A Phase II Clinical Trial to Analyse Olaparib Response in Patients With BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer (COMETA-Breast Study)
Overview
- Phase
- Phase 2
- Intervention
- Olaparib
- Conditions
- Advanced Breast Cancer
- Sponsor
- Spanish Breast Cancer Research Group
- Enrollment
- 11
- Locations
- 16
- Primary Endpoint
- Overall Response Rate (ORR)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is a multicenter single-arm phase II clinical trial to evaluate the efficacy and safety of olaparib in patients diagnosed of advanced triple negative breast cancer (TNBC) with methylation of BRCA1 and/or BRCA2 promoters assessed in DNA from metastatic lesions and absence of BRCA1 and 2 germline mutations.
Detailed Description
Patients must have received at least one previous regimen in the advance disease setting and must have at least one measurable lesion that can be accurately assessed according to RECIST v.1.1. Potential eligible patients will be screened to assess somatic (s) BRCA promoter methylation at an reference central laboratory. Germinal (g) BRCA mutational status will be analyzed also centrally at 'Myriad Genetics GmBh' laboratory unless the BRCA mutational status is already known based on a Myriad previous report. Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be enrolled in the study and receive olaparib. Blood and tumor samples collected from all screened patients could be used for the biomarker analysis, including the assessment of germline methylation status and gene expression levels of BRCA1/2. An early efficacy review will be performed after 12 evaluable patients are enrolled; if at least 4 of them show tumour response, additional patients will be included to complete a total of 34 patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- •(Any asterisked\* are applicable as an inclusion criteria prior to perform the BRCA methylation testing via central testing)
- •\*The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
- •Female ≥ 18 years of age on day of signing informed consent.
- •Patient with histological confirmation of breast cancer with evidence of advanced disease not amenable to resection or radiation therapy with curative intent.
- •Documented Triple Negative (TN) 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 Estrogen Receptor (ER) and Progesterone Receptor (PgR) expression) and Human Epidermal growth factor Receptor 2 (HER2) negative status (defined as IHC score 0/1+ or negative by in situ hybridization defined according to local criteria).
- •Patient must have received at least one previous regimen in the advance disease setting.
- •Absence of deleterious or suspected deleterious germline mutations in BRCA1 and BRCA
- •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.
- •Availability of a tumour tissue sample from the metastatic lesions (every effort should be done to obtain the sample after the previous therapeutic regimen for advanced disease) for central testing.
- •Documented methylation of BRCA1 and/or 2 promoters based on central testing by analysis on the most recent tumour from metastatic lesions available.
Exclusion Criteria
- •(Any asterisked\* are applicable as an inclusion criteria prior to perform the BRCA methylation testing via central testing)
- •Involvement in the planning and/or conduct of the study (applies to the sponsor and/or study site staff).
- •Previous enrolment in the present study.
- •Participation in another clinical study with an investigational product during the last 4 weeks.
- •\*Any previous treatment with a Poly Adenosine diphosphate-Ribose Polymerase (PARP) inhibitor, including olaparib.
- •\*Patients with other malignancy within the last 5 years, 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 to TN, with no evidence of disease for ≥ 5 years since they completed their adjuvant treatment.
- •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).
- •Resting ECG with corrected QT interval (QTc) \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
- •\*Concomitant use of known strong Cytochrome P3A (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.
- •\*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.
Arms & Interventions
Olaparib
Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be included in the study to receive olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
Intervention: Olaparib
Outcomes
Primary Outcomes
Overall Response Rate (ORR)
Time Frame: Through study treatment, and average of 8 weeks
ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions. Tumor response will be assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). Efficacy population is a subset of the intend to treat population that has received at least one dose of study medication and has performed at least one tumor response assessment according to RECIST v.1.1 (unless a progression, death or unacceptable toxicity is seen before the first tumor response assessment).
Secondary Outcomes
- Clinical Benefit Rate (CBR)(Through study treatment, and average of 8 weeks)
- Response Duration (RD)(Through study treatment, up to 19 months)
- Progression Free Survival (PFS)(Through study treatment, and average of 8 weeks)
- Overall Survival (OS)(Up to 14 months)
- The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment(Through study treatment, and average of 8 weeks)
- Correlation Value Between BRCA1 Methylation Status and Efficacy Outcome Data(Through study treatment, and average of 8 weeks)
- Correlation Value Between BRCA2 Methylation Status and Efficacy Outcome Data(Through study treatment, and average of 8 weeks)