Silibinin in Association With Concomitant Chemoradiotherapy and Maintenance Temozolomide in STAT3 Positive IDH Wild-type, Newly Diagnosed Glioblastoma Patients

Official title

Silibinin in Association With Concomitant Chemoradiotherapy and Maintenance Temozolomide in STAT3 Positive IDH Wild-type, Newly Diagnosed Glioblastoma Patients: a Multicenter, Double-blind, Placebo-controlled, Randomized Study

Overview

Multicenter, double-blind, placebo-controlled, randomized trial. Patients affected by STAT3 positive newly diagnosed glioblastoma will be eligible. Patients are randomized using a stratified block randomization method with a 1:1 ratio in two arms: • Experimental/Control arm: Concomitant radiotherapy (60 gy in 30 fractions) + temozolomide 75mg/mq + silibinin/placebo 2 sachets/day dissolved in water throughout concomitant treatment followed by temozolomide cp, 150 mg/m2-200mg/m2, g1-5 q28d + silibinin/placebo 2 sachets/day dissolved in water, day 1-28, q28d for 6-12 cycles. Silibinin/Placebo may be continued until disease progression at the discretion of the physician. Patients will be stratified based on: * Type of surgery (complete Vs partial) * MGMT methylation status (methylated Vs non-methylated) * ECOG PS (0-1 Vs 2)

Interventions

• Dietary supplement Silibinin as STAT3 inhibitor
  Sillbrain will be available as granulate in sachets of 3.7g and it will be administered twice a day during chemo-radiotherapy and day 1-28 in maintenance phase every cycle. Each 3.7 g sachet of Sillbrain contains 500 mg silibinin. Every patient will assume 2 sachets/day for a total of 1 g/day of silibinin.
• Other Placebo
  Placebo will be available as granulate in sachets of 3.7g and it will be administered twice a day during chemo-radiotherapy and day 1-28 in maintenance phase every cycle. Every patient will assume 2 sachets/day for a total of 1 g/day of placebo.

Primary outcome measures

• Progression Free Survival (PFS) [Time frame: Through study completion, an average of 2 years]

Secondary outcome measures (7)

• Liver Toxicity [Time frame: Through study completion, an average of 2 years]
• Liver Toxicity [Time frame: Through study completion, an average of 2 years]
• Liver Toxicity [Time frame: Through study completion, an average of 2 years]
• 6/9-months Progression Free Survival (6/9m-PFS) [Time frame: Through study completion, an average of 2 years]
• Objective Response Rate (ORR) [Time frame: Through study completion, an average of 2 years]
• EORTC QLQ-C30_Quality of Life [Time frame: Through study completion, an average of 2 years]
• QLQ-BN20_Quality of Life [Time frame: Through study completion, an average of 2 years]

Eligibility criteria

Inclusion criteria

• New histologically confirmed diagnosis of glioblastoma (WHO 2021)
• Local availability of MGMT methylation status
• Immunohistochemical positivity of activated STAT3 (pSTAT3) expression on the tumor tissue sample. STAT3 expression will be evaluated centrally by UOC Anatomia Patologica of Azienda Ospedale Università di Padova.
• Chemoradiotherapy start within 7 weeks from surgery
• Patients without disease progression after surgery
• Availability of paraffin-embedded tumor tissue
• Age ≥18 years
• ECOG PS 0-2; Karnofsky 100-70
• Signing of informed consent prior to any study procedure
• Patients (both males and females) should employ adequate contraceptive measures, which should be maintained during the whole duration of the trial (from screening to 6 months after the last dose of Temozolomide).
• Have adequate bone marrow, liver and kidney function, as measured by the following laboratory assessments conducted within 10 days before the start of study treatment:
• Hemoglobin > 9.0 g/dl
• Absolute neutrophil count (ANC) ≥1500/mm3 without granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors
• Platelet count ≥100,000/μl
• WBC ≥3.0 x 10 9 /L
• Total bilirubin <1.5 times the upper limit of normal
• ALT and AST <3 x the upper limit of normal
• Serum creatinine <1.5 times the upper limit of normal
• Glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the abbreviated formula Modified Diet in Renal Disease
• Alkaline phosphatase <2.5 x ULN
• PT-INR/PTT <1.5 x upper limit of normal (patients who are therapeutically anticoagulated with anticoagulant drugs will be able to participate provided there is no history of abnormal background in these parameters, based on history).
• Complete urinalysis
• Stable and decreasing corticosteroid dosage in the last 10 days before brain MRI

Exclusion criteria

• Patients diagnosed with glioblastoma (WHO grade IV 2021) who have only had a diagnostic biopsy
• Chemotherapy, immunotherapy, or antineoplastic therapy for glioblastoma
• Negative immunohistochemistry of STAT3 expression on the tumor tissue sample
• Diagnosis of another tumor or secondary brain localization
• In the investigator's judgment, any evidence of severe or uncontrolled systemic disease including: uncontrolled hypertension; hemorrhagic diathesis; active infection with HBV, HCV, HIV. Screening for such chronic conditions is not required by the protocol; bone marrow reserve or organ dysfunction as demonstrated by laboratory tests.
• Patients who are unable to comply with study procedures and requirements.
• Contraindication to Brain MRI
• Pregnant or breastfeeding patients
• Patients who are unable to swallow capsules or sachets dissolved in water.
• Patient unable to sign the Informed Consent
• Glioblastoma leptomeningeal dissemination
• Congestive heart failure classified as New York Heart Association (NYHA) Class 2 or higher; Unstable angina (symptoms of angina at rest) or new onset angina ≤3 months prior to screening; myocardial infarction <6 months prior to 'start of study treatment; cardiac arrhythmias requiring antiarrhythmic therapy, with the exception of beta-blockers or digoxin; uncontrolled hypertension (systolic blood pressure \[SBP\]>140 mmHg or diastolic blood pressure \[DBP\] >90 mmHg) despite optimal medical management.
• Arterial thrombotic or embolic events such as stroke and/or transient ischemic attacks) or
• Pulmonary embolism in the 6 months prior to the start of study treatment
• Ongoing infection with grade 2 or higher severity (NCI-CTCAE v 5.0)
• Known history of human immunodeficiency virus (HIV) infection; hepatitis B or C active or chronic requiring treatment with antiviral therapy
• History of organ allotransplantation
• Evidence or history of any bleeding diathesis (including mild hemophilia), regardless of its severity;
• Injuries, ulcers or bone fractures that have not fully resolved.
• Renal failure requiring hemodialysis or peritoneal dialysis
• Presenting interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained.
• Persistent proteinuria >3.5 g/24 hours as measured by urinary protein-creatinine ratio from a urine sample (≥ Grade 3, NCI-CTCAE v 5.0). CTCAE 5.0 is also available in Appendix 1.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 16 centers

• IRCCS Istituto delle Scienze Neurologiche di Bologna — Bologna
• IRST Dino Amadori — Meldola
• Azienda Ospedaliero Universitaria Policlinico "G. Rodolico - San Marco " — Catania
• Azienda Ospedaliera Universitaria - Careggi — Florence
• ARNAS G.Brotzu P.O Armando Businco — Cagliari
• USL Nord Ovest Toscana - Livorno — Livorno
• Ospedale del Mare, ASL Napoli1 Centro — Naples
• Istituto Oncologico Veneto — Padova
• … and 8 more centers

Identifiers

NCT: NCT06964815 · IOV-GB-01-2024-STRONG

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