HER2-positive BRCAmutated or Homologous Recombination Deficiency (HRD) advanced breast cancer MedDRA version: 20.0 Level: LLT Classification code 10072737 Term: Advanced breast cancer System Organ Class: 100000004864
Conditions
Interventions
Trade Name: LYNPARZA
Pharmaceutical Form: Tablet
INN or Proposed INN: Olaparib
CAS Number: 763113-22-0
Current Sponsor code: AZD2281
Sponsors
Medica Scientia Innovation Research (MedSIR)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provision of informed consent prior to any study specific procedures. 2. Male or female =18 years of age at the time of signing the Informed Consent Form (ICF). 3. Histologically and/or cytologically confirmed breast cancer with evidence of advanced disease (locoregionally recurrent or metastatic) not amenable to resection or radiation therapy with curative intent. 4. Patients with histologically and/or cytologically locally confirmed diagnosis of Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 criteria. 5. [Cohort A]: Patients with documented germinal mutation in Breast Cancer (BRCA)1 or BRCA2 genes that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Patients with germinal BRCA1/2 mutations that are considered to be non-detrimental (e.g., “Variants of uncertain clinical significance” or “Variant of unknown significance” or “Variant, favor polymorphism” or “benign polymorphism,” etc.) will not be eligible for the study. Patients with known germinal BRCA status prior to enrollment are considered eligible to participate.[Exploratory cohort B]: Patients with wild-type germinal BRCA1/2 genes with Homologous Recombination Deficiency (HRD)-positive status based on HRDetect test. 6. History of progression on HER2-directed therapy for the treatment of HER2-positive breast cancer with not more than three prior regimens of chemotherapy and/or trastuzumab-lapatinib in advanced scenario, and at least one regimen of chemotherapy including trastuzumab. 7. Eastern Cooperative Oncology Group (ECOG) performance status score = 1. 8. Life expectancy greater or equal to 16 weeks. 9. Patients must have evaluable or measurable disease by Computed Tomography (CT) scan or Magnetic resonance imaging (MRI), according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. 10. Patients must have normal organ and bone marrow function within 35 days prior to administration of study treatment as defined below: • Hematological: White blood cell (WBC) count >3.0 x 109/L, absolute neutrophil count (ANC) =1.5 x 109/L, platelet count =100.0 x109/L, and hemoglobin = 10 g/dL with no blood transfusions (packed red blood cells and platelet transfusions in the past 35 days are permitted). • Hepatic: bilirubin = 1.5 times the upper limit of normal (x ULN) (=2.0 in patients with known Gilberts syndrome) or direct bilirubin = 1 x ULN; alkaline phosphatase (ALP), Aspartate aminotransferase (AST) / Serum Glutamic Oxaloacetic Transaminase (SGOT), and Alanine aminotransferase (ALT) / Serum Glutamic Pyruvate Transaminase (SGPT) = 2.5 x institutional ULN unless liver metastases are present, in which case they must be = 5 x ULN. • Renal: Serum creatinine = 1.5 x ULN or based on a 24-hour urine test or estimated creatinine clearance = 51 mL/min using the Cockcroft-Gault equation: Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72a where F=0.85 for females and F=1 for males. 11. Patients have been informed about the nature of study, including the exploratory studies and has agreed to participate and si
Exclusion criteria
Exclusion criteria: 1.Patients that have previously received any poly(ADP-ribose) polymerase (PARP)inhibitor (PARPi)for any reason,including olaparib 2.Previous treatment with carboplatin or other platinum containing compounds in the last 12 months prior to entry to the study 3.Patients who have not received any previous chemotherapy in the advanced setting 4.Involvement in the planning and/or conduct of the study 5.Previous enrolment in the present study 6.Patients simultaneously enrolled in any interventional clinical trial 7.Patients who have received any systemic chemotherapy during the last 3 weeks prior initiating protocol therapy 8.Patients who have had radiation therapy encompassing>20%of the bone marrow within 3 weeks prior to start of treatment,excepting for palliative radiation therapy to a small field>1-week prior to Day 1 of study 9.Resting ECG indicating uncontrolled,potentially reversible cardiac conditions,as judged by the investigator or patients with congenital long QT syndrome 10.Patients with symptomatic visceral disease are not eligible 11.Concomitant use of known strong Cytochrome P450 (CYP)3A inhibitors or moderate CYP3A inhibitors.The required washout period prior to starting olaparib is 2 weeks 12.Concomitant use of known strong or moderate CYP3A inducers.The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents 13.Persistent toxicities CTCAE grade 2)caused by previous cancer therapy,excluding alopecia 14.Patients with Myelodysplastic syndrome(MDS)/Acute myeloid leukemia(AML)or with features suggestive of MDS/AML 15.Patients having diagnosis,detection,or treatment of another type of cancer during the last 5 years prior to initiating protocol therapy(except adequately treated non-melanoma skin cancer,curatively treated in situ cancer of the cervix,definitively treated ductal carcinoma in situ,stage 1,grade 1 endometrial carcinoma),or other solid tumors including lymphomas(without bone marrow involvement)curatively treated with no evidence of disease for =5 years) 16.Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery 17.Patients considered a high medical risk due to a serious,uncontrolled medical disorder,non-malignant systemic disease or active,uncontrolled infection 18.Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication 19.Immunocompromised patients 20.Patients with a known hypersensitivity to olaparib or trastuzumab or any of the excipients of the products 21.Clinically significant cardiovascular disease(stroke, unstable angina pectoris,or documented myocardial infarction)within 6 months prior to study entry;history of documented congestive heart failure(New York Heart Association II-III-IV);symptomatic pericarditis;documented cardiomyopathy;ventricular arrhythmias with the exception of benign premature ventricular contractions;conduction abnormality requiring a pacemaker;other arrhythmias not controlled with medication 22.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the efficacy – as determined by the Overall Response Rate (ORR) and Progression-free Survival (PFS) based on RECIST v.1.1 – of olaparib in combination with trastuzumab in patients with HER2-positive, germinal BRCA1/2 mutated ABC. ; Secondary Objective: • To assess the efficacy – as determined by the Clinical benefit rate (CBR) – of olaparib in combination with trastuzumab based on RECIST v.1.1. • To determine the Duration of Response (DoR) based on RECIST v.1.1. • To evaluate the tumor burden based on RECIST v.1.1. • To assess the Overall Survival (OS) (OS will be collected at the end of the study) based on RECIST v.1.1. • To determine the treatment discontinuation and dose reduction rates due to adverse events (AEs), based on NCI CTCAE version 5.0. • To assess the ORR in patients with wild-type germinal BRCA/HRDpositive cohort B based on RECIST v.1.1. • To assess the PFS in patients with wild-type germinal BRCA/HRDpositive cohort B based on RECIST v.1.1. • To assess the safety and tolerability of olaparib in combination with trastuzumab. • To evaluate the health-related quality of life (HRQoL) patient reported outcomes (PRO). ; Primary end point(s): • ORR in germinal BRCA-mutated cohort A, defined as the number of patients with CR or PR divided by the number of patients in the analysis population, as assessed by the Investigator per RECIST v.1.1. • PFS in germinal BRCA-mutated cohort A, defined as the period of time from the date of study treatment initiation to the date of the first documentation of objective progressive disease (PD) or death due to any cause in absence of documented PD, as assessed by the Investigator according to RECIST v.1.1. ;Timepoint(s) of evaluation of this end point: Since s | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • CBR as best response, defined as the percentage of patients who experience a CR, PR or SD for at least 24 weeks and assessed by the Investigator per RECIST v.1.1. • DoR, defined as the time from documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first, as assessed by the Investigator per RECIST v.1.1. • Tumor burden, defined as the percentage of tumor shrinkage from baseline (obtained from the sum of the largest diameters of the target lesions) as assessed by the Investigator per RECIST v.1.1. • OS, defined as the time from date of initiation to date of death due to any cause, as assessed by the Investigator per RECIST v.1.1. • Discontinuation and dose reduction rates due to AEs - defined as the percentage of patients who discontinue treatment or reduce its dose because experience a clinical AE, respectively - will be evaluated using the NCI CTCAE version 5.0. • ORR in in wild-type germinal BRCA/HRD-positive cohort B, defined as the number of patients with CR or PR divided by the number of patients in the analysis population, as assessed by the Investigator per RECIST v.1.1. • PFS in in wild-type germinal BRCA/HRD-positive cohort B, defined as the period of time from the date of study treatment initiation to the date of the first documentation of objective PD or death due to any cause in absence of documented PD, as assessed by the Investigator according to RECIST v.1.1. • Safety profile and AEs will be evaluated using the NCI CTCAE version 5.0. Grade 3 and 4 AEs and SAEs will be assessed to determine the safety and tolerability of olaparib in combination with trastuzumab. • HRQoL PRO measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, the breast | — |
Countries
Spain
Contacts
Public ContactEnsayos clínicos
Medica Scientia Innovation Research (MedSIR)
Outcome results
None listed