Itraconazole (ITRA) with Standard Radiotherapy (RT) and Temozolomide (TMZ) in Patients with Newly Diagnosed Glioblastoma Multiforme (GBM) ITRA-RAD: Phase I Clinical Study

Simple Summary

Glioblastoma (GBM) is an aggressive primary brain tumor with poor survival outcomes despite current standard-of-care treatment, highlighting the urgent need for novel therapeutic strategies. One promising approach involves targeting the Hedgehog (Hh) signaling pathway, which has been implicated in tumor growth and progression. Itraconazole (ITRA), a widely used antifungal agent, has demonstrated inhibitory effects on this pathway in preclinical studies. Based on this rationale, the present study investigates the safety and feasibility of combining itraconazole with standard GBM therapy, consisting of radiotherapy and temozolomide chemotherapy.

Abstract

Preclinical studies and data from other cancers suggest that inhibition of the Hedgehog (Hh) pathway also has antiproliferative effects on glioma cells. A key component of this pathway is the Smoothened (SMO) protein, which is expressed in high-grade gliomas. Itraconazole (ITRA), a widely used antifungal agent, inhibits SMO, the PI3K/AKT/mTOR pathway, and the VEGF/VEGFR-2 axis—both of which are critical for GBM progression and angiogenesis. This protocol describes a prospective, single-center, dose-escalation phase I study with the classical 3 + 3 design in order to determine the MTD of ITRA. The study enrolls patients with a newly histologically confirmed diagnosis of GBM, without previous treatment except surgery. They will be treated with standard RT schedule (60 Gy in 30 fractions) with concurrent TMZ 75 mg/m² and ITRA 2 × 100 mg, 200 mg, or 300 mg daily. The primary endpoint is to determine the MTD of ITRA given concurrently with RT + TMZ. Secondary endpoints include safety and tolerability of ITRA, overall survival (OS), progression-free survival (PFS), overall objective response rate, use of corticosteroids, treatment compliance, and health-related quality of life (EORTC QLQ-C30 and BN20). Participants will be monitored for one week post-treatment. All relevant statistics will be primarily descriptive.

1. Introduction

Despite significant advances in understanding the molecular biology of glioblastoma (GBM) [1] and the development of new targeted therapies [2,3,4], this tumor remains an aggressive and recurrent malignancy with a reported median overall survival of approximately 20 months [5]. The current standard of care includes surgical resection followed by concurrent chemoradiotherapy (CRT) with temozolomide (TMZ) and subsequent maintenance therapy with TMZ with or without tumor-treating fields [5,6].

The Hedgehog (Hh) signaling pathway is critical during embryonic development, where it regulates cell growth and differentiation. The Hh family comprises three extracellular ligands—Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh)—as well as a transmembrane protein Smoothened (SMO), glioma-associated (GLI) transcription factors, which are effectors of that pathway [7]. While normally silent in adult tissues, aberrant activation of Hh signaling has been implicated in the pathogenesis of several cancers, including GBM, contributing to the initiation of cancerogenesis, maintenance and progression of tumors [8]. SMO is notably overexpressed in high-grade gliomas compared to lower-grade lesions and normal brain tissue [9]. Moreover, Shh signaling is essential for the maintenance and self-renewal of glioma-initiating cells (GICs), with the inhibition of the pathway demonstrating significant anti-glioma effects in both in vitro and in vivo models [10,11,12]. Importantly, CRT itself can activate the Hh pathway, potentially limiting its efficacy [13].

Vismodegib (GDC-0449), an oral SMO inhibitor approved for locally advanced or metastatic basal cell carcinoma, has shown limited efficacy as a monotherapy in recurrent GBM (rGBM), as demonstrated in a phase 0/II trial [14]. By screening of approximately 2400 FDA-approved or post-phase I drugs, Itraconazole (ITRA), a common antifungal agent, was identified as a potent inhibitor of the Hh pathway [15].

Unlike vismodegib, ITRA has a broader range of influence, targeting not only SMO but also key pathways involved in GBM progression and angiogenesis, including PI3K/AKT/mTOR (PAM) and VEGF/VEGFR2 signaling [16]. Mechanistically, ITRA inhibits SMO and prevents its ciliary accumulation caused by Hh activation. In an orthotopic U87 GBM model, ITRA significantly suppressed tumor growth [17]. In xenograft models of non-small cell lung cancer, it was shown that ITRA inhibited VEGF- and basic fibroblast growth factor–induced angiogenic stimulation, as measured by endothelial cell proliferation, migration, and tube formation [18].

