Table 2.

Phase 1b or 2 clinical trials.

Study (Year)	Trial name	Patient criteria	Number of patients	Drug	Primary endpoint	Outcome
Todo et al26 (2022)	A phase I/II study of triple-mutated oncolytic herpes virus G47Δ in patients with progressive glioblastoma	Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies	13	G47Δ, a triple-mutated oncolytic herpes simplex virus type 1	To assess the safety (primary endpoint) of G47Δ, a triple-mutated oncolytic herpes simplex virus type 1	G47Δ was well-tolerated. Median overall survival was 7.3 months and the 1-year survival rate was 38.5 %.
Su et al27 (2022)	Phase I/II trial of vorinostat and radiation and maintenance vorinostat in children with diffuse intrinsic pontine glioma: A Children's Oncology Group report	Children with diffuse intrinsic pontine glioma	12	Vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor.	To determine the efficacy of the drug regimen by comparing the risk of progression or death	It was well tolerated, but did not improve overall survival.
Compter et al28 (2021)	Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: a phase IB trial	Patients with a newly diagnosed glioblastoma	13	Chloroquine in combination with radiotherapy and concurrent daily temozolomide	To explore the safety, pharmacokinetics and maximum tolerated dosages.	The maximum tolerated dose of chloroquine was 200 mg daily. Median overall survival was 16 months, with a 2-year survival rate of 38 %. Favorable toxicity and promising overall survival support further clinical studies of chloroquine for glioblastoma.
El-Khouly et al29 (2021)	A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma	Children with progressive diffuse intrinsic pontine glioma	9	Combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor erlotinib	To determine the safety, tolerability, and preliminary efficacy of combined treatment.	The median progression-free survival (PFS) at the start of the study was 7.3 months. The median overall survival (OS) was 13.8 months, and overall quality of life (QoL) was stable during treatment.
Narita et al30 (2021)	Safety and efficacy of depatuxizumab mafodotin in Japanese patients with malignant glioma: A nonrandomized, phase 1/2 trial	Japanese patients with World Health Organization (WHO) grade III/IV glioma.	53	Antibody-drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux-M) alone or combined with chemotherapy or chemoradiotherapy.	6-month progression-free survival (PFS) in patients with EGFR-amplified tumors receiving second-line Depatux-M plus chemotherapy.	The study was halted due to lack of survival benefit with first-line Depatux-M. Second-line Depatux-M plus chemotherapy showed a 6-month PFS estimate of 25.6 %.
Lim et al31 (2021)	Autologous adoptive immune-cell therapy elicited a durable response with enhanced immune reaction signatures in patients with recurrent glioblastoma: An open label, phase I/IIa trial	Patients with recurrent glioblastoma multiforme (GM).	14	Ex-vivo-expanded, and activated natural killer cells and T lymphocytes	To investigate the safety and efficacy of adoptive, ex-vivo-expanded, and activated natural killer cells and T lymphocytes from peripheral blood mononuclear cells of patients with recurrent GBM	Autologous adoptive immune-cell therapy was considered an effective treatment option for individuals with recurrent GBM (glioblastoma multiforme) who exhibited high immune responses in their tumor microenvironments.
Frappaz et al32 (2021)	MEVITEM-a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation	Patients with recurrent/refractory medulloblastoma	24	Vismodegib (sonic hedgehog inhibitor) + temozolomide (TMZ)	To explore the 6-month progression-free survival (PFS-6)	The addition of vismodegib to TMZ did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma.
Baxter et al33 (2020)	A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study	Patients with newly diagnosed diffuse pontine glioma.	65	Veliparib (a poly-ADP ribose polymerase inhibitor) and radiation followed by veliparib and temozolomide.	To determine the recommended phase II dose (RP2D) of veliparib when administered concurrently with radiation therapy, assess the pharmacokinetic parameters of veliparib during radiation treatment, evaluate the feasibility of intrapatient dose escalation of TMZ (temozolomide), document any toxicities associated with the protocol therapy, and estimate the overall survival distribution in comparison to historical series.	Veliparib at 65 mg/m2 b.i.d. Was the recommended phase II dose (RP2D) with radiation therapy, but it caused serious side effects such as intratumoral hemorrhage, rash, and nervous system disorder. The treatment did not improve survival compared to previous cases, so enrollment was stopped. The 1-year and 2-year survival rates were 37.2 % and 5.3 % respectively.
Brenner et al34 (2020)	Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study	Patients with recurrent glioblastoma	72	VB-111 (a type of adenovirus that does not replicate and contains a Fas-chimera transgene. It is designed to induce the targeted death of tumor blood vessel cells and stimulate a specific immune response against the tumor.) with or without bevacizumab	To assess the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma.	VB-111 was well tolerated, with the most common side effect being a temporary mild-moderate fever. The primed combination group showed significantly longer median overall survival compared to the LE and unprimed combination groups. Patients in the primed combination group also had a longer median progression-free survival compared to the LE group.
van den Bent et al35 (2020)	A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma.	Adult patients with recurrent glioblastoma	33	Capmatinib (a kinase inhibitor that targets mesenchymal epithelial transition) and Buparlisib (PI3K/AKT kinase inhibitor)	To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D)	The maximum tolerated dose was Capmatinib Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, common adverse events were headache, constipation, fatigue, and increased lipase. The combination of Capmatinib and buparlisib didn't show significant activity in PTEN-deficient glioblastoma patients, highlighting the need for stricter molecular selection strategies.
Wick et al36 (2020)	Phase 1 b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma	Patients with newly diagnosed malignant glioma	Galunisertib alone (n = 56); Combination of galunisertib and with temozolomide-based radiochemotherapy (n = 40)	Galunisertib (a TGF-β inhibitor) with temozolomide-based radiochemotherapy (TMZ/RTX)	To confirm the tolerability and pharmacodynamic profile of galunisertib when used alongside TMZ/RTX.	No significant differences were observed in terms of efficacy, safety, or pharmacokinetics between the two treatment approaches.