Vortioxetine for Newly Diagnosed Glioblastoma (ReVoGlio)

A Phase II Drug Repurposing Trial of Vortioxetine for the Treatment of Patients With Newly Diagnosed Glioblastoma

There is a very urgent need to improve on the currently limited treatment options for patients with glioblastoma. Despite extensive knowledge on the molecular pathogenesis of glioblastoma obtained through genomic, transcriptional and proteomic profiling, targeted therapy efforts have not yielded major advances, likely because of interindividual and intraindividual tumor heterogeneity and redundant oncogenic pathway activation.

Accordingly, there is a strong rationale to approach the challenge of glioblastoma from a different angle, e.g., by ex vivo drug sensitivity profiling which is agnostic to the molecular profile of a tumor. This approach that we have termed "pharmacoscopy", has previously been explored in liquid cancers and probably led to improved patient outcomes. Using pharmacoscopy, the antidepressant drug, vortioxetine, has been identified as a lead candidate for further exploration in patients with glioblastoma. Vortioxetine also demonstrated synergistic anti-glioma activity in combination with temozolomide or lomustine.

The ReVoGlio trial aims at demonstrating that vortioxetine, a drug selected based on ex vivo drug profiling (pharmacoscopy), is of benefit for patients with newly diagnosed glioblastoma.

Study Overview

• Status: Not yet recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Vortioxetine

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Weller, Prof. Dr. med.; Phone Number: +41 44 255 55 00; Email: ReVoGlio@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, age ≥18 years
2. Patients with histologically confirmed newly diagnosed glioblastoma per CNS WHO 2021 classification
3. O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status known or tissue available for testing
4. Karnofsky performance status (KPS) ≥ 70%
5. Intent to treat with standard radiochemotherapy per EANO guidelines (radiotherapy will 60 Gy in 1.8-2 Gy fractions. Concomitant chemotherapy with temozolomide (75 mg/m2 daily throughout radiotherapy, including at weekends) followed by six cycles of maintenance temozolomide (150-200 mg/m2, 5 out of 28 days). Short course radiotherapy at 40 Gy is not allowed.
6. Female patients must be either documented not to be Women of Childbearing Potential (WOCBP) or must have a negative pregnancy test within 14 days of starting treatment. Additionally WOCBP must agree to use, from the screening to 6 months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion or vasectomized partner. WOCBP are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).
7. Male subjects able to father children must agree to use two acceptable methods of contraception throughout the study and during 6 months following the last study drug administration (e.g., condom with spermicidal gel). Double-barrier contraception is required.
8. Personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
9. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

1. Prior treatment for newly diagnosed glioblastoma except surgery. 2. Intent to be treated with tumor-treating fields. 3. Inability to undergo contrast-enhanced MRI. 4. Inadequate bone marrow, renal and hepatic function:

• Absolute neutrophil count (ANC) < 1.5 x 10.9/L; platelets < 100 x 10.9/L
• Hemoglobin (Hb) < 9.0 g/dl. Blood marrow values must be measured independently of transfusion.
• Chronically impaired renal function as indicated by creatinine clearance < 50 mL/min or serum creatinine > 1.5 upper limit of normal (ULN).

• Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN) 9. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol, in the opinion of the investigator.

  10. Any contra-indication to vortioxetine. 11. Medically documented history of active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g., risk of doing harm to self or others), or patients with active severe personality disorders.

  12. Pregnancy or breast feeding. 13. Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.

  14. Concurrent malignancies unless the patient has been disease-free without intervention for at least one year.

  15. Requirement of concurrent use of other anti-cancer treatments or agents other than study medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vortioxetine in addition to the standard of care	Drug: Vortioxetine; Vortioxetine will be added to standard of care temozolomide chemoradiotherapy for patients with newly diagnosed glioblastoma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS is defined as the time from registration until the first event of interest: progressive disease or death from any cause. Patients not having an event at the time of analysis and patients starting a new anticancer therapy in the absence of an event will be censored at the date of their last tumor assessment showing non-progression before starting a new treatment. The PFS will be determined locally per RANO 2.0 criteria	through study completion for each patient, an average of 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	All AE will be assessed according to CTCAE v5.0	From date of randomization until 30 days after vortioxetine interruption
Overall survival (OS)	OS will be calculated from registration until death from any cause. Patients not experiencing an event will be censored at the last date they were known to be alive. OS will be assessed in relation to external control data.	until death, an average of 17 months
Neurological function 1	measured by NANO scale	through study completion for each patient, an average of 6 months
Neurological function 2	measured by the RANO seizure scale	through study completion for each patient, an average of 6 months
Neurological function 3	measured by Karnofsky performance status	through study completion for each patient, an average of 6 months
Neurological function 4	measured by steroid consumption	through study completion for each patient, an average of 6 months
Quality of life 1	assessed by QLQ C30 questionnaire	through study completion for each patient, an average of 6 months
Quality of life 2	assessed by BN20 questionnaire	through study completion for each patient, an average of 6 months
Anxiety	assessed by the Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1959)	through study completion for each patient, an average of 6 months
Response to treatment	Response (type of response and response rate per local and central assessment in patients with measurable disease) and progression-free survival to treatment by central review of the MRI	through study completion for each patient, an average of 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic role of extent of resection and residual tumor	Assessment of a statistical association between extent of surgical resection / residual tumor (measured in mm3) and outcome (survival)	until death, an average of 17 months
Prognostic role of the G8 frailty index	Assessment of a statistical association between the G8 total score and outcome (survival)	through study completion for each patient, an average of 6 months
Drug exposure	Plasmatic concentration of vortioxetine	through study completion for each patient, an average of 6 months

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: University Hospital, Basel, Switzerland; Kantonsspital Aarau; University Hospital, Zürich; Cantonal Hospital of St. Gallen; Cantonal Hospital of Lucerne, Switzerland

Publications and helpful links

General Publications

• Lee S, Weiss T, Buhler M, Mena J, Lottenbach Z, Wegmann R, Sun M, Bihl M, Augustynek B, Baumann SP, Goetze S, van Drogen A, Pedrioli PGA, Penton D, Festl Y, Buck A, Kirschenbaum D, Zeitlberger AM, Neidert MC, Vasella F, Rushing EJ, Wollscheid B, Hediger MA, Weller M, Snijder B. High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity. Nat Med. 2024 Nov;30(11):3196-3208. doi: 10.1038/s41591-024-03224-y. Epub 2024 Sep 20.

Study record dates

Study Major Dates

• Study Start (Estimated): December 15, 2025
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: September 28, 2025
• First Submitted That Met QC Criteria: December 2, 2025
• First Posted (Actual): December 16, 2025

Study Record Updates

• Last Update Posted (Actual): December 16, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Glioblastoma; Vortioxetine; Drug repurposing
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Vortioxetine
• Other Study ID Numbers: ReVoGlio

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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