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

December 10, 2023 updated by: Alessia Pellerino, Azienda Ospedaliera Città della Salute e della Scienza di Torino

A Phase 2 Randomized, Multicenter Trial on Silibinin To Prevent Intracranial Recurrence After Gross-Total Resection of Single Brain Metastasis From Non-Small Cell Lung Cancer or Breast Cancer

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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is the first placebo-controlled study evaluating the efficacy of silibinin as STAT3 inhibitor in preventing recurrence in the brain after gross-total resection of a brain metastasis (BM) from non-small-cell lung cancer (NSCLC) or breast cancer (BC).

Participants will be randomized 1:1 to silibinin 1 g/day taken orally in comparison with oral placebo 1 g/day. A contrast-enhanced brain MRI will be performed every 8 weeks to evaluate intracranial local and distance recurrence

Study Type

Interventional

Enrollment (Estimated)

70

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Genova, Italy
        • Not yet recruiting
        • Unità Operativa di Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino di Genova
        • Contact:
      • Messina, Italy
        • Recruiting
        • Neurosurgery Unit, Department of Biomedical, Dental Science and Morphological and Functional Images, University of Messina
        • Contact:
          • Filippo Flavio Angileri
        • Sub-Investigator:
          • Maria Caffo
      • Rome, Italy
        • Not yet recruiting
        • Institute of Neurosurgery, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, Catholic University
        • Contact:
          • Alessandro Olivi
      • Rome, Italy
        • Not yet recruiting
        • Neuro-Oncology Unit, IRCCS Regina Elena National Cancer Institute
        • Contact:
          • Andrea Pace
      • Rome, Italy
        • Not yet recruiting
        • Precision Medicine in Breast Cancer Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
        • Contact:
          • Alessandra Fabi
      • Turin, Italy, 10126

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 or central assessment
  • patient 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 age
  • Karnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomization

  • patient has adequate bone marrow, renal, and hepatic function ≤ 21 days prior to randomization 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 to achieve hemoglobin ≥ 9.0 g/dl is acceptable)
    4. renal function: calculated creatinine clearance ≥ 30 ml/min by the Cockcroft-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 if total bilirubin is < 3 times ULN
  • Electrocardiogram (ECG) without evidence of acute cardiac ischemia ≤ 21 days prior to randomization

  • Female 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 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 line with 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 ring with spermicidal jellies or cream) unless not deemed acceptable as highly effective 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 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 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 metastasis before 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, or cervix) 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 be eligible 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-T elevations ≥ 2 mm using the analysis of an EKG performed within 21 days prior to enrollment
    • New York Heart Association grade2 or greater congestive heart failure requiring hospitalization 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 time of enrollment
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring 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 be able to receive silibinin plus standard of care according to the systemic disease
    • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the Investigator may put the subject at high risk of toxicity
    • Any other major medical illnesses or psychiatric impairments that in the Investigator's opinion will prevent administrations or completion of protocol therapy
  • Patient 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 intent
  • Inability to undergo contrast-enhanced MRI scans

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Silibinin
Silibinin (STAT3 inhibitor) 1 g/day taken orally every day
Dietary supplement: Silibinin
Silibinin 1 g/day taken orally plus standard systemic therapy for NSCLC or BC
Other Names:
  • Sillbrain
Placebo Comparator: Placebo
Placebo 1 g/day taken orally every day
Other: Placebo
Placebo 1 g/day taken orally plus standard systemic therapy for NSCLC or BC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
intracranial local recurrence
Time Frame: up to 12-24 months
to investigate whether silibinin delay the intracranial local recurrence in comparison to placebo
up to 12-24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
intracranial distant recurrence
Time Frame: up to 12-24 months
to investigate whether silibinin delay or avoid the intracranial distant recurrence in comparison to placebo
up to 12-24 months
Intracranial progression-free survival
Time Frame: up to 12-24 months
intracranial local plus distant recurrence
up to 12-24 months
Overall progression-free survival
Time Frame: up to 12-24 months
intracranial plus systemic PFS
up to 12-24 months
Overall survival
Time Frame: up to 24 months
to investigate whether silibinin improve the overall survival in comparison to placebo
up to 24 months
Assessment of the quality of life of brain metastasis patients
Time Frame: 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, 48 weeks, 56 weeks, thereafter every 24 weeks
EORTC QLQ-C30 and EORTC QLQ-BN20
8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, 48 weeks, 56 weeks, thereafter every 24 weeks
to determine incidence of adverse events
Time Frame: up to 12-24 months
up to 12-24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2023

Primary Completion (Estimated)

September 1, 2025

Study Completion (Estimated)

September 1, 2027

Study Registration Dates

First Submitted

January 4, 2023

First Submitted That Met QC Criteria

January 9, 2023

First Posted (Actual)

January 19, 2023

Study Record Updates

Last Update Posted (Estimated)

December 15, 2023

Last Update Submitted That Met QC Criteria

December 10, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SILMET_0107665

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Principal Investigators will provide access to related study documents (e.g. protocol, statistical analysis plan, clinical study report) upon request from qualified researchers, and subjects with certain criteria, conditions, and exception that will be discussed with PI

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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