BRCA1 Mutation, BRCA2 Mutation, TNBC - Triple-Negative Breast Cancer
Conditions
Keywords
Olaparib, Durvalumab, PARPi
Brief summary
This is a multicenter randomized phase ll clinical trial to evaluate the pathological complete response (pCR) in the tumour burden (primary and lymph nodes) with olaparib alone or in the olaparib and durvalumab arm in TNBC patients candidate for neoadjuvant strategy showing a t/gBRCAmut or BRCAness/HRD profile.
Detailed description
Eligible patients will be registered for central testing of BRCA mutatinal status and HRD/BRCAness profile with central review of ER, PgR, TILs and PD-L1. Eligible patients will be randomly assigned to either olparib or olaparib and durvalumab (=neoadjuvant treatment) in a 1:1 ratio. The treatment duration in both arms will last 16 weeks and both treatments are considered as experimental treatments in this study. After completion of neoadjuvant systemic treatment, patients will undergo surgery and followed-up for 2 years after investigational drug discontinuation. After surgery, adjuvant treatment will be left at the investigator's decision.
Interventions
DRUGolaparib
olaparib 300 mg per os BID
DRUGDurvalumab
durvalumab 1500 mg IV Q4 weeks
Sponsors
AstraZeneca
European Organisation for Research and Treatment of Cancer - EORTC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Eligible patients after central screening are randomized to olaparib vs olaparib and durvalumab
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
at registration: * Histologically confirmed, invasive TNBC, defined as: * ER and PR negative (not eligible for endocrine therapy) defined as immunohistochemistry (IHC) nuclear staining ≤ 10% AND * HER2 negative (not eligible for anti-HER2 therapy): * Early-stage disease, defined as cT1c-T2, N0-N1, M0 * Medically fit for a neoadjuvant strategy and for radical surgery as by the investigator's decision * No prior systemic therapy nor definitive surgery for BC * Age ≥18 years * Women and men can be included * ECOG performance status (PS) 0-1
Exclusion criteria
at registration: * Previous treatment with a PARPi * Previous treatment with an anti-PD-1/PD-L1, anti-PD-L2 or anti-CTLA-4 antibody * Evidence of macroscopic distant metastases, investigated according to local institutional guidelines * Patients who underwent sentinel node biopsy before neoadjuvant therapy * History of previous invasive BC * Bilateral and/or multifocal and/or multicentric BC * Malabsorption syndrome or other chronic condition that would significantly interfere with enteral absorption * History of allogenic transplantation of bone marrow or an organ. * History of another primary malignancy. * Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of such. * Congenital long QT syndrome. * History of active primary immunodeficiency Inclusion criteria at randomization: * Deleterious germline or somatic mutation in BRCA 1 and/or BRCA 2 or homologue repair deficiency (HRD) status as determined by central testing. * Tumour tissue available from primary tumour (fine needle aspiration cytology or lymph node metastasis tissue are not acceptable). * Normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: * 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 * AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN * Total bilirubin ≤ 1.5 x ULN (exception: higher bilirubin in patients with confirmed Gilbert's syndrome are allowed according to the investigator's decision) * Creatinine clearance estimated of ≥ 51 mL/min/1.73m2 using the MDRD equation * Body weight \>30 kg * Participation in translational research is mandatory * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test in the screening period and confirmed prior to treatment on day 1. * Female patients of childbearing/reproductive potential must use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after the last dose of treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods include: * Intrauterine device (IUD) * Intrauterine hormone-releasing system (IUS) * Bilateral tubal occlusion * Vasectomized partner * Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient) * Male patients must use a condom during treatment and for 3 months after the last dose of study treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see above) if they are of childbearing potential. * Female subjects who are breast feeding must discontinue nursing prior to the first dose of study treatment and until 3 months after the last study treatment. * Registration to a National Health Care System
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| rate of pathological complete response (pCR) at the time of surgery | 5 years from first patient in | pCR is defined as the absence of invasive residual disease in the breast and in the axillary lymph nodes (ypT0/is ypN0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 2-year overall survival (OS) rate | 7.5 years from first patient in | OS is defined as date of randomization to the date of death, whatever comes first |
| Surgery rate | 7.5 years from first patient in | — |
| Breast conservation rate | 7.5 years from first patient in | — |
| Score on the Systemic side effects scale | 7.5 years from first patient in | according to the modified QLQ-BR45 (IL170) questionnaire |
| Treatment response rate according to RECIST v1.1 | 7.5 years from first patient in | — |
| Safety | 7.5 years from first patient in | Rate of Adverse events not related directly with the surgical procedure (NCI-CTCAE Version 5.0) Rate of Post-operative complications (Clavien-Dindo Classification of Surgical Complications) |
| Global health status/QoL score | 7.5 years from first patient in | score according to EORTC QLQ-C30 questionnaire |
| Other pathological response | 7.5 years from first patient in | Residual cancer burden score (RCB), defined on the specimen collected at the time of surgery |
| Probability of being event-free at 2 years | 7.5 years from first patient in | events considered being disease progression on neoadjuvant therapy, any event precluding surgery, locoregional recurrence, distant recurrence, second primary invasive cancer (breast and non-breast origin) and death from any cause |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory endpoints: To assess the evolution of the other scales HRQoL in both arms | 7.5 years from first patient in | according to EORTC QLQ-C30 questionnaire and the modified QLQ-BR45 (IL170) questionnaire |
| Exploratory endpoints: Translational research | 7.5 years from first patient in | Preliminary assessment of biomarkers that might act as pharmacodynamic indicators and predictors of activity of the experimental treatment by IHC, immunomonitoring, genetic and imaging studies. |
| Exploratory endpoints: the impact of olaparib alone or olaparib in combination with durvalumab on ovarian function (in patients ≤ 50 years) | 7.5 years from first patient in | Change in ovarian reserve over time as measured by AMH; Proportion of premenopausal women at baseline who become postmenopausal after neoadjuvant treatment and during follow-up as measured by FSH and E2 |
Outcome results
None listed