This is a multicentric phase II open-label clinical trial aiming to assess the efficacy of the combination of trimipramine and atezolizumab with bevacizumab in patients with recurrent glioblastoma. Eligible patients will be assigned to two cohorts depending on whether there is a medical indication for a neurosurgical resection from first recurrent tumor or not.
The aim of the cohort 1 (patients without indication for surgery) is to analyze the clinical efficacy of this triple combination in recurrent glioblastoma. 48 patients will be registered.
The aim of cohort 2 (patients with indication for surgery) is to confirm the level of trimipramine that can be achieved in the tumor tissue and cerebrospinal fluid collected during surgery. At least 5 patients will be registered.
All patients will receive the combination treatment (trimipramine and atezolizumab associated with bevacizumab) for a maximum period of 2 years from registration. The treatment schedule is slightly different for the 2 cohorts because of the neurosurgical resection foreseen for cohort 2 and the requirement to start bevacizumab only after the surgery. After the end of treatment, all patients will be followed up for safety during 90 days from first treatment administration and then up to 3 years from registration.
Histologically or cytologically confirmed glioblastoma, according to World Health Organization [WHO] 2021 with unequivocal first progression after standard (6 weeks radiotherapy [RT]) with concurrent & adjuvant temozolomide [TMZ] chemotherapy.
Patients must be at least 3 months off the concomitant part of chemo-radiotherapy.
Stable or decreasing dose of steroids for 7 days prior to the baseline
Magnetic Resonance Imaging [MRI] scan.
Patient must be in first progression/recurrence and have not received more than one line of chemotherapy (concurrent and adjuvant temozolomide). Treatment of Time to Treatment Failure [TTF] fields (Optune®) is allowed during first line but will be stopped at registration.
Patients must not have prostate enlargement with urinary retention or angle-closure glaucoma at registration.
Any other experimental drug must be discontinued at least 30 days prior to registration
Patients under ongoing treatment with an antidepressant must be eligible for a switch to trimipramine. Patients currently under TriCyclic Antidepressant [TCAs] (amitriptyline, clomipramine, nortriptyline, imipramine), selective serotonin reuptake inhibitors (sertraline, paroxetine, fluvoxamine, citalopram, escitalopram) or serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine) must be weaned off these medications for at least 14 days before the introduction of trimipramine.
Parallel
Trimipramine
DrugTrimipramine: daily oral intake at 75mg/ day for 7 days, then at 150 mg/ day
Cohort 1: Atezolizumab
Biological/VaccineAtezolizumab: intravenous administration at 1200 mg on the first day of 3-week cycles.
Bevacizumab
Biological/VaccineBevacizumab will be administered intravenously at 15 mg/kg on the first day of 3-week cycles.
Cohort 2: Atezolizumab
Biological/VaccineAtezolizumab will be administered intravenously at a fixed dose of 1200 mg on the first day of 3-week cycles. Administration will occur once, then will be interrupted during a recovery period of 14-days post surgery, and then resumed.
Cohort 2: Bevacizumab
Biological/VaccineBevacizumab will be administered intravenously at 15 mg/kg on the first day of 3-week cycles. The first administration will take place 5 weeks after surgery.
Cohort 1: Progression-free survival rate [PFSR]
Progression-free survival rate \[PFSR\]: evaluated at 6 months after registration using the Response Assessment in Neuro-Oncology \[RANO\] verion 2.0 critieria
Cohort 2: Level of trimipramine in the tumor tissue and cerebrospinal fluid [CSF]
Level of trimipramine in the tumor tissue and CSF collected during surgery will be assessed by measuring the trimipramine concentration by laboratory analysis.
Click on the lead sponsor to view all of their trials.
