| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple negative breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the pathological complete response (pCR) after neoadjuvant treatment with olaparib alone and with olaparib in combination with durvalumab in patients with TNBC showing a tumour mutation in BRCA1/2 (tBRCA1/2) or a HRD signature based on methylation. In this study, pCR is defined as ypT0/is ypN0 at time of surgery. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess tumour response as per RECIST v1.1 after neoadjuvant therapy
• To assess the surgery rate and the rate of breast conserving surgery after neoadjuvant systemic treatment
• To assess the efficacy profile of olaparib or olaparib and durvalumab as neoadjuvant systemic therapies with other pathological response classifications (RCB and ypT0 ypN0).
• To assess the event-free survival in both treatment arms
• To assess the overall survival in both treatment arms
• To assess the safety profile of olaparib or olaparib and durvalumab as neoadjuvant systemic therapies and post-surgical complications
• To assess the evolution of Health-Related Quality of Life (HRQoL) in both arms, more specifically with regards to the following two scales: the global health status/QoL scale from the EORTC-QLQ-C30 questionnaire and the systemic side effects scale from the modified QLQ-BR45 questionnaire (IL170). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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 of study treatment. Patients must have recovered from the surgical procedure. Implanted port placement is not considered as a major surgery.
25) Known allergy or hypersensitivity to any excipient of olaparib and/or durvalumab.
26) Participation in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of pCR at the time of surgery (ypT0/is ypN0) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Treatment response rate according to RECIST v1.1
2) Surgery rate
3) Breast conservation rate
4) Other pathological response classification as assessed by: Residual cancer burden (RCB) score, Rate of pCR (ypT0 ypN0)
5) Probability of being event-free at 2 years, 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.
6) 2-year overall survival (OS) rate
7) Safety: 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)
8) Global health status/QoL score according to EORTC QLQ-C30 questionnaire
9) Score on the Systemic side effects scale according to the modified QLQ-BR45 (IL170) questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) At C2D1 and after the end of neoadjuvant treatment
2) 30 days after surgery
3) 30 days after surgery
4) At surgery
5) 2 years after randomization
6) 2 years after randomization
7) Safety: within 42 days prior to randomization, at D1 of every cycle, after the end of neoadjuvant treatment, 30 days after surgery, every 6 months during follow-up
Rate of Post-operative complications: 30 days after surgery
8) Within 28 days prior to randomization, at D1C2, after the end of neoadjuvant treatment and 30 days after surgery
9) Within 28 days prior to randomization, at D1C2, after the end of neoadjuvant treatment and 30 days after surgery |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Jordan |
| France |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Belgium |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study occurs when all of the following criteria have been satisfied:
• All patients have completed their end of study visit. If a participant discontinues the follow-up for one of the following reasons: withdrawal of consent, loss to follow-up, or death, the end of study participation is defined as the time point when one of these events occurred.
• The trial is mature for all analyses defined in the protocol and the database has been cleaned and locked for these analyses. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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