SILibinin in NSCLC and BC Patients With Single Brain METastasis (SILMET)

Inclusion Criteria:

• Histologically confirmed BM from NSCLC or BC by local pathology
• Single BM (maximum diameter of 3 cm) on MRI before surgery
• Complete surgical resection (MRI-verified within 14 days prior randomization)
• pSTAT3 score in reactive astrocytes of peritumoral tissue confirmed by local orcentral assessment
• patient must have recovered from the effects of surgery, including post-operativeinfection, suture/stample removal from brain surgery and wound healing beforerandomization
• ≥ 18 - 70 years of age
• Karnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomization
• patient has adequate bone marrow, renal, and hepatic function ≤ 21 days prior torandomization as follows:

1. absolute neutrophil count (ANC) ≥ 1500/mm3
2. platelets ≥ 100000/ mm3
3. Hemoglobin ≥ 9.0 g/dl (Note: the use of transfusion or other intervention toachieve hemoglobin ≥ 9.0 g/dl is acceptable)
4. renal function: calculated creatinine clearance ≥ 30 ml/min by theCockcroft-Gault formula
5. hepatic function: total bilirubin ≤ 1.5 times upper limit of normal (ULN),aspartate aminotransferase (AST), and alanine transferase (ALT) ≤ 3 times ULN.Subjects with Gilbert's syndrome documented in medical history may be enrolled iftotal bilirubin is < 3 times ULN

• Electrocardiogram (ECG) without evidence of acute cardiac ischemia ≤ 21 days prior torandomization
• Female subject of childbearing potential (i.e. those who are not postmenopausal for atleast 1 year or surgically sterile by bilateral salpingectomy, bilateral oophorectomyor hysterectomy) should practice at least one accepted method of birth control listedbelow during study entry, for the entire duration of the study and for at least 6months after treatment with silibinin has ended. Male subjects should practice atleast one accepted method of birth control listed below during study entry, for theentire duration of the study and for at least 6 months after treatment with silibininhas ended. If using a condom, practice at least one other method of birth controllisted below during the study for at least 6 months after silibinin treatment:
• Combined (estrogen and progesterone contained) hormonal contraception (oral,intravaginal, transdermal) associated with the inhibition of ovulation
• Progesterone-only hormonal contraception (oral, intravaginal, transdermal)associated with the inhibition of ovulation
• Bilateral tubal occlusion/ligation
• True abstinence: refraining from heterosexual intercourse when this is in linewith the preferred and usual lifestyle of the subject
• A vasectomized male subject or a vasectomized partner of a female subject
• Intrauterine device, IUD (females)
• Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ringwith spermicidal jellies or cream) unless not deemed acceptable as highlyeffective contraception by local regulations
• Women of child-bearing potential must have a negative pregnancy test (urine o serum)within 7 days prior the randomization
• Must voluntarily sign and date informed consent form, for both tumor tissue biomarkertesting and study participation, approved by an Independent Ethic Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening orstudy-specific procedures

Exclusion Criteria:

• Absence of expression of STAT3 on the reactive astrocytes of brain metastases
• Incomplete surgical resection and/or diameters > 3 centimeters of brain metastasisbefore surgery
• Brain metastases that previously received any type of radiation therapy
• Progressive systemic disease requiring a change of the antineoplastic therapy
• Prior invasive malignancy (except for non-melanomatous skin cancer, oral cavity, orcervix) unless disease free for ≥ 2 years
• Prior, concomitant, or planned treatment with experimental agents
• Patients has had major immunologic reaction
• Patient has had a history of hypersensitivity to silibinin or excipient
• Patient is unsuitable to receive steroids
• Patient is a lactating or pregnant female
• Severe, active co-morbidity, defined as follows:
• Severe hepatic impairment (Child-Pugh C or higher [score of 10 or higher]);subject with mild or moderate hepatic impairment (Child-Pugh score of 5-9) may beeligible for treatment
• Unstable angina and/or congestive heart failure within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Evidence of recent myocardial infarction or ischemia by the findings of S-Televations ≥ 2 mm using the analysis of an EKG performed within 21 days prior toenrollment
• New York Heart Association grade2 or greater congestive heart failure requiringhospitalization within 12 months prior to enrollment
• History of stroke, cerebral vascular accident or transient ischemic attack within 6 months
• Serious and inadequately controlled cardiac arrhythmia
• Acute bacterial or fungal infection requiring intravenous antibiotics at the timeof enrollment
• Chronic obstructive pulmonary disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy at the time of enrollment
• Subject with clinically defined Acquired Immune-Deficiency Syndrome (AIDS)-defining illness. This is necessary to ensure subjects are likely to beable to receive silibinin plus standard of care according to the systemic disease
• Active connective tissue disorders, such as lupus or scleroderma, that in theopinion of the Investigator may put the subject at high risk of toxicity
• Any other major medical illnesses or psychiatric impairments that in theInvestigator's opinion will prevent administrations or completion of protocoltherapy
• Patient treated on any other therapeutic clinical protocols within 30 days prior tostudy entry or during participation in the study except intra-operative therapy toguide resection or experimental imaging without therapeutic intent
• Inability to undergo contrast-enhanced MRI scans