Pembrolizumab in Combination With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancer
- Conditions
- Breast Cancer
- Registration Number
- NCT03025035
- Lead Sponsor
- Yuan Yuan
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- Not specified
Inclusion Criteria:<br><br> - Be willing and able to provide written informed consent/assent for the trial<br><br> - Be =18 years of age on day of signing informed consent<br><br> - Advanced BRCA-mutated and/or HDR-defect breast cancer progressing on or after prior<br> therapy for metastatic disease or locally advanced disease; Prior therapy is defined<br> as follows: for triple negative breast cancer - progressing after at least 1 line of<br> any prior chemotherapy; for HER2 positive disease must have progressed after at<br> least two HER2 directed therapies in the metastatic setting including<br> ado-trastuzumab emtansine (T-DM1); for hormone receptor positive disease (ER, PR, or<br> both) must have progressed after a CDK4/CDK6 inhibitor plus hormonal therapy.<br> Patients with progression within 12 months from previous neoadjuvant or adjuvant<br> treatment could be enrolled in the study as 1st line therapy in metastatic setting.<br><br> - Measurable disease by RECIST 1.1, with at least one lesion, not previously<br> irradiated, that can be accurately measured at baseline as = 10 mm in the longest<br> diameter (except lymph nodes which must have short axis = 15 mm) with computed<br> tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for<br> accurate repeated measurements. Patients with non-measurable bone metastases in<br> addition to measurable disease are eligible; however patients with non-measurable<br> bone disease as the only site(s) of disease are not eligible.<br><br> - ECOG 0 or 1<br><br> - Documented BRCA deleterious germline or somatic mutation and/or HDR-defect.<br><br> - FFPE tumor tissue available for analysis<br><br> - Adequate organ function<br><br> - Female subjects: Postmenopausal or evidence of non-childbearing status for women of<br> childbearing potential: negative urine or serum pregnancy test within 28 days of<br> study treatment and confirmed prior to treatment on day 1. Postmenopausal is defined<br> as:<br><br> 1. Amenorrheic for 1 year or more following cessation of exogenous hormonal<br> treatments Luteinizing hormone (LH) and Follicle stimulating hormone (FSH)<br> levels in the post menopausal range for women under 50<br><br> 2. radiation-induced oophorectomy with last menses >1 year ago<br><br> 3. chemotherapy-induced menopause with >1 year interval since last menses<br><br> 4. surgical sterilization (bilateral oophorectomy or hysterectomy)<br><br> - Women of childbearing potential and their partners, who are sexually active, must<br> agree to the use of TWO highly effective forms of contraception in combination. This<br> should be started from the signing of the informed consent and continue throughout<br> the period of taking study treatment and for at least 1 month after last dose of<br> study drug(s), or they must totally/truly abstain from any form of sexual<br> intercourse.<br><br> - Male patients must use a condom during treatment and for 3 months after the last<br> dose of olaparib when having sexual intercourse with a pregnant woman or with a<br> woman of childbearing potential. Female partners of male patients should also use a<br> highly effective form of contraception if they are of childbearing potential<br><br> - Patients must have a life expectancy = 16 weeks<br><br>Exclusion Criteria:<br><br> - Is currently participating or has participated in a study of investigational agent<br> or using an investigational device with 30 days of the first dose of pembrolizumab.<br><br> 1. Has had prior chemotherapy, targeted small molecule therapy, or radiation<br> therapy within 3 weeks prior to study Day 1.<br><br> 2. Subjects must have recovered (i.e., = Grade 1 or at baseline) from any adverse<br> events due to a previously administered agent. Subjects with = Grade 2<br> neuropathy are an exception to this criterion and may qualify for the study.<br><br> 3. If subject received major surgery, they must have recovered adequately from the<br> toxicity and/or complications from the intervention prior to starting therapy.<br><br> - Is receiving systemic steroid therapy within three days prior to the first dose of<br> pembrolizumab or receiving any other form of immunosuppressive medication<br><br> - Is expected to require any other form of systemic or localized antineoplastic<br> therapy while on trial.<br><br> 1. Subjects with ER+/PR+ disease may be given endocrine therapy.<br><br> 2. Subjects with HER2+ disease will be required to discontinue trastuzumab<br> (Herceptin).<br><br> - Has participated in another MK03475 trial.<br><br> a. Note: Patients with or without prior PARP-inhibitor exposure may be included.<br><br> - Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,<br> clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,<br> saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.<br> ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required<br> washout period prior to starting olaparib is 2 weeks.<br><br> - Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,<br> rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or<br> moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout<br> period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3<br> weeks for other agents.<br><br> - Major surgery within 2 weeks of starting study treatment and patients must have<br> recovered from any effects of any major surgery.<br><br> - Has known hypersensitivity to pembrolizumab or any of its excipients<br><br> - Has a known additional malignancy that is progressing or requires active treatment.<br> Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the<br> skin, or in situ cervical cancer that has undergone potentially curative therapy.<br><br> - Has known history of prior malignancy except if the patient has undergone<br> potentially curative therapy with no evidence of that disease recurrence for 5 years<br> since initiation of that therapy.<br><br> - Has known active central nervous system (CNS) metastases and/or carcinomatous<br> meningitis. Subjects with previously treated brain metastases may participate<br> provided they are stable (without evidence of progression by MRI for at least four<br> weeks prior to the first dose of pembrolizumab and any neurologic symptoms have<br> returned to baseline), have no evidence of new or enlarging brain metastases, and<br> are using no steroids for at least three days prior to study medication.<br><br> - Has evidence of interstitial lung disease or active, non-infectious pneumonitis<br><br> - Has active tuberculosis<br><br> - Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as<br> judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic<br> arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte<br> disturbances, etc.), or patients with congenital long QT syndrome.<br><br> - Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade<br> 2) caused by previous cancer therapy, excluding alopecia.<br><br> - Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features<br> suggestive of MDS/AML.<br><br> - Patients unable to swallow orally administered medication and patients with<br> gastrointestinal
Not provided
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Overall response rate (ORR) per RECIST1.1
- Secondary Outcome Measures
Name Time Method Progression free survival (PFS), per RECIST 1.1;Overall survival (OS);Clinical Benefit Rate (CBR = CR+PR+SD) per RECIST 1.1;Duration of Response (DOR) for Complete Response (CR) and Partial Response (PR) per RECIST 1.1