Olaparib+Trastuzumab in HER2[+] Breast Cancer Susceptibility Gene (BRCA) Mutated Advanced Breast Cancer

  • End date
    Sep 27, 2022
  • participants needed
  • sponsor
Updated on 27 January 2021
ct scan
platelet count
measurable disease
liver metastasis
blood transfusion
ovarian suppression
urine test


This is a multicenter, open-label, single-arm, phase II clinical trial, phase II trial will evaluate the efficacy and safety of olaparib plus trastuzumab in patients with HER2[+], BRCA-mutated advanced breast cancer


This open-label, multicenter, single arm, two cohorts, Simon's Two-Stage minimax design, phase II clinical trial will assess the efficacy of olaparib in combination with trastuzumab in patients with HER2-positive ABC with gene alterations in HRR DNA pathway. To be included in the cohort A of the study, patients must exhibit germinal deleterious mutations in BRCA1 or BRCA2 genes.

Eligible patients will have histologically proven diagnosis of adenocarcinoma of the breast with evidence of advanced disease, and at least one measurable disease as per RECIST v.1.1. Patients will have a documented history of progression on HER2-directed therapy for the treatment of HER2-positive breast cancer with not limits on prior therapies of chemotherapy and/or trastuzumab-lapatinib in advanced scenario, and at least one regimen of chemotherapy including trastuzumab.

The accrual goal will be a total of 20 patients

Condition Advanced Breast Cancer
Treatment Olaparib [Lynparza®] plus Trastuzumab [Herceptin®]
Clinical Study IdentifierNCT03931551
Last Modified on27 January 2021


Yes No Not Sure

Inclusion Criteria

Provision of informed consent prior to any study specific procedures
Obtention and signing of the molecular preselection consent regarding the mutational BRCA status confirmation prior to provision of the informed consent
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
Male or female 18 years of age at the time of signing the Informed Consent Form (ICF)
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) May 2018 criteria
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
Criteria of resistance to trastuzumab defined as
Relapse on (neo) adjuvant treatment or within 6 months from completion, or
Progression on a trastuzumab regimen for advanced disease. No limitations on the number of prior trastuzumab regimens
At least one prior systemic regimen for advanced disease including a pertuzumab or T-DM1 based regimen. No limitations on the number of prior systemic regimens
Eastern Cooperative Oncology Group (ECOG) performance status score 1
Life expectancy greater or equal to 16 weeks
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
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
creatinine (mg/dL) x 72a where F=0.85 for females and F=1 for males
exploratory studies and has agreed to participate and signed the ICF prior to
participation in any study-related activities
Postmenopausal status is defined as either
Prior bilateral oophorectomy; Or
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
Age > 60 years; Or Age < 60 years and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, and Follicle-stimulating hormone (FSH) and estradiol in postmenopausal range; Or Age < 60 years and taking tamoxifen or toremifene and FSH and plasma estradiol level in postmenopausal ranges; Or Radiation-induced castration with >1-year interval since last menses. Premenopausal status is defined as all those women who do not meet any of above criteria
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
\. Patients have been informed about the nature of study, including the
\. Males, postmenopausal and premenopausal women. Premenopausal women of
childbearing potential (not undergoing to tubal ligation or hysterectomy) must
have a negative blood or urine pregnancy test within 28 days prior to the
start of study treatment and confirmed on Day 1 prior to commencing treatment
\. Snap frozen or formalin fixed paraffin-embedded (FFPE) tumor sample is
Note: Documented hysterectomy must be confirmed with medical records of the
mandatory for exploratory central testing
actual procedure or confirmed by an ultrasound. Tubal ligation must be
\. Patients must fulfil the relative field on the informed consent for
confirmed with medical records of the actual procedure, otherwise the patient
donating blood samples and serial biopsies at baseline and on disease
must be willing to use 2 highly effective forms of contraception in
progression for the exploratory biomarker studies
combination male condom plus an acceptable hormonal or non-hormonal method)
throughout the study. Information must be captured appropriately within the
site's source documents. Correct forms of contraception for males and females
are detailed in Appendix 5: Acceptable birth control methods
\. Patients is willing and able to comply with the protocol for the duration
of the study including undergoing treatment and scheduled visits and

Exclusion Criteria

Patients that have previously received any poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) for any reason, including olaparib
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
Concomitant use of known strong Cytochrome P450 (CYP)3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
Persistent toxicities (Common Terminology Criteria for Adverse Events (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia
Patients with Myelodysplastic syndrome (MDS) / Acute myeloid leukemia (AML) or with features suggestive of MDS/AML
Patients considered a high medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution CT scan or any psychiatric disorder that prohibits obtaining informed consent
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]
Involvement in the planning and/or conduct of the study (applies to both Sponsor's staff and/or staff at the study site)
Patients currently receiving anti-coagulant therapy (low molecular weight heparin and warfarin with careful monitoring of patients are permitted), or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed)
Patients simultaneously enrolled in any interventional clinical trial
Patients who have received any systemic chemotherapy during the last 3 weeks prior initiating protocol therapy
Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
Female patients who are pregnant or breastfeeding, or adults of reproductive
potential who are not using effective birth control methods
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)
Patients unwilling to or unable to comply with the protocol for the duration
Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
of the study including undergoing treatment and scheduled visits and
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
Immunocompromised patients (e.g., patients who are known to be serologically positive for human immunodeficiency virus and those with undetectable viral load)
Patients with a known hypersensitivity to olaparib or trastuzumab or any of the excipients of the products
Left ventricular ejection fraction below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO)
Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment
Patients with pulmonary disease requiring continuous oxygen therapy
Previous history of bleeding diathesis
Patients with known active hepatitis (i.e. Hepatitis B or C)
Patients with moderate or severe hepatic impairment
Chronic daily treatment with corticosteroids with a dose of 10 mg/day methylprednisolone equivalent (excluding inhaled steroids), except for prophylaxis use
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation
Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment and in a dose < 10 mg/day methylprednisolone equivalent. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
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