ITRA has demonstrated promising activity in clinical studies conducted on other malignancies. In basal cell carcinoma, ITRA monotherapy reduced tumor size by 24% and GLI1 expression by 65%, with no increase in toxicity [19]. In NSCLC, ITRA combined with pemetrexed significantly prolonged overall survival (30 vs. 8 months) compared to pemetrexed alone without additional toxicity [20]. In surgically resectable NSCLC, short-term ITRA (for 10–14 days) treatment induced early antivascular and antitumor effects [20]. A phase II trial in castration-resistant prostate cancer showed better tumor responses at higher ITRA doses (600 mg/day), although with more frequent grade 3 toxicities; no grade 4 events occurred [21]. Notably, ITRA combined with chemotherapy in advanced gastric cancer provided a high conversion surgery rate and acceptable toxicity [22]. Also, ITRA monotherapy improved quality of life in hereditary hemorrhagic telangiectasia by reducing VEGF-mediated bleeding [23].

Given the dual role of the Hh pathway in GBM progression and therapy resistance, the combination of ITRA with standard CRT and TMZ might be a promising therapeutic strategy deserving further clinical investigation.

2. Objectives

The primary aim is to determine the maximum tolerated dose (MTD) of ITRA given concurrently with RT and TMZ.

2.1. Secondary Aims

• To determine the safety profile of ITRA given concurrently with RT + TMZ as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0;
• To determine the effect of ITRA given concurrently with RT + TMZ on overall survival (OS);
• To assess the tolerability of the treatment regimen;
• To evaluate patient-reported health-related quality of life outcomes.

Primary Endpoint—to determine the maximum tolerated dose (MTD) of ITRA given concurrently with RT + TMZ.

2.2. Secondary Endpoints

• Safety and tolerability of ITRA given concurrently with RT + TMZ;
• Overall survival (OS);
• Progression-free survival (PFS);
• Overall objective response rate;
• Use of corticosteroids;
• Treatment compliance;
• Health-related quality of life (HRQoL—EORTC Quality of Life Questionnaire (QLQ)-C30 and Brain Cancer Module (BN20)).

3. Methods and Study Design

3.1. Trial Design and Setting

The planned CT is a non-commercial, exploratory, investigator-initiated, monocentric, prospective, non-blinded, dose-escalating phase I study with the classical 3 + 3 design in order to determine the MTD of ITRA to be administered concomitantly with RT and TMZ. Potential study participants will be identified as part of the multidisciplinary tumor conference at the University Hospital Magdeburg and Klinikum Magdeburg. The patients will be informed of this trial in the clinics where the surgery will be performed. After receiving histological confirmation of GBM, patients will receive an information leaflet about this study. At their first presentation to the Department of Radiation Therapy for consideration of adjuvant treatment, patients will be screened and recruited if they are willing to participate in the study. For a detailed schedule of patient visits, please refer to Appendix A (Table A1). The clinical trial is registered in the EU Clinical Trials Registry (CTIS) under the EUCT number 2024-519239-40-01, decision date: 21 March 2025; https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-519239-40-01 (accessed on 9 March 2026). The current protocol version is V02/25.02.2026. This protocol adheres to the SPIRIT 2025 checklist (Table S1).

3.2. Inclusion Criteria

• Histologically confirmed diagnosis of GBM;
• No previous treatment except for surgery (i.e., no previous RT, local chemotherapy, or systemic therapy) is allowed. Subjects must be able to undergo serial MRIs (computerized tomography may not substitute for MRI);
• Patients who were not candidates for surgery and had a biopsy only, and could be treated with standard RT (60 Gy in 30 fractions) and TMZ;
• ≥18 years of age;
• Adequate renal and hepatic function and hematopoietic capacity;
• ECOG performance status of ≤2, and must be able to swallow whole capsules;
• Must be able to understand and comply with the protocol requirements and have signed the informed consent document.

