Open-label Phase II Clinical Trial to Test the Efficacy of the Combination of Trimipramine and Atezolizumab With Bevacizumab in Patients With Recurrent Glioblastoma
Overview
- Phase
- Phase 2
- Intervention
- Trimipramine
- Conditions
- Not specified
- Sponsor
- Centre Hospitalier Universitaire Vaudois
- Enrollment
- 59
- Locations
- 8
- Primary Endpoint
- Cohort 1: Progression-free survival rate [PFSR]
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
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.
Investigators
Andreas Hottinger
Professor in Neuro-Oncology
Centre Hospitalier Universitaire Vaudois
Eligibility Criteria
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-
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.
Arms & Interventions
Cohort 1: Recurrent GBM without indication for re-resection
Eligible patients will receive: trimipramine, bevacizumab and atezolizumab. Trimipramine will be taken orally daily (75 mg the first week and thereafter 150 mg), bevacizumab (15 mg/kg) and atezolizumab (1200 mg) will be administered intravenously every 3 weeks. Maximum treatment duration is 2 years. Patients will undergo clinical examination, vital signs measurements, and clinical laboratory evaluations regularly. Safety events will be collected up to 90 days after treatment end. Neurological assessment, quality of life assessment, brain Magnetic Resonance Imaging \[MRI\] and radiological assessment with Response Assessment in Neuro-Oncology \[RANO\] scale as per local guidelines will be performed every 9 weeks during study treatment administrations. Thereafter, these assessments will be performed every 12 weeks until clinical or radiological recurrence, for up to 3 years after registration.
Intervention: Trimipramine
Cohort 1: Recurrent GBM without indication for re-resection
Eligible patients will receive: trimipramine, bevacizumab and atezolizumab. Trimipramine will be taken orally daily (75 mg the first week and thereafter 150 mg), bevacizumab (15 mg/kg) and atezolizumab (1200 mg) will be administered intravenously every 3 weeks. Maximum treatment duration is 2 years. Patients will undergo clinical examination, vital signs measurements, and clinical laboratory evaluations regularly. Safety events will be collected up to 90 days after treatment end. Neurological assessment, quality of life assessment, brain Magnetic Resonance Imaging \[MRI\] and radiological assessment with Response Assessment in Neuro-Oncology \[RANO\] scale as per local guidelines will be performed every 9 weeks during study treatment administrations. Thereafter, these assessments will be performed every 12 weeks until clinical or radiological recurrence, for up to 3 years after registration.
Intervention: Bevacizumab
Cohort 2: recurrent GBm with an indication for re-resection
Eligible patients will receive: Trimipramine taken orally daily (75 mg the first week and thereafter 150 mg) and atezolizumab (1200 mg) administered intravenously. Neurosurgical resection from first recurrent tumor will be planned 1 cycle after trial treatment start. Trimipramine will be continued during surgery and recovery period (minimum 2 weeks). Atezolizumab will be re-started after a minimum recovery period of 14 days after surgery at a fixed dose of 1200 mg administered intravenously, every 3 weeks. Bevacizumab will be started one cycle after the re-start of atezolizumab, at least 35 days after surgery. It will be administered intravenously at a dose of 15 mg/kg every 3 weeks for a maximum of 32 cycles of 21 days. Patients will undergo clinical and safety follow-up up to 3 years post-registration as for Cohort 1.
Intervention: Trimipramine
Cohort 1: Recurrent GBM without indication for re-resection
Eligible patients will receive: trimipramine, bevacizumab and atezolizumab. Trimipramine will be taken orally daily (75 mg the first week and thereafter 150 mg), bevacizumab (15 mg/kg) and atezolizumab (1200 mg) will be administered intravenously every 3 weeks. Maximum treatment duration is 2 years. Patients will undergo clinical examination, vital signs measurements, and clinical laboratory evaluations regularly. Safety events will be collected up to 90 days after treatment end. Neurological assessment, quality of life assessment, brain Magnetic Resonance Imaging \[MRI\] and radiological assessment with Response Assessment in Neuro-Oncology \[RANO\] scale as per local guidelines will be performed every 9 weeks during study treatment administrations. Thereafter, these assessments will be performed every 12 weeks until clinical or radiological recurrence, for up to 3 years after registration.
Intervention: Cohort 1: Atezolizumab
Cohort 2: recurrent GBm with an indication for re-resection
Eligible patients will receive: Trimipramine taken orally daily (75 mg the first week and thereafter 150 mg) and atezolizumab (1200 mg) administered intravenously. Neurosurgical resection from first recurrent tumor will be planned 1 cycle after trial treatment start. Trimipramine will be continued during surgery and recovery period (minimum 2 weeks). Atezolizumab will be re-started after a minimum recovery period of 14 days after surgery at a fixed dose of 1200 mg administered intravenously, every 3 weeks. Bevacizumab will be started one cycle after the re-start of atezolizumab, at least 35 days after surgery. It will be administered intravenously at a dose of 15 mg/kg every 3 weeks for a maximum of 32 cycles of 21 days. Patients will undergo clinical and safety follow-up up to 3 years post-registration as for Cohort 1.
Intervention: Cohort 2: Atezolizumab
Cohort 2: recurrent GBm with an indication for re-resection
Eligible patients will receive: Trimipramine taken orally daily (75 mg the first week and thereafter 150 mg) and atezolizumab (1200 mg) administered intravenously. Neurosurgical resection from first recurrent tumor will be planned 1 cycle after trial treatment start. Trimipramine will be continued during surgery and recovery period (minimum 2 weeks). Atezolizumab will be re-started after a minimum recovery period of 14 days after surgery at a fixed dose of 1200 mg administered intravenously, every 3 weeks. Bevacizumab will be started one cycle after the re-start of atezolizumab, at least 35 days after surgery. It will be administered intravenously at a dose of 15 mg/kg every 3 weeks for a maximum of 32 cycles of 21 days. Patients will undergo clinical and safety follow-up up to 3 years post-registration as for Cohort 1.
Intervention: Cohort 2: Bevacizumab
Outcomes
Primary Outcomes
Cohort 1: Progression-free survival rate [PFSR]
Time Frame: 6 months after last patient's registration
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]
Time Frame: 3 months after last patient's surgery
Level of trimipramine in the tumor tissue and CSF collected during surgery will be assessed by measuring the trimipramine concentration by laboratory analysis.