This multicenter, single-arm, two-cohort, Simon's two-stage minimax design, phase II trial
will evaluate the efficacy and safety of olaparib plus trastuzumab in patients with HER2[+],
BRCA-mutated or wild-type BRCA/HRD 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. In the second stage of the study, patients must show wild-type germinal
BRCA1/2 genes with HRD positive status based on HRDetect test, in order to be included in the
exploratory cohort B.
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 more than three prior regimens of
chemotherapy and/or trastuzumab-lapatinib in advanced scenario, and at least one regimen of
chemotherapy including trastuzumab.
Patients will be accrued in a Simon's Two-Stage minimax design. The accrual goal will be a
total of 20 patients: 7 patients in the first stage and 13 patients in the second stage.
Additionally, in the second stage, the investigators will accrual 13 patients on the
exploratory cohort B.
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 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
HER2-positive breast cancer according to the ASCO/CAP 2013 criteria.
Note: tissue (slides or blocks) must be available for HER2 confirmation by local
5. [Cohort A]: Patients with documented germinal mutation in BRCA1 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
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
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 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 72 a 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 signed the Informed Consent Form (ICF) prior
to participation in any study-related activities.
12. 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:
f) Prior bilateral oophorectomy; Or g) Age > 60 years; Or h) Age < 60 years and
amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene
or ovarian suppression, and Folliclestimulating hormone (FSH) and estradiol in
postmenopausal range; Or i) Age < 60 years and taking tamoxifen or toremifene and
FSH and plasma estradiol level in postmenopausal ranges; Or j) 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
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.
13. Patients is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations.
14. [Cohort A] Snap frozen or formalin fixed paraffin-embedded (FFPE) tumor sample is
mandatory for exploratory central testing.
[Exploratory cohort B] For inclusion in the exploratory cohort B, snap frozen or FFPE
metastatic tissue since the last progression is mandatory for testing HRD status. As
alternative, an archived tumor sample will be used.
15. Patients of both cohorts 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.
1. Patients that have previously received any 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 (applies to both Sponsor's
staff and/or staff at the study site).
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 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.
10. Patients with symptomatic visceral disease are not eligible.
11. Concomitant use of known strong CYP3A 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.
12. 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.
13. Persistent toxicities (CTCAE grade 2) caused by previous cancer therapy, excluding
14. Patients with MDS / 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, nonmalignant 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.
18. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
19. Immunocompromised patients (e.g., patients who are known to be serologically positive
for human immunodeficiency virus and those with undetectable viral load).
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. Left ventricular ejection fraction below 55% as determined by multiple-gated
acquisition (MUGA) scan or echocardiography (ECHO).
23. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite
adequate antihypertensive treatment.
24. 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).
25. Patients with pulmonary disease requiring continuous oxygen therapy.
26. Previous history of bleeding diathesis.
27. Patients with known active hepatitis (i.e. Hepatitis B or C).
28. Patients with moderate or severe hepatic impairment.
29. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day
methylprednisolone equivalent (excluding inhaled steroids), except for prophylaxis
30. Previous allogenic bone marrow transplant or double umbilical cord blood
31. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable, if received in the past 35 days
prior to starting study treatment).
32. 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.
33. Female patients who are pregnant or breastfeeding, or adults of reproductive potential
who are not using effective birth control methods.
34. Patients unwilling to or unable to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations.