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 (VIOLETTE Study)
- Conditions
- Triple negative Breast CancerMedDRA version: 20.0Level: PTClassification code 10075566Term: Triple negative breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2017-002361-22-DE
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Not Recruiting
- Sex
- All
- Target Recruitment
- 1300
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 nonamplified
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
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 we
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method