Efficacy of the Combination of Trimipramine and Atezolizumab With Bevacizumab in Patients With Recurrent Glioblastoma: a Phase 2 Trial

Inclusion Criteria: * 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. * Maximum dose of dexamethasone (or equivalent) 4 mg at time of inclusion. * No surgery or other invasive procedures (major surgical procedure, open biopsy or significant traumatic injury) within 4 weeks prior to registration. * No core biopsy or other minor surgical procedure within 7 days prior to registration. (Placement of a central vascular access device, if performed at least 2 days prior to trial treatment administration, is allowed). * Patients who require anti-convulsant therapy must be taking non-enzyme inducing antiepileptic drugs \[non-EIAED\]. Patients previously on EIAED must be switched to non-EIAED at least 2 weeks prior to registration. * Measurable disease per Response Assessment in Neuro-Oncology \[RANO\] version 2.0 criteria. Recurrent disease must be at least one bi-dimensionally measurable contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on MRI scan done within 28 days prior to registration. * Karnofsky performance status 70-100. * Adequate bone marrow function: neutrophil count ≥ 1.5 x 10\^9/L, platelet count ≥ 100 x 109/L, hemoglobin ≥ 90 g/L. * Adequate hepatic function: total bilirubin ≤ 1.5 x Upper Limit of Normal \[ULN\] (except for patients with Gilbert's syndrome ≤ 3.0 x ULN), aspartate aminotransferase \[AST\] and alanine transaminase \[ALT\] and alkaline phosphatase \[AP\] ≤ 2.5 x ULN. * Adequate renal function: estimated glomerular filtration rate \[eGFR\] ≥ 45 mL/min/1.73 m2 (according to Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] formula). * Urine dipstick for proteinuria \< 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤ 1 g of protein/24 hours. * Adequate coagulation function: International Normalized Ratio \[INR\] ≤ 1.5 x ULN (the ULN for INR is defined with the value 1.2 for all sites, in case no ULN is documented in the laboratory certificates/sheets). Use of full-dose anticoagulants is permitted as long as the INR is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks before registration, as per American Society for Clinical Oncology \[ASCO\] guidelines, low molecular weight heparin \[LMWH\] should be the preferred approach. Concomitant anticoagulation with aspirin (up to 300 mg/day) and anticoagulation with LMWH is allowed. * Women of childbearing potential must use highly effective contraception , are not pregnant or breast-feeding and agree not to become pregnant during trial treatment and until 6 months after the last dose of investigational drug. A negative pregnancy test before inclusion into the trial is required for all women of childbearing potential. * Men agree not to donate sperm or to father a child during trial treatment and until 6 months after the last dose of investigational drug. * Patient is able and willing to swallow trial drug as whole tablet. Only for Cohort 2: * Consent to giving access of part of the tumor tissue and Cerebrospinal Fluid \[CSF\] obtained during the routine neurosurgical procedure for pharmacology and translational studies. Tumor tissue will only be made available once it is established that enough tumor tissue is available for standard neuropathological analysis. * Patients that have a medical indication for a neurosurgical resection from first recurrent tumor. Exclusion Criteria: * 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. Note: Patients treated with fluoxetine prior to enrollment will only be eligible for this trial after a two-month washout period before starting the study treatment. * Prior treatment with atezolizumab or any other immune checkpoint inhibitors. * Prior treatment with bevacizumab or other Vascular Endothelial Growth Factor \[VEGF\] inhibitors or VEGF-receptor signaling inhibitors. * Concomitant or prior use of immunosuppressive medication within 5 half-lives before registration, with the exceptions of intranasal and inhaled corticosteroids. * Life expectancy of less than 12 weeks. * Active systemic prior malignancy. Patients with a prior malignancy (basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix) and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. * Blood pressure combination treatment wit