Table 3.

Phase 2 clinical trials.

Study (Year)	Trial name	Patient criteria	Number of patients	Drug	Primary endpoint	Outcome
Lassman et al37 (2022)	A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma	Patients with recurrent glioblastoma and Karnofsky Performance Status ≥60.	76	Selinexor (an oral selective inhibitor of exportin-1 (XPO1))	To assess intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma.	Single-agent selinexor at 80 mg weekly showed promising responses and PFS6, with ongoing trials exploring combination therapies for glioblastoma.
Preusser et al38 (2022)	Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)	Adult patients with recurrent WHO grade 2 or 3 meningioma.	90	Local standard of care arm (LOC), n = 29; trabectedin (alkylating agent) arm, n = 61	To assess progression-free survival (PFS).	No benefits in terms of progression-free survival (PFS) and overall survival (OS) compared to the standard treatment (LOC) in patients with non-benign meningioma. Additionally, trabectedin was found to be associated with increased toxicity levels compared to the standard treatment.
Bota et al39 (2022)	Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment	Adults (18–70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful tumor initiating cells (TIC) culture, and sufficient monocytes collected.	60	AV-GBM-1 (Aivita glioblastoma multiforme vaccine – 1: a tumor-initiating cell targeted dendritic cell vaccine)	To assess the manufacturing success rate of the Aivita glioblastoma multiforme vaccine - 1 (AV-GBM-1), investigate associated adverse events (AE), and analyze survival outcomes.	The success rates for TIC production and monocyte collection were 97 %. Median progression-free survival (mPFS) from enrollment was 10.4 months, while median overall survival (mOS) was 16.0 months. The two-year overall survival rate was 27 %. The mPFS exceeded historical benchmarks, but no improvement in mOS was observed.
Fangusaro J et al40 (2021)	A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study	Children with recurrent/progressive optic pathway and hypothalamic gliomas (OPHGs).	25	Selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor.	To evaluate the efficacy of selumetinib.	Selumetinib showed positive responses and prolonged disease stability in children with optic pathway gliomas.
Gilbert et al41 (2021)	A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma	Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma.	50	Temozolomide (TMZ) and lapatinib	To evaluate the effectiveness of this targeted treatment approach for ependymomas with specific molecular features	The treatment was well tolerated and showed promising results. The median progression-free survival (PFS) was 7.8 months, with 55 % and 38 % of patients having PFS rates at 6 and 12 months respectively. This treatment can be considered as a salvage regimen for adult patients with recurrent ependymoma, offering disease control and symptom improvement.
Nayak et al42 (2021)	Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma	Patients with recurrent glioblastoma	80	The study included two cohorts: cohort A with 50 patients receiving pembrolizumab in combination with bevacizumab, and cohort B with 30 patients receiving pembrolizumab alone.	To assess 6-month progression-free survival (PFS-6)	Pembrolizumab, with or without bevacizumab, showed limited benefit and tolerability.
Cheung et al43 (2021)	Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression	Patients with high risk-neuroblastomas (HR-NB) who achieved remission after salvage therapies.	102	Anti-di/trisialoganglioside monoclonal antibody (Anti-GD2/GD3) vaccine plus oral β-glucan.	To assess the kinetics of mounting antibody response to vaccine and its prognostic impact on survival.	Patients with a history of disease progression (PD) episodes and prior anti-GD2 monoclonal antibody (mAb) therapy showed promising outcomes when treated with a GD2/GD3 vaccine plus β-glucan. The 5-year progression-free survival (PFS) was 32 % ± 6 % and overall survival (OS) was 71 % ± 7 %. Serum antibody levels against GD2 and GD3 significantly increased with β-glucan treatment. Higher antibody levels were associated with improved survival.
Levy et al44 (2021)	Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial	Patients with relapsed/refractory medulloblastoma (MB) or central nervous system primitive neuroendocrine tumor (CNS PNET)	105	Patients were randomly assigned to two treatment groups. Both groups received temozolomide (150 mg/m2/day orally, days 1–5) and irinotecan (50 mg/m2/day IV, days 1–5); the second group also received bevacizumab (10 mg/kg IV on days 1 and 15).	To compared the overall survival (OS) of patients with the specified regimen.	The median overall survival (OS) was reported to be 13 months in the standard arm and 19 months with the addition of bevacizumab. The addition of bevacizumab to TMZ/irinotecan reduced the risk of death in children with recurrent MB and was well tolerated.
Brown et al45 (2021)	A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma	Patients with newly diagnosed glioblastoma.	90	Proton radiotherapy (PT) or intensity-modulated radiotherapy (IMRT)	The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs).	The median follow-up was 48.7 months. Time to cognitive failure did not differ significantly between treatment arms. Proton therapy (PT) was associated with lower fatigue rates but showed no significant differences in other patient-reported outcomes (PROs) at 6 months. There were no differences in progression-free survival (PFS) or overall survival (OS) between treatment arms.
Peereboom et al46 (2021)	A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma	Patients With Recurrent/Progressive Glioblastoma	47	RO4929097 (an oral gamma secretase inhibitor).	To determine the 6-month progression-free survival rate (PFS6) in patients with progressive glioblastoma (GBM) and to achieve a 50 % reduction in the formation of neurospheres in fresh tissue obtained from patients treated with RO4929097 (an oral gamma secretase inhibitor).	7 of the patients underwent tumor resection. Only 4 % achieved a 6-month progression-free survival (PFS6), and neurosphere formation inhibition was observed in just 1 out of the 7 patient samples.
Brastianos et al47 (2021)	Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis	Patients with leptomeningeal disease.	18	Combination of ipilimumab (cytotoxic T lymphocyte antigen-4 inhibitor) and nivolumab (programmed death-1 inhibitor).	To evaluate the overall survival at 3 months (OS3) as the primary outcome. Secondary endpoints include assessing toxicity, cumulative time-to-progression at 3 months, and progression-free survival.	The study achieved the primary endpoint of 3-month overall survival (OS3), with 8 out of 18 patients (OS3 0.44; 90 % CI: 0.24 to 0.66) alive at that time. Combined ipilimumab and nivolumab showed promising activity in patients with leptomeningeal disease (LMD) and an acceptable safety profile.
Wright et al48 (2021)	A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma	Patients with low-grade glioma	23	Everolimus (mTOR inhibitor)	To assess the effectiveness, pharmacokinetics (PK), and pharmacodynamics of everolimus as a standalone treatment in pediatric patients with radiographically progressive low-grade glioma (LGG).	The 2-, 3-, and 5-year progression-free survival rates were 39 %, 26 %, and 26 % respectively. Overall survival rates were all 93 %. Everolimus demonstrated tolerability with manageable toxicities.
Tabouret et al49 (2021)	TEMOBIC: Phase II Trial of Neoadjuvant Chemotherapy for Unresectable Anaplastic Gliomas: An ANOCEF Study	Adult patients diagnosed with unresectable anaplastic oligodendroglioma or mixed gliomas, as per the World Health Organization (WHO) 2007 classification.	55	Combination of carmustine (BCNU:nitrosourea) and temozolomide prior to undergoing radiotherapy.	To assess progression-free survival and response to therapy.	IDH mutation correlated with improved PFS and OS, while MGMT promoter methylation associated with better OS. BCNU and temozolomide combination demonstrated efficacy but had limited use due to toxicity.
Sim et al50 (2021)	A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study	Patients with unmethylated MGMT glioblastoma	125	The experimental arm received veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide, while the standard arm received concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide.	To extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.	The veliparib-containing regimen was well tolerated, but there was insufficient evidence of clinical benefit in this specific population.
Dufour et al51 (2021)	Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5	Patients aged 5–19 years with newly diagnosed high-risk medulloblastoma	51	Etoposide and carboplatin followed by two courses of high-dose thiotepa (alkylating agent) with hematological stem cell support. Risk-adapted craniospinal radiation therapy was given within 45 days after the stem cell rescue, followed by temozolomide 1–3 months later.	To evaluate the 3-year progression-free survival (PFS) and identify the molecular characteristics linked to PFS in children and adolescents aged 5–19 years who were diagnosed with high-risk medulloblastoma.	The 3-year and 5-year progression-free survival rates were 78 % and 76 % respectively, and the overall survival rates were 84 % and 76 % respectively. Medulloblastoma subtype and molecular subgroup were significant prognostic factors.
Goldman et al52 (2020)	Phase II study of peginterferon alpha-2b for patients with unresectable or recurrent craniopharyngiomas: a Pediatric Brain Tumor Consortium report	Patients with unresectable or recurrent craniopharyngiomas	19	Patients were enrolled in one of 2 strata: patients previously treated with surgery alone (stratum 1) or who received radiation (stratum 2). Pegylated interferon alpha-2b was then given to both strata.	To determine tolerability and progression-free survival	The therapy was well tolerated without severe toxicities. The use of pegylated interferon alpha-2b as a treatment for recurrent craniopharyngiomas in children and young adults was well tolerated. While objective responses were limited, the encouraging results in progression-free survival suggest the need for further studies.
Puduvalli et al53 (2020)	A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma	Adults (aged 18 years and above) diagnosed with recurrent glioblastoma multiforme (GBM) after previous radiation therapy. Patients were required to have adequate organ function, a Karnofsky Performance Score (KPS) of 60 or higher, and no prior treatment with bevacizumab or histone deacetylase (HDAC) inhibitors.	90	Bevacizumab + Vorinostat (histone deacetylase inhibitor) versus Bevacizumab alone	Progression-free survival (PFS)	There was no significant difference observed in median progression-free survival (PFS) (3.7 months vs 3.9 months, p = 0.94) and median overall survival (OS) (7.8 months vs 9.3 months, p = 0.64) between the two treatment arms.
Fisher et al54 (2020)	Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424	Patients with low-grade gliomas, who present with three or more risk factors, including but not limited to the following: age equal to or exceeding 40 years, presence of astrocytoma, occurrence of a bihemispheric tumor, tumor size equal to or exceeding 6 cm, or preoperative neurologic function status greater than one, face distinct challenges in their medical journey.	136	Radiation alongside the administration of TMZ.	Overall survival (OS) at 3 years	The 5-year and 10-year OS rates were 60.9 % and 34.6 %, respectively, while the 5-year and 10-year progression-free survival (PFS) rates were 46.8 % and 25.5 %, respectively. Long-term results confirmed the efficacy of the RT-TMZ regimen, outperforming radiation-only control groups. Acceptable levels of toxicity were observed.
Van Den Bent et al55 (2020)	INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma	Patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide.	260	Depatuxizumab mafodotin (Depatux-M): an antibody-drug conjugate that targets tumor cells, administered with temozolomide as part of the treatment regimen.	Overall survival	Combining Depatux-M with temozolomide shows promise for treating recurrent glioblastoma with amplified EGFR, especially in patients who relapse after initial treatment. The 12-month survival rate was approximately 39.7 %, with a 24-month survival rate of around 19.8 %.
Balana et al56 (2020)	A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01)	Patients with glioblastoma who had not progressed after 6 cycles of temozolomide	159	Patients were randomly assigned to either discontinue temozolomide (control arm) or continue with the same doses they were receiving in cycle 6 for a maximum of 12 cycles (experimental arm).	Differences in 6-month progression-free survival (PFS)	Continuing temozolomide after 6 adjuvant cycles did not show any differences in 6-month progression-free survival (PFS), overall survival (OS), or PFS compared to stopping temozolomide.
Cloughesy et al57 (2020)	A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)	Patients with recurrent glioblastoma (rGBM)	256	Ofranergene obadenovec (VB-111), which is an anticancer viral therapy, along with bevacizumab or to receive bevacizumab alone (control arm).	Overall survival (OS)	The combination of Ofranergene obadenovec (VB-111) and bevacizumab did not significantly improve overall survival (OS) compared to bevacizumab alone, with median OS of 6.8 months in the combination arm and 7.9 months in the control arm.
Lafay-Cousin et al58 (2020)	Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children's Oncology Group (ACNS1221)	Children younger than 4 years of age with either nodular-desmoplastic or extensive-nodularity medullaoblastoma	25	The modified HIT SKK 2000 regimen described elsewhere59,60 was used for their treatment, excluding intraventricular methotrexate.	To achieve a comparable outcome, specifically a 2-year progression-free survival (PFS) rate of at least 90 %, while minimizing treatment-related neurotoxicity.	The two-year progression-free survival (PFS) rate was 52 % (95 % CI, 32.4 %–71.6 %), and the overall survival rate was 92 % (95 % CI, 80.8 %–100.0 %) in the study. However, the modified regimen of conventional systemic chemotherapy, which excluded serial intraventricular methotrexate injection, did not meet the targeted 2-year PFS rate of 90 %.
Wen et al61 (2019)	A Randomized Double-Blind Placebo-Controlled Phase II Trial of Dendritic Cell Vaccine ICT-107 in Newly Diagnosed Patients with Glioblastoma	Patients with GBM and HLA-A1+ and/or -A2+ genes and residual tumor ≤1 cm3.	124	Patients in the study were assigned to receive either ICT-107, which involved autologous dendritic cells pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens, or a control treatment with unpulsed dendritic cells followed by adjuvant temozolomide for 12 months.	Median overall survival	No significant difference in overall survival (OS) compared to control. However, ICT-107 showed improved progression-free survival (PFS) by 2.2 months (P = 0.011) without compromising quality of life (QoL). HLA-A2 subgroup patients demonstrated increased clinical and immunological activity.
Lee et al62 (2019)	Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma	Adult patients with bevacizumab-refractory GBM and variants, Karnofsky performance score (KPS) ≥60, measurable disease, and normal organ and marrow function.	15	Ponatinib (protein kinase inhibitor)	3-month progression-free survival.	No positive responses to treatment were observed. The drug ponatinib showed minimal activity in GBM patients who were refractory to bevacizumab.
Wen et al63 (2019)	Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial	Patients With Recurrent Glioblastoma	65	Buparlisib (pan-PI3K inhibitor) for a period of 7–13 days prior to the surgery.	PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.	Buparlisib showed limited efficacy as a single-agent treatment for recurrent glioblastoma, with only 8 % achieving a 6-month progression-free survival rate.
Kaley et al64 (2019)	Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma	Adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy.	30	Perifosine (PRF) - oral alkylphospholipid which has anti-cancer effects.	6-month progression free survival (PFS6) rate	While PRF was tolerable, it did not prove effective when used alone for GBM.
Blakeley et al65 (2019)	Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma	Adult patients with Newly Diagnosed Glioblastoma	81	Iniparib (induces cell death through intracellular conversion to nitro radical ions)	To achieve an improved mOS compared to a historical control	Iniparib, when used in combination with radiotherapy and temozolomide, was well tolerated in newly diagnosed GBM patients at doses up to 17.2 mg/kg weekly.
Brandes et al66 (2019)	A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma	Patients with newly diagnosed glioblastoma	296	Patients with glioblastoma received surgery, radiotherapy, temozolomide, and bevacizumab (BEV). Upon progression (PD1), they were assigned to lomustine (CCNU) plus BEV or placebo until further progression (PD2), then continued with BEV or placebo and chemotherapy.	To determine survival from randomization.	There were no significant differences in median progression-free survival (PFS2 and PFS3) or time to deterioration in health-related quality of life between the two groups. The study did not find evidence supporting the continued use of BEV in recurrent glioblastoma.