Olaparib and durvalumab before surgery as treatment for patients with a BRCA-associated triple negative subtype of breast cancer (NOBLE)

Phase 1

• Conditions: Triple negative breast cancer; MedDRA 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: EUCTR2022-003594-33-IT
• Lead Sponsor: EORTC AISBL/IVZW

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2023-02-06
• Last Update Posted: 11 September 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 152

Inclusion Criteria

1) Histologically confirmed TNBC as per local assessment
2) Early-stage disease, defined as cT1c-T2, N0-N1, M0
3) Medically fit for a neoadjuvant strategy and for radical surgery as per the investigator’s decision
4) Tumour tissue available from primary tumour (fine needle aspiration cytology or lymph node metastasis tissue are not acceptable) for central testing of BRCA mutation and HRD based on methylation and for translational research purposes
5) No prior systemic therapy nor definitive surgery for BC
6) Age =18 years
7) Women and men can be included
8) ECOG performance status (PS) 0-1
9) Life expectancy of at least 6 months
10) Written informed consent (PISIC) before the collection of biomaterial and registration according to ICH/GCP, and national/local regulations
11) Pathogenic tumoural mutation in BRCA 1 and/or BRCA 2 (tBRCA 1/2) and/or HRD based on methylation (BRCAme and RAD51Cme) as determined by central testing
12) Normal organ and bone marrow function measured prior to administration of study treatment
13) Women of childbearing potential (WOCBP) must have a negative highly sensitive urine or serum pregnancy test in the screening period and confirmed prior to treatment on day 1
14) Women of childbearing potential and their partners, who are sexually active, must agree to the use of one highly effective form of contraception and their partners must use a male condom
15) Male patients must use a condom during treatment and for 3 months after the last dose of olaparib and/or durvalumab 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 if they are of childbearing potential. Male patients should not donate sperm throughout the period of study treatment and for 3 months following the last dose of study drugs.
16) Female subjects who are breast feeding must discontinue nursing prior to the first dose of study treatment and until 3 months after the last dose of olaparib and/or durvalumab.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 122
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30

Exclusion Criteria

1) Previous treatment with a PARPi
2) Previous treatment with an anti-PD-1/PD-L1, anti-PD-L2 or anti-CTLA-4 antibody
3) Patients who underwent sentinel node biopsy before neoadjuvant therapy
4) History of previous invasive BC
5) Bilateral and/or multifocal and/or multicentric BC
6) Patients unable to swallow orally administered medication, malabsorption syndrome or other chronic condition that would significantly interfere with enteral absorption
7) Active or prior documented autoimmune or inflammatory disorders
8) History of allogenic bone marrow transplantation, umbilical cord blood transplantation or organ transplantation
9) History of another primary malignancy
10) Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of such
11) History of active primary immunodeficiency
12) Contraindication to MRI or to the contrast medium used for MRI (gadolinium-contrast based agents)
13) History of human immunodeficiency virus (HIV) (positive HIV 1/2-antibodies)
14) Active Hepatitis B or Hepatitis C
15) Any bacterial, viral or fungal infection = grade 3 according to CTCAE version 5
16) History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, interstitial lung disease or evidence of active pneumonitis on screening (TAP-CT-scan)
17) Mean QT interval corrected for heart rate (QTc) = 500ms using Fridericia’s Correction. Patients with congenital long QT syndrome are excluded regardless of QTc at baseline.
18) Any of the following intercurrent illnesses: symptomatic congestive heart failure, symptomatic coronary disease requiring anti-anginal medication, symptomatic peripheral artery disease, symptomatic cardiac arrhythmia, myocardial infarction within the last 3 months, stroke within the last 3 months, severe chronic obstructive pulmonary disease, decompensated cirrhosis, serious chronic gastrointestinal conditions associated with diarrhoea, uncontrolled epilepsy, any other severe medical condition that substantially increases the risk of incurring AEs
19) Psychiatric illness/social situations or addiction (chronic alcoholism or drug addiction) that would, in the judgment of the investigator, limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
20) Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab
21) Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study treatment and up to 30 days after the last dose.
22) Concomitant use of strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, voriconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir, nefazodone, mibefradil, grapefruit juice or extracts) The required washout period prior to starting study treatment (olaparib) should correspond to at least five half-lives of the concerned medication.
23) Concomitant use of strong CYP3A inducers (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort). The required washout period prior to starting study treatment (olaparib) is 5 weeks for phenobarbital and enzalutamide, and at least 5 half-lives for other agents.
24) Major surgery within 4 weeks prior to the first dose

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified