Patients with advanced triple negative breast cancer (TNBC) with BRCA1 and/or BRCA2 promoter methylation assessed in DNA from metastatic lesions and absence of BRCA1 and 2 germline mutations. MedDRA version: 19.0 Level: PT Classification code 10075566 Term: Triple negative breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Olaparib
Product Code: AZD2281
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: OLAPARIB
CAS Number: 763113-22-0
Current Sponsor code: D0810000000//AZD2281, KU-0059436
Other
Sponsors
GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients are eligible to be included in the study only if they meet all of the following criteria. Any asterisked* are also applicable as an inclusion criteria prior to perform the BRCA testing via central testing: 1.The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study. 2.Female = 18 years of age on day of signing informed consent. 3.Patient with histological confirmation of breast cancer with evidence of advanced disease not amenable to resection or radiation therapy with curative intent. 4.Documented triple negative disease by immunohistochemistry (IHC) and/or in situ hybridization based on local testing (preferably assessed on the most recent tumour biopsy available). TN is defined as negative hormone receptor status (< 1% of tumour cells with ER and PgR expression) and HER2-negative status (defined as IHC score 0/1+ or negative by in situ hybridization defined according to local criteria). 5.Patient must have received at least one previous regimen in the advance disease setting. 6.Absence of deleterious or suspected deleterious germline mutations in BRCA1 and BRCA2. Germinal BRCA mutational status will be centrally assessed in Myriad laboratories to check eligibility unless the test has been previously performed at Myriad and absence of mutations has been determined. 7.Availability of a tumour tissue sample from the metastatic lesions (preferably obtained after the previous therapeutic regimen for advance disease) for central testing. 8.Documented methylation of BRCA1 and/or 2 promoters based on central testing by analysis on the most recent tumour from metastatic lesions available (preferably obtained after the previous therapeutic regimen for advance disease). 9.At least one lesion measurable not previously irradiated, that can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must have short axis = 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) or clinical examination and which is suitable for accurate repeated measurements according to RECIST v.1.1. 10.Patient must have 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 transfusions in the past 28 days. -Absolute neutrophil count (ANC) = 1.5 x 109/L -Platelet count = 100 x 109/L -Total bilirubin = 1.5 x institutional upper limit of normal (ULN) -Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase, SGOT) /Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase, SGPT) ] = 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be = 5 x ULN -Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of =51 mL/min: Estimated creatinine clearance =(140-age [years]) x weight (kg) (x F)a / serum creatinine (mg/dL) x 72 a where F=0.85 for females. 11.Please refer to protocol. 12.Please refer to protocol. 13.*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. Postmenopausal patient is defined as a woman fulfilling any one of the following criteria (based on the NCCN definition of menopause [National Comprehensive Cancer Network 2008]): -Prior bilateral
Exclusion criteria
Exclusion criteria: Patients will be excluded from the study if they meet any of the following criteria. Any asterisked* are also applicable as an exclusion criteria prior to perform the BRCA testing via central testing: 1.Please refer to protocol. 2.Please refer to protocol. 3.Participation in another clinical study with an investigational product during the last 4 weeks. 4.*Any previous treatment with a PARP inhibitor, including olaparib. 5.*Patients with second primary cancer, except: adequately treated non-melanoma skin cancer (basal cell or squamous cell carcinoma), curatively treated in-situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for = 5 years prior to study inclusion. Patients with a history of localised breast cancer with a tumor histology different of TN, with no evidence of disease for = 5 years since they completed their adjuvant chemotherapy. 6.Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons), within 3 weeks prior to study treatment (or a longer period depending on the defined characteristics of the agents used). 7.Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. 8.*Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. Please refer to section 5.5.2.1 about strong and moderate CYP3A inhibitors. 9.*Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Please refer to section 5.5.2.2 about strong and moderate CYP3A inducers. 10.*Persistent toxicities (> NCI-CTCAE grade 2) caused by previous cancer therapy (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion). 11.*Patients with myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) or with features suggestive of MDS/AML. 12.*Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with brain metastases may be eligible for the study only if more than 4 weeks from treatment completion for these metastases (including radiation and/or surgery), are clinically stable at the time of study entry. Please refer to protocol for read this completed criteria. 13.Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. 14.*Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 15.*Breast feeding women. 16.*Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV). 17.*Patients with known active hep
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To analyse the olaparib efficacy in the treatment of patients diagnosed of advanced triple negative breast cancer (TNBC) with BRCA1 and/or BRCA2 promoter methylation assessed in somatic DNA.;Secondary Objective: -To analyse other efficacy measures. -To analyse olaparib safety. -To explore changes in the methylation status of BRCA1/2 promoter in germline DNA prior and after treatment discontinuation for any reason and correlate germline BRCA1/2 methylation data with efficacy parameters. -To correlate BRCA1/2 methylation between germline and somatic DNA and between primary tumor and metastatic lesions. -To correlate BRCA1/2 expression with methylation status of BRCA1/2 promoter and efficacy parameters.;Primary end point(s): Objective Response Rate (ORR) defined as Complete Response (CR) plus Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.;Timepoint(s) of evaluation of this end point: Twelve evaluable patients will be analyzed in a first stage, and if at least 4 patients of them have tumour response, additional patients will be recruited to get a total of 31 evaluable patients. This study will be considered complete following the data cut-off date and data-lock for the final analysis; the data cut-off date will be the date of last patient´s death or the date when there is sufficient data to achieve the final analysis, whichever comes first. It is estimated that the final analysis could be performed approximately 30 months after the enrolment of the first patient. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Clinical Benefit Rate (CBR), Response Duration (RD), Progression Free Survival (PFS) and Overall Survival (OS). -Adverse events defined by the NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.0. -The methylation status of BRCA 1 and 2 promoters will be measured in germline DNA from blood cells at the beginning of the study and after disease progression, or at the end of study treatment by other reason, and in paired primary and metastatic lesions. It will be analysed: 1) changes of germline methylation pre and post-treatment; 2) correlation between germline methylation status and efficacy outcome data; 3) correlation between germline and somatic methylation status and 4) correlation between primary and metastatic lesions. -mRNA levels of BRCA1 and 2 will be assessed in blood and available tumor samples. Expression data will be correlated with promoter methylation status of BRCA and outcome data.;Timepoint(s) of evaluation of this end point: This study will be considered complete following the data cut-off date and data-lock for the final analysis; the data cut-off date will be the date of last patient´s death or the date when there is sufficient data to achieve the final analysis, whichever comes first. It is estimated that the final analysis could be performed approximately 30 months after the enrolment of the first patient because, considering a median Overall Survival (OS) of 12 months, it is estimated that more than 50% of death events will have occurred at that time and OS analysis could be performed. | — |
Countries
Spain
Contacts
Public ContactClinical Operations Department
GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
Outcome results
None listed