3.3. Exclusion Criteria

• Previous treatment with systemic chemotherapy, RT or any other type of investigational agent for the treatment of brain tumors.
• Evidence of acute intracranial or intratumoural hemorrhage > grade 1, either by MRI or computed tomography scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study.
• Pregnant or breastfeeding women.
• Compensated or decompensated congestive heart failure.
• Serious liver disease, such as cirrhosis, acute or chronic hepatitis.
• Other serious illnesses such as significant cardiac arrhythmias, severe respiratory failure or acute kidney failure.
• Other diagnoses of malignancy, except for surgically excised non-melanoma skin cancer or carcinoma in situ of the cervix or treated early-stage prostate cancer.
• Previously identified allergy or hypersensitivity to components of either the ITRA or the TMZ formulations.
• Current treatment with ITRA for fungal infection.

We plan to use a classical 3 + 3 design to determine the MTD of ITRA. The sample size will range from 9 patients if no DLTs occur to up to 18 patients if DLTs occur in any dose cohort. For detailed information, please refer to Section 3.5.

3.4. Treatment Design

RT with concomitant TMZ is a standard of care for patients with newly diagnosed GBM. RT treatment must begin >2 weeks and ≤4 weeks after surgery. RT will be given daily, five days per week (Monday through Friday) over a period of six weeks at a dose of 2 Gy per fraction for a total dose of 60 Gy. Volumetric Intensity Modulated Arc Therapy (VMAT) will be delivered with linear accelerators with a nominal energy of 6 megavolts (MV) or more. Postoperative MRI imaging will be fused with planning CT to define a gross tumor volume (GTV). Contrast-enhanced T1 as well as T2 (in case of secondary GBM) will be used. Treatment verification and documentation will be carried out weekly with cone-beam CT. Surgical cavity and T1 enhancing lesion will be fused and expanded 1.5 cm and adapted according to anatomical borders and organs at risk (OARs—refer to Table 1) to define the clinical target volume (CTV). In case of secondary GBM, the non-enhancing T2 component will be expanded by 1 cm to create a CTV. Planning target volume (PTV) will be created by a 0.4 cm expansion of CTV.

Table 1. Dose constraints for organs at risk (OAR).

Organ/Structure	Dose Constraint
Optic Chiasm and Optic Nerves	Dmax < 54 Gy
Retina	Dmax < 45 Gy
Brainstem	Dmax < 54 Gy
Cochlea	Dmean < 50 Gy
Pituitary Gland	Dmax < 50 Gy
Lens	Dmax < 10 Gy
Lacrimal Gland	Dmax < 40 Gy
Hippocampus	<9 Gy (if reasonably achievable)

TMZ treatment will commence from the first day of treatment with RT and will be administered continuously (including weekends) until the last day of RT at a daily oral dose of 75 mg/m² for a maximum of 42 days. The TMZ dose will be calculated using the actual body-surface area.

Treatment with ITRA should start 5 days before RT + TMZ treatment. ITRA should be taken daily (including weekends) 2–3 h before planned radiotherapy together with TMZ until and including the last day of radiotherapy. A morning dose of ITRA should be taken immediately after a full meal. In patients with reduced gastric acidity, such as patients receiving proton pump inhibitors (PPI) or subjects with achlorhydria caused by other diseases, ITRA will be administered under fasted conditions with an acidic beverage (such as a non-diet cola) after pretreatment with a PPI. An evening dose of ITRA should be taken immediately after a full meal in subjects without reduced gastric acidity; otherwise, ITRA should be taken under fasted conditions with an acidic beverage (such as a non-diet cola) after pretreatment with a PPI. During weekends without RT (Saturday and Sunday), TMZ and ITRA will be taken as described. The participants will receive a counted amount of IMP in the original blister pack to take home and take it independently. They have to return the empty and/or remaining blister packs every week.

3.5. Dose Escalation and Determination of Maximum Tolerated Dose (MTD)

According to the study design, three dose levels of itraconazole (ITRA) will be evaluated (Table 2):

Table 2. Dose escalation scheme (3 + 3 design) for ITRA.

