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

This study aims to evaluate the efficacy of silibinin in preventing recurrence in the brain after complete resection of a brain metastasis (BM) from non-small-cell lung cancer (NSCLC) or breast cancer (BC).

Inclusion Criteria:Histologically confirmed BM from NSCLC or BC by local pathologySingle BM (maximum diameter of 3 cm) on MRI before surgeryComplete surgical resection (MRI-verified within 14 days prior randomization)pSTAT3 score in reactive astrocytes of peritumoral tissue confirmed by local or central assessmentpatient must have recovered from the effects of surgery, including post-operative infection, suture/stample removal from brain surgery and wound healing before randomization≥ 18 - 70 years of ageKarnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomizationpatient has adequate bone marrow, renal, and hepatic function ≤ 21 days prior to randomization as follows:absolute neutrophil count (ANC) ≥ 1500/mm3platelets ≥ 100000/ mm3Hemoglobin ≥ 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin ≥ 9.0 g/dl is acceptable)renal function: calculated creatinine clearance ≥ 30 ml/min by the Cockcroft-Gault formulahepatic 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 if total bilirubin is < 3 times ULNElectrocardiogram (ECG) without evidence of acute cardiac ischemia ≤ 21 days prior to randomizationFemale subject of childbearing potential (i.e. those who are not postmenopausal for at least 1 year or surgically sterile by bilateral salpingectomy, bilateral oophorectomy or hysterectomy) should practice at least one accepted method of birth control listed below during study entry, for the entire duration of the study and for at least 6 months after treatment with silibinin has ended. Male subjects should practice at least one accepted method of birth control listed below during study entry, for the entire duration of the study and for at least 6 months after treatment with silibinin has ended. If using a condom, practice at least one other method of birth control listed 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 ovulationProgesterone-only hormonal contraception (oral, intravaginal, transdermal) associated with the inhibition of ovulationBilateral tubal occlusion/ligationTrue abstinence: refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subjectA vasectomized male subject or a vasectomized partner of a female subjectIntrauterine device, IUD (females)Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream) unless not deemed acceptable as highly effective contraception by local regulationsWomen of child-bearing potential must have a negative pregnancy test (urine o serum) within 7 days prior the randomizationMust voluntarily sign and date informed consent form, for both tumor tissue biomarker testing and study participation, approved by an Independent Ethic Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific proceduresExclusion Criteria:Absence of expression of STAT3 on the reactive astrocytes of brain metastasesIncomplete surgical resection and/or diameters > 3 centimeters of brain metastasis before surgeryBrain metastases that previously received any type of radiation therapyProgressive systemic disease requiring a change of the antineoplastic therapyPrior invasive malignancy (except for non-melanomatous skin cancer, oral cavity, or cervix) unless disease free for ≥ 2 yearsPrior, concomitant, or planned treatment with experimental agentsPatients has had major immunologic reactionPatient has had a history of hypersensitivity to silibinin or excipientPatient is unsuitable to receive steroidsPatient is a lactating or pregnant femaleSevere, 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 be eligible for treatmentUnstable angina and/or congestive heart failure within the last 6 monthsTransmural myocardial infarction within the last 6 monthsEvidence of recent myocardial infarction or ischemia by the findings of S-T elevations ≥ 2 mm using the analysis of an EKG performed within 21 days prior to enrollmentNew York Heart Association grade2 or greater congestive heart failure requiring hospitalization within 12 months prior to enrollmentHistory of stroke, cerebral vascular accident or transient ischemic attack within 6 monthsSerious and inadequately controlled cardiac arrhythmiaAcute bacterial or fungal infection requiring intravenous antibiotics at the time of enrollmentChronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of enrollmentSubject with clinically defined Acquired Immune-Deficiency Syndrome (AIDS)-defining illness. This is necessary to ensure subjects are likely to be able to receive silibinin plus standard of care according to the systemic diseaseActive connective tissue disorders, such as lupus or scleroderma, that in the opinion of the Investigator may put the subject at high risk of toxicityAny other major medical illnesses or psychiatric impairments that in the Investigator's opinion will prevent administrations or completion of protocol therapyPatient treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study except intra-operative therapy to guide resection or experimental imaging without therapeutic intentInability to undergo contrast-enhanced MRI scans