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)
- Conditions
- Breast CancerHomologous Recombinant Repair (HRR)-related genes10006291
- Registration Number
- NL-OMON50520
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 3
Protocol V2.0 section 3.1
At Screening Part 1, prior to HRR mutation testing being carried out, the
criteria marked with an asterisk (*) must be fulfilled by the patients who do
not have a known BRCAm status and are being considered for this study. , 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 with evidence of metastatic
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
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..
* 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 (eg, 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.
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 (Hb) ?10.0 g/dL with no blood transfusions (packed red blood
cells) in the past 28 days
(b) Absolute neutrophil count (ANC) ? 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 (ULN) unless the
patient has documented Gilbert*s Syndrome
(e) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT)
*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 (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 and F<=1 for males
9. * ECOG PS 0-1 within 28 days of randomisation.
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.
11. Women of childbearing potential and their partners,
Protocol V2.0 section 3.2
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
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 CSP V6.0 - 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
defined by New York Heart Association (NYHA) * Class 2:
- Unstable angina pectoris
- Congestive heart failure
- Acute myocardial infarction
- Conduction abnormality not controlled with pacemaker or medication
- 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 mode
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>PFS using Blinded Independent Central Review (BICR) according to Response<br /><br>Evaluation Criteria in Solid Tumours (RECIST 1.1) Sensitivity analysis of PFS<br /><br>using Investigator assessments according to RECIST 1.1<br /><br><br /><br>Protocol v7.0 06May2020 p.136</p><br>
- Secondary Outcome Measures
Name Time Method