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
The accrual goal will be a total of 20 patients
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
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
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
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
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
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
26. Previous allogenic bone marrow transplant or double umbilical cord blood
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.