Cohort/Dose Level	Initial No. of Patients	DLTs Observed	Decision
First Cohort—2 × 100 mg ITRA	3	0	Escalate to 2 × 200 mg ITRA
	3 → expand to 6	1 in initial 3 → 0 in additional 3	Escalate to 2 × 200 mg ITRA
	3 → expand to 6	1 in initial 3 → ≥1 in additional 3	MTD reached (2 × 100 mg ITRA)
	3	≥2	Trial stopped/declared failure
Second Cohort—2 × 200 mg ITRA	3	0	Escalate to 2 × 300 mg ITRA
	3 → expand to 6	1 in initial 3 → 0 in additional 3	2 × 300 mg ITRA tested (potential MTD)
	3 → expand to 6	1 in initial 3 → ≥1 in additional 3	MTD = 2 × 200 mg ITRA
	3	≥2	MTD = 2 × 100 mg ITRA
Third Cohort—2 × 300 mg ITRA	3	0	MTD = 2 × 300 mg ITRA
	3 → expand to 6	1 in initial 3 → 0 or 1 in additional 3	MTD = 2 × 300 mg ITRA
	3 → expand to 6	≥2	MTD = 2 × 200 mg ITRA

Legend: DLT = dose-limiting toxicity; MTD = maximum tolerated dose.

• In total, 2 × 100 mg ITRA daily.
• In total, 2 × 200 mg ITRA daily.
• In total, 2 × 300 mg ITRA daily.

The starting dose will be 2 × 100 mg ITRA daily.

Dose-limiting toxicity (DLT) is defined as follows: any treatment-related grade 4 non-haematologic (non-laboratory) adverse event (AE); any treatment-related grade 3 non-haematologic clinical (non-laboratory) AE (except fatigue) lasting >3 days despite optimal medical intervention; or any grade ≥ 3 non-haematologic laboratory abnormality if any of the following apply:

• Medical intervention is necessary to treat the patient;
• The AE leads to hospitalization;
• The AE persists for ≥7 days.

Additionally, any adverse event (deemed by the local investigator and/or sponsor to be treatment-related) that results in seven or more dose omissions during the first 28 days after dose administration will be considered a DLT.

If patients experience a DLT with an onset date during the first 12 days, ITRA administration should be permanently discontinued. Serious adverse events (SAEs) will be followed up for one week after V9 for each patient.

Prior to the initiation of the clinical trial, all concomitant medications will be reviewed, and potential contraindications will be assessed. Co-administration of itraconazole (ITRA) with the following drugs is contraindicated: ergot alkaloids, irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, and simvastatin. If a patient enrolled in this clinical trial is being treated with any of the contraindicated drugs at baseline, they will be switched to suitable alternative medications with the same therapeutic indication prior to trial entry.

3.6. Data Collection, Management and Analysis

The occurrence of dose-limiting toxicities (DLTs), which constitute the primary endpoint of this study, will be documented using the adverse event (AE) form in relation to the administered dose. Laboratory results obtained at individual study visits will serve to further evaluate the safety profile, tolerability, and potential treatment response. In addition, health-related quality of life (HRQoL) will be assessed at baseline and at the end of treatment using validated EORTC instruments: the QLQ-C30 and the Brain Cancer Module (BN20).

The collection, transfer, storage and evaluation of personal data within this clinical trial is carried out in accordance with the current legal regulations (General Data Protection Regulation/GDPR and State Data Protection Act of Saxony-Anhalt). The prerequisite for this is the voluntary consent of the participants as part of the declaration of consent before taking part in the clinical trial. Informed consent will be obtained by the study physician. Personal data will be stored electronically within a secure departmental database, with access limited exclusively to authorized investigators. Access by third parties is strictly prohibited.

As part of this clinical trial, data will be recorded using a paper Case Report Form (CRF). Adverse events (AEs) and serious adverse events (SAEs) will be documented and reported systematically, in compliance with the specifications outlined in the trial protocol.

Administration of the approved investigational drug is not expected to cause any serious or unexpected side effects, and early discontinuation of the entire clinical trial is considered unlikely. All possible side effects and adverse events will be systematically recorded.

The principal investigator and/or the sponsor reserve the right to terminate the clinical trial early for relevant medical or regulatory reasons. A detailed list of potential reasons is provided in the study protocol.

All relevant analyses will be primarily descriptive. The analysis will begin with a descriptive summary of demographic and medical history data, clinical examination findings (neurological, physical, and laboratory parameters) prior to the initiation of treatment, as well as baseline quality of life assessments. Qualitative variables will be summarized using absolute frequencies and percentages. For quantitative variables, measures of central tendency and dispersion will be reported. Descriptive analyses will also be performed for study variables assessed over time and at the end of treatment.

The clinical trial will be coordinated, and data monitoring will be performed by the Center for Clinical Studies, Magdeburg, which is responsible for the day-to-day management and operational oversight of the study. This includes ensuring compliance with Good Clinical Practice guidelines, coordinating site activities, managing data collection, and facilitating communication among investigators. The coordinating team will meet regularly to review study progress, recruitment, and any emerging issues requiring operational attention. A Trial Steering Committee will provide overall supervision of the trial on behalf of the sponsor and ensure that it is conducted in accordance with the approved protocol, ethical standards, and regulatory requirements. Monitoring and audit visits will be scheduled and communicated in advance by the monitoring team. The Data Monitoring Committee is independent from the sponsor and has no competing interests. Following approval by the responsible ethics committee, any protocol amendments will be promptly communicated to all relevant parties. It is not planned to give access to the full protocol, participant-level data, or statistical code. The results of the clinical trial will be published in accordance with applicable regulations and ethical standards.

4. Discussion

The objective of this study is to determine the MTD of ITRA to be administered concurrently with RT and TMZ and to determine the recommended phase II dose (RP2D) of ITRA to be used in further randomized studies in combination with concomitant RT and TMZ in patients with newly diagnosed GBM. The ultimate goal of our intervention (ITRA plus TMZ and RT) is to delay disease progression and improve survival of patients with GBM. This is based on the fact that ITRA can inhibit several signaling pathways associated with the progression of GBM and the development of treatment resistance (Hh, PI3K/AKT/mTOR, VEGF/VEGFR2).

Although no Phase 0 studies have been conducted to determine the ITRA brain concentration and ITRA has not yet been administered to patients with GBM, it can be anticipated that ITRA crosses the blood–brain barrier. Ideally, ITRA concentrations in the tumor and in the brain should be measured during treatment with RT. However, this would require performing invasive tumor biopsies on patients who are already undergoing treatment with RT, TMZ, and ITRA, which is ethically unacceptable. Excellent results have been reported in the treatment of Cryptococcal Meningitis [24], CNS histoplasmosis [25], and Aspergillus brain abscesses [26]. Based on the properties of ITRA (being a poorly water-soluble drug) and cerebrospinal fluid (CSF) being an aqueous solution, significant amounts of ITRA would not be predicted to be detected in CSF. However, ITRA is highly lipophilic and therefore has been detected in many organs and tissues (skin, lung, kidney, liver, fat, spleen, muscle and bone) at a higher concentration than that seen in plasma (by a factor of 1.5–20) [27]. Lipophilicity is also one of the most important drug characteristics related to its optimal penetration into the CNS [28]. It has been shown that one hour after a single intravenous dose of ITRA, concentrations in the brains of healthy rats exceeded plasma concentrations by a factor of 1.7, and after 24 h, concentrations were 24 times higher [29]. Finally, RT may increase the permeability of the blood–brain barrier, which may lead to additional penetration of ITRA into GBM tissue [30].

The acidity of the stomach plays an important role in the solubility of ingested drugs by promoting their absorption. ITRA is a weak base that is only ionized at low pH values. Various classes of medication, such as PPI, histamine receptor antagonists and antacids, increase the pH value of the stomach and thus reduce the absorption of ITRA. Achlorhydria is a condition in which the stomach does not produce hydrochloric acid, a component of stomach acid, resulting in reduced acidity. In an open, randomized, three-way crossover study, it was shown that the bioavailability of itraconazole was significantly reduced when the pH of the stomach was increased by pretreatment with ranitidine. This effect was counteracted by the simultaneous administration of an acidic beverage such as Coca-Cola (pH = 2.7), which transiently decreased the pH of the stomach. For these reasons, patients participating in this study should take ITRA with a cola beverage if they are taking medications that lower stomach acid or have been diagnosed with achlorhydria for other reasons.

ITRA is extensively metabolized by the liver into various metabolites, and a small amount is excreted unchanged in the urine. Drugs, which are well known as enzymatic inducers (rifampicin, rifabutin, diphenylhydantoin and carbamazepine), reduce serum levels of ITRA, while enzymatic inhibitors such as clarithromycin, erythromycin, ritonavir and indinavir increase ITRA serum concentrations. ITRA is a potent inhibitor of cytochrome P450 3A4, a member of the cytochrome P450 family of oxidizing enzymes, which play a fundamental role in the oxidation of small foreign organic molecules, such as toxins or drugs, so that they can be eliminated from the body. For this reason, ITRA will be administered with particular caution or will be contraindicated if the patient is already being treated or is to be treated with drugs that may interact with ITRA.

