Prospective Double Arm Randomized Trial: WBRT Alone and WBRT Plus Silibinin

Prospective Double Arm Randomized Trial for Patients With Multiple Brain Metastasis and/or Leptomeningeal Carcinomatosis: Comparison of WBRT Alone and WBRT Plus Silibinin (Sillbrain)

The occurrence of brain metastases (BMs) is increasing given the availability of a more accurate radiological imaging such as MRI for detecting also small brain lesions and the most effective systemic therapy able to control extracranial disease. Although, the new target therapy and immunotherapy has proven to be effective on brain metastasis too, a subgroup of patients shows prove themselves unresponsive to medical treatment. A further subgroup of patients exhibit diffuse brain disease for the presence of multiple brain lesion (>10 BMs) or leptomeningeal carcinomatosis. Among these patients the most treatment employed is represented by whole brain RT. Since the 1950s, whole-brain radiation therapy (WBRT) has been the most widely used treatment for patients with multiple brain metastases, given its effectiveness in palliation, widespread availability, and ease to delivery. However, the median overall survival recorded is restricted to 3 months, on the average. A better understanding of the molecular and cellular mechanisms underlying brain metastasis might be expected to lead to improvements in the overall survival rate for these patients. Recent studies have revealed complex interactions between metastatic cancer cells and their microenvironment in the brain. Priego et al. describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. Silibinin (or silybin) is a natural polyphenolic flavonoid isolated from seed extracts of the herb milk thistle (Silybum marianum). Silibinin has been shown to impair STAT3 activation. Preclinical studies show that Silibinin has an anticancer effects in vitro and in vivo.

Based on this background, the investigators designed a double arm randomized trial evaluating the benefit of Silibinin (in the form of marketed supplement) associated to WBRT respect to WBRT alone.

Study Overview

• Status: Recruiting
• Conditions: Brain Metastases, Adult
• Intervention / Treatment: Other: Silibinin

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Elena Clerici; Phone Number: 0282247310; Email: elena.clerici@humanitas.it

Study Locations

• Italy
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Recruiting
      • IRCCS Humanitas Research Hospital
      • Contact: Elena Clerici, MD; Phone Number: +390282247310; Email: elena.clerici@humanitas.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >18 years
• Histological or cytological confirmation of solid tumor malignancy
• Clinical indication for whole brain radiotherapy
• Karnofsky performance status (KPS) ≥60
• Written informed consent

Exclusion Criteria:

• Prior WBRT
• KPS < 60
• Diagnosis of Lymphoproliferative disease
• Pregnant women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WBRT + Silibinin; Patients undergo WBRT concomitant to Silibinin	Other: Silibinin; WBRT will be concomitant to Silibinin. Silibinin at dose of 500 mg must be administrated twice a day for the first month, after once a day continuously. Total dose and fractionation of WBRT: 30 Gy in 10 fractions.
No Intervention: WBRT; Patients undergo WBRT alone, total dose of 30 Gy in 10 fractions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Outcome will be evaluated in months	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity in term of use of corticosteroid therapy	Outcome will be evaluated in term of use or not of corticosteroids	12 months
Brain Distant Failure (BDF)	Outcome will be evaluated in months	12 months
Progression Free Survival (PFS)	Outcome will be evaluated in months	12 months

Collaborators and Investigators

• Sponsor: Istituto Clinico Humanitas

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2023
• Primary Completion (Anticipated): March 30, 2025
• Study Completion (Anticipated): March 30, 2026

Study Registration Dates

• First Submitted: March 20, 2023
• First Submitted That Met QC Criteria: March 20, 2023
• First Posted (Actual): March 31, 2023

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: WBRT; Brain Metastases; Silibinin
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Antineoplastic Agents, Phytogenic; Silybin
• Other Study ID Numbers: 3406

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No