteur :
Type de sponsor : Industriel

Coordonnateur :
Centre investigateur
Informations relatives aux investigateurs
Centre investigateur :
Centre François BACLESSE - 3 avenue du Général Harris - 14000 CAEN
Apicrypt :

Investigateur :
Christelle LEVY


Statut de l'essai : CLOS

MAJ : 13/11/2020