In GBM patients, dexamethasone is commonly used for symptomatic treatment of increased intracranial pressure. ITRA is a potent inhibitor of cytochrome P450 3A4. It has been reported that ITRA markedly increases the plasma concentrations of dexamethasone and enhances its adrenal suppressant effect [31]. Based on this fact, in this trial treatment with dexamethasone will not be allowed. Subjects requiring steroid medication to treat symptoms of increased intracranial pressure will be treated with prednisolone due to the fact that ITRA has no effect on prednisolone pharmacokinetics [32]. Both bind to the glucocorticoid receptor in the cell nucleus, where they influence the expression of certain genes involved in the anti-inflammatory response [33]. Their main difference lies in their potency—dexamethasone is five to six times more potent than prednisolone. In addition, dexamethasone has a longer duration of action compared to prednisolone (half-life 36–72 vs. 12–36 h).

The dose of prednisolone will be calculated using the online Corticosteroid Conversion Calculator [34]. Data on medication with corticosteroids, antiepileptics and analgesics will be recorded in the Case Report Form until the last follow-up visit.

The inclusion and exclusion criteria for our study are the same as those of the original Stupp study. We will also include patients for whom surgical resection was not possible if they can be treated with the standard Stupp regimen (60 Gy in 30 fractions with simultaneous administration of 75 mg/m² temozolomide based on body-surface area).

The side effect profile of ITRA is well known. Patients with fungal infections tolerate ITRA well, even with prolonged use at higher doses. The dose and duration of ITRA treatment for fungal infections are variable (100–400 mg daily for one week to three months) and depend on the type of fungal pathogen and the organs affected. In a randomized trial, 46 men with chemotherapy-naive metastatic castration-resistant prostate cancer were randomized to treatment with ITRA at low (200 mg/day) (n = 17) or high dose (600 mg/day) (n = 29) until disease progression or unacceptable toxicity. The median duration of ITRA treatment was 11.9 weeks in the low-dose group and 23.6 weeks in the high-dose group. Fatigue, pain, nausea, and constipation were common toxicities in both arms. In the low-dose group, three patients developed grade 3 toxicities (fatigue, anorexia, skin rash), while in the high-dose group, grade 3 toxicities were observed in six patients (three patients developed hypokalemia, two patients developed hypertension, and one patient developed skin rash).

There are no known interactions between ITRA and TMZ, but due to the fact that we plan to also use a 600 mg daily dose (the final cohort), which has already shown relevant toxicities, and that our study is not designed as a seamless phase I/II, we assume that a classical 3 + 3 design would be most appropriate [35]. The 3 + 3 design is primarily driven by the appearance of possible toxicities and thus is indeed a conservative approach, but appears appropriate due to our expectation of a low event rate. However, it fails to provide clinical information in terms of follow-up assessment, which was not the primary objective of this trial. In addition, other approaches, such as any design based on Bayesian statistics, need prior information, which was not available for the trial’s primary hypothesis. Thus, we need to point out that the trial is exploratory in nature and needs to be interpreted as such.

Studies on the use of ITRA in antifungal therapy have shown that most side effects occur within the first two months of treatment [36]. For this reason, and given that our participants will visit our clinic once a month after completing treatment and that no overlapping toxicities between ITRA, TMZ, and RT have been reported, we have concluded that a follow-up period of one week is sufficient.

Despite the fact that ITRA has complex pharmacodynamic and pharmacokinetic properties, we are confident that, with careful consideration, this drug could be administered to patients with newly diagnosed GBM with concurrent RT and TMZ treatment. It is a common and inexpensive antifungal drug that is widely available. If a positive effect on survival is observed in a randomized trial, ITRA could be used in clinical practice. Due to the ease of administration and cost of the drug, this treatment approach could have a major impact on the treatment of GBM patients worldwide.

5. Conclusions

Due to its aggressiveness, high recurrence rate, and limited treatment options, the management of GBM remains a therapeutic challenge. ITRA is an antifungal agent with a well-studied toxicity profile. This drug has shown promising preliminary results in other types of cancer, and we believe that ITRA could also enhance the efficacy of standard therapy with radiation therapy and temozolomide without increasing its toxicity. If this is confirmed, the addition of this readily available and cost-effective drug could have a tremendous impact worldwide on the treatment of this tumor, for which there remains a significant unmet need.