Selected clinical trials evaluating TMZ-based therapeutic strategies in GBM patients.
| Trial No./Year/Status/Phase | Description | Mechanism of action/pathway involved | Ref. |
|---|---|---|---|
| Trial investigating the safety, tolerability, and pharmacokinetics of pitavastatin (statin) in combination with TMZ in patients with recurrent or progressive GBM. | Pitavastatin inhibits HMG-CoA reductase, potentially disrupting cholesterol synthesis and prenylation pathways critical for cell survival and enhance TMZ sensitivity through redox and metabolic modulation. | [124] |
| A multicenter, double-blind, placebo-controlled trial evaluated the efficacy of combining nabiximols (a cannabinoid extract, trade name Sativex®) with TMZ in patients with recurrent MGMT-methylated GBM. | Modulation of cannabinoid receptors, potentially affecting tumor growth and chemotherapy response. | [114] |
| Open-label dose-escalation study assessing the safety and maximum tolerated dose of regorafenib and TMZ, with or without radiotherapy, in newly diagnosed MGMT-methylated, IDH-wild-type GBM patients. | Regorafenib is a multi-kinase inhibitor targeting tumor proliferation and angiogenesis pathways. | ongoing |
| The trial evaluates the safety and efficacy of daratumumab (an anti-CD38 monoclonal antibody) combined with radiation therapy and TMZ in newly diagnosed GBM patients. | Daratumumab targets CD38, which is expressed on tumor cells, enhancing the anti-tumor effects of standard therapies. | ongoing |
| Randomized placebo-controlled trial of dasatinib with RT/TMZ in newly diagnosed GBM; no survival benefit was observed. | Dasatinib inhibits Src protein-tyrosine kinase to reduce invasion and enhance radiosensitivity with RT/TMZ. | [125] |
| Evaluated the safety and efficacy of combining TTFields, pembrolizumab (an anti–PD-1 monoclonal antibody), and TMZ in patients with newly diagnosed GBM. | TTFields disrupt cancer cell division, while pembrolizumab exerts immune checkpoint inhibition. | [126] |
| Retrospective analysis of phase III trial assessing the impact of TMZ dosing time (morning vs. evening) on treatment efficacy in newly diagnosed GBM patients. | Chronotherapy approach based on circadian regulation influencing DNA repair and TMZ sensitivity. | [127] |
| Compared the efficacy of TMZ combined with interferon alfa versus TMZ alone in patients with newly diagnosed high-grade gliomas. The combination treatment prolonged survival, especially in patients with MGMT unmethylated tumors, with tolerable toxic effects. | Immunomodulation of interferon alfa enhancing antitumor activity. | [128] |
| Investigated the safety and efficacy of a combination therapy (CUSP9v3) involving nine repurposed drugs alongside continuous low-dose TMZ in patients with recurrent GBM. | Multi-targeted approach aiming to disrupt various survival pathways in GBM cells. | [129, 130] |
| Trial evaluating the safety and tolerability of combining TN-TC11G (a THC/CBD-based therapy) with standard radiotherapy and TMZ in patients with newly diagnosed GBM. | THC/CBD exerts anti-tumor, anti-inflammatory, and pro-apoptotic effects combined with DNA-damaging TMZ and radiation. | ongoing |
| Trial assessing the safety and efficacy of DeltEx γδ T cell immunotherapy (allogeneic/autologous) in combination with maintenance TMZ in patients with newly diagnosed or recurrent GBM. | Immunotherapy using engineered γδ T cells to enhance immune-mediated tumor killing combined with TMZ to maintain cytotoxic pressure. | ongoing |
| Trial evaluating the safety and dosing of Triapine (a ribonucleotide reductase inhibitor) in combination with TMZ in patients with recurrent GBM. | Triapine impairs DNA synthesis and repair, and in combination with TMZ, enhances cytotoxic DNA damage. | ongoing |
| Trial testing the safety and maximum tolerated dose of adavosertib combined with RT and TMZ in patients with newly diagnosed or recurrent GBM. | Adavosertib blocks Wee1 kinase, abrogates G2/M checkpoint, and drives RT/TMZ-damaged cells into premature mitosis causing mitotic catastrophe and death. | [131] |
| Pre-surgery “pulsatile” lapatinib (tyrosine-kinase inhibitor) in recurrent EGFR-amplified high-grade glioma to assess brain penetration and EGFR inhibition. | Lapatinib blocks EGFR signalling preventing downstream pathways critical for cell survival and proliferation. | / |
| Randomized trial evaluating whether the combination of lomustine, TMZ, and radiation improves overall survival in newly diagnosed MGMT-methylated GBM patients. | DNA alkylation and crosslinking (lomustine + TMZ) combined with DNA damage from radiation to enhance cytotoxicity in MGMT-methylated GBM. | [132] |
R: recruiting; C: completed; ANR: active, not recruiting; HMG-CoA: 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; RT: radiotherapy; TTFields: Tumor Treating Fields; THC: tetrahydrocannabinol; CBD: cannabidiol; EGFR: epidermal growth factor receptor.