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

 1. Obtention and signing of the molecular preselection consent regarding the mutational
 BRCA status confirmation prior to provision of the informed consent.

 2. Provision of informed consent prior to any study specific procedures.

 3. Male or female ≥18 years of age at the time of signing the Informed Consent Form
 (ICF).

 4. 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.

 5. 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.

 6. 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.

 7. 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.

 8. 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.

 9. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 1.

 10. Life expectancy greater or equal to 16 weeks.

 11. 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.

 12. 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

 -  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.

 13. Patients have been informed about the nature of study, including the exploratory
 studies and has agreed to participate and signed the ICF prior to participation in any
 study-related activities.

 14. 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

 -  Postmenopausal status is defined as either:

 -  Prior bilateral oophorectomy; Or

 -  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.

 Note: Documented hysterectomy must be confirmed with medical records of the actual
 procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical
 records of the actual procedure, otherwise the patient must be willing to use 2 highly
 effective forms of contraception in 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.

 15. Patients is willing and able to comply with the protocol for the duration of the study
 including undergoing treatment and scheduled visits and examinations.

 16. Snap frozen or formalin fixed paraffin-embedded (FFPE) tumor sample is mandatory for
 exploratory central testing.

 17. Patients must fulfil the relative field on the informed consent for donating blood
 samples and serial biopsies at baseline and on disease progression for the exploratory
 biomarker studies.

 Exclusion Criteria:

 1. Patients that have previously received any poly(ADP-ribose) polymerase (PARP)
 inhibitor (PARPi) for any reason, including olaparib.

 2. Involvement in the planning and/or conduct of the study (applies to both Sponsor's
 staff and/or staff at the study site).

 3. Patients simultaneously enrolled in any interventional clinical trial.

 4. Patients who have received any systemic chemotherapy during the last 3 weeks prior
 initiating protocol therapy.

 5. 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.

 6. 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.

 7. 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.

 8. 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.

 9. Persistent toxicities (Common Terminology Criteria for Adverse Events (CTCAE) grade 2)
 caused by previous cancer therapy, excluding alopecia.

 10. Patients with Myelodysplastic syndrome (MDS) / Acute myeloid leukemia (AML) or with
 features suggestive of MDS/AML.

 11. 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).

 12. Major surgery within 2 weeks of starting study treatment and patients must have
 recovered from any effects of any major surgery.

 13. 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.

 14. Patients unable to swallow orally administered medication and patients with
 gastrointestinal disorders likely to interfere with absorption of the study
 medication.

 15. Immunocompromised patients (e.g., patients who are known to be serologically positive
 for human immunodeficiency virus and those with undetectable viral load).

 16. Patients with a known hypersensitivity to olaparib or trastuzumab or any of the
 excipients of the products.

 17. 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].

 18. Left ventricular ejection fraction below 55% as determined by multiple-gated
 acquisition (MUGA) scan or echocardiography (ECHO).

 19. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite
 adequate antihypertensive treatment.

 20. 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).

 21. Patients with pulmonary disease requiring continuous oxygen therapy.

 22. Previous history of bleeding diathesis.

 23. Patients with known active hepatitis (i.e. Hepatitis B or C).

 24. Patients with moderate or severe hepatic impairment.

 25. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day
 methylprednisolone equivalent (excluding inhaled steroids), except for prophylaxis
 use.

 26. Previous allogenic bone marrow transplant or double umbilical cord blood
 transplantation.

 27. 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.

 Female patients who are pregnant or breastfeeding, or adults of reproductive potential who
 are not using effective birth control methods.

 Patients unwilling to or unable to comply with the protocol for the duration of the study
 including undergoing treatment and scheduled visits and examinations.