A Phase II, Open Label, Randomised, Multi-centre Study to Assess the Safety and Efficacy of Agents Targeting DNA Damage Repair in Combination with Olaparib versus Olaparib Monotherapy in the Treatment of Metastatic Triple Negative Breast Cancer Patients Stratified by Alterations in Homologous Recombinant Repair (HRR)-related Genes (including BRCA1/2) (VIOLETTE)

AstraZeneca AB0 个研究点目标入组 1,300 人开始时间: 2018年2月20日最近更新: 2021年4月5日

适应症

试验速览

阶段: 1 期
状态: 进行中（未招募）
发起方: AstraZeneca AB
入组人数: 1,300

研究概览入排标准研究者记录与标识符相似试验

研究概览

简要总结

暂无简介。

研究设计

研究类型: Interventional clinical trial of medicinal product

入排标准

性别: All

入选标准

•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
•4. Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic or incurable advanced locoregional disease (defined as ER and PgR negative [IHC nuclear staining <1% positive] and HER2 negative [IHC 0, 1+ or IHC 2+ with corresponding ISH non-amplified of ratio less than 2.0 or ISH non-amplified ratio less than 2.0] as per ASCO-CAP HER2 guideline recommendations 2013 (ASCO-CAP).
•Note: An Allred score of 0-2 is acceptable however for a score of 2 the Proportion score must be checked to make sure it is 1 (=1% cells are ER positive)
•5. Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic or incurable advanced locoregional disease with an anthracycline (doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic setting
•Patients who have received platinum (cisplatin or carboplatin, either as monotherapy or in combination) for advanced breast cancer are eligible to enter the study provided there has been no evidence of disease progression during the platinum chemotherapy
•Patients who have received prior platinum based chemotherapy are eligible if platinum was given either as potentially curative treatment for a prior non breast cancer (ovarian cancer) with no evidence of disease for =5 years prior to study entry or as adjuvant/neoadjuvant treatment for breast cancer provided at least 12 months have elapsed between the last dose of platinum-based treatment and randomisation
•6. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay
•- FFPE tumour tissue blocks are required for each patient, but if not available, tissue sections are accepted. At least twenty (thirty preferable) unstained sections without cover slips must be submitted to ensure sufficient material for the prospective Lynparza HRR testing to determine study eligibility and research that will aid understanding of the patient population relative to treatment with DDR and other cancer agents
•- If a patient has a previously known qualifying BRCA1/2 mutation or other HRR mutation, then the patient can be invited to consent to the full study. The patient will need to consent to provide an archival tumour block or tissue sections for central assessment of the HRR mutation status
•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 below:
•a) Haemoglobin =10.0 g/dL with no blood transfusions (packed red blood cells) in the past 28 days
•b) Absolute neutrophil count = 1.5 x 109 /L
•c) Platelet count =100 x 109 /L with no platelet transfusions in the past 28 days
•d) Total bilirubin =1.5 x institutional upper limit of normal unless the patient has documented Gilbert’s Syndrome
•e) Aspartate aminotransferase /alanine aminotransferase =2.5 x institutional ULN unless liver metastases are present in which case they must be =5 x ULN
•f) Patients must have creatinine clearance of =51 mL/min est

排除标准

•1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or staff at the study site)
•2. 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
•3. More than 2 prior lines of cytotoxic chemotherapy for metastatic disease
•- Prior treatments with hormonal therapy and non hormonal targeted therapy are allowed and not counted as a prior line of cytotoxic chemotherapy
•- For the purposes of this protocol, the combination of an aromatase inhibitor and everolimus is not considered cytotoxic chemotherapy
•- Treatment with biologics will not be considered as prior line of therapy
•4. Previous randomisation in the present study
•5. 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)
•6. 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
•7. Patients with MDS/AML or with features suggestive of MDS/AML
•8. 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 (including lymphomas [without bone marrow involvement])
•9. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470 msec/female patients and >450 msec for male patients (as calculated per institutional standards) obtained from 3 ECGs performed 2-5 minutes apart at study entry, or congenital long QT syndrome. No longer applicable from CSPv6.0 AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction
•10. Any of the following cardiac diseases currently or within the last 6 months
•- Unstable angina pectoris
•- Congestive heart failure = Class 2 as defined by the New York Heart Association
•- Acute myocardial infarction
•- Conduction abnormality not controlled with pacemaker or medication (patients with a conduction abnormality controlled with pacemaker or medication at the time of screening are eligible)
•- Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
•11. Concomitant use of known strong cytochrome P (CYP) 3A 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 study treatment is 2 weeks
•NAP from CSPv7.0 - Patient has

研究者

发起方

AstraZeneca AB

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