Table 3 Previous and ongoing clinical trials inclusive of single-agent treatments directed against protein and lipid kinases in high-grade gliomas. DIPG – diffuse intrinsic pontine glioma; DLT – Dose-limiting toxicity; EGFR – epidermal growth factor receptor; ERK – extracellular signal-regulated kinase; FGFR – fibroblast growth factor receptor; GBM – glioblastoma; HGG – high-grade glioma; MAPK – mitogen-activated protein kinase; MEK – mitogen-activated protein kinase kinase; MET – mesenchymal-epithelial transition factor; MTD – maximum tolerated dose; PD – pharmacodynamic; PDGFR – platelet-derived growth factor receptor; PFS – progression-free survival; pHGG – pediatric high-grade gliomas; PI3K – phosphatidylinositol-3 kinase; PK – pharmacokinetic; RT – radiation therapy; VEGFR – vascular endothelial growth factor

EGFR

Erlotinib

Recurrent EGFRvIII GBM

I

Clinical benefit rate, no results yet (NCT01257594)

Pediatric recurrent brain tumors and brain stem glioma [65]

I

Tolerable safety profile in pediatric patients (NCT00418327)

Recurrent GBM [66]

I/II

High toxicity and minimal benefit as monotherapy (NCT00301418)

Young patients with newly diagnosed GBM [67]

I/II

Tolerable safety profile but poor efficacy (NCT00124657)

Recurrent GBM [68]

II

Insufficient single-agent activity and no improvement in survival (NCT00086879)

Recurrent GBM

II

Disease progression in all patients, study terminated (NCT00387894)

Recurrent or progressive GBM

II

Response rate, no results yet (NCT00054496)

Gefitinib

Adult GBM [69]

I/II

Well tolerated when combined with RT, but median survival is similar to RT alone (NCT00052208)

Newly diagnosed pediatric brain stem gliomas [70]

I/II

Tolerable safety profile (NCT00042991)

Newly diagnosed GBM [71]

II

No improvement in overall survival (NCT00014170)

Recurrent GBM after standard treatment [72]

II

Dephosphorylates EGFR without affecting downstream signaling (NCT00250887)

Afatinib

Recurrent GBM

I/II

Tolerable safety profile but limited single-agent efficacy (NCT00727506)

Lapatinib

(EGFR/HER2)

Recurrent HGG

I

Determine PK and PD parameters, no results yet (NCT02101905)

Dacomitinib

Recurrent GBM with EGFR amplification or EGFRvIII [73]

II

Limited single-agent activity (NCT01520870)

Epitinib

GBM

I

Objective response rate, no results yet (NCT03231501)

Tesevatinib

Recurrent GBM

II

Limited single-agent activity (NCT02844439)

PI3K

Paxalisib

pHGG

I

Determine the MTD, adverse effects, and pharmacokinetic profile, no results yet (NCT03696355)

Newly diagnosed GBM

II

Determine DLTs, no results yet (NCT03522298)

MEK

Trametinib

Pediatric gliomas with MAPK/ERK activation

II

Objective response rate, no results yet (NCT03363217)

ERK

Ulixertinib

Advanced solid tumors with MAPK pathway mutations, including recurrent/refractory gliomas

II

Objective response rate, no results yet (NCT03698994, NCT03155620, NCT02465060, NCT04566393)

FGFR

Pemigatinib

Recurrent GBM with activating FGFR1-3 alterations

II

Objective response rate, no results yet (NCT05267106)

Infigratinib

Recurrent GBM with FGFR1-3 alterations [20]

II

16% PFS at 6 months (limited efficacy, but disease control in a subset of patients with FGFR1/3 point mutations and FGFR3-TACC3 fusions) (NCT01975701)

Recurrent HGG with FGFR1/3 point mutations or FGFR3-TACC3 translocation

I

Determine the PK parameters and 6-month PFS for expansion cohort, no results yet (NCT04424966)

Erdafitinib

Advanced solid tumors with FGFR mutations, including relapsed malignant gliomas

II

Response rate, no results yet (NCT03210714); objective response rate, no results yet (MATCH trial: NCT02465060)

PDGFR

Crenolanib

DIPG or recurrent pHGG [21]

I

Toxicity profile similar to adults, but no preliminary signs of efficacy (NCT01393912)

Recurrent GBM with PDGFR alteration

II

PFS at 6 months, no results yet (NCT02626364)

Avapritinib

(KIT/PDGFRA)

Pediatric solid tumors with KIT/PDGFRA alteration

I/II

Determine dose for phase II and overall response rate, no results yet (NCT04773782)

MET

Bozitinib

(PLB-1001)

Recurrent glioma with MET fusion [22]

I

Tolerable safety profile and partial response in two patients (NCT02978261)

Vebreltinib

(APL-101)

Advanced solid tumors, including GBM

I/II

Determine the MTD, DLT, and objective response rate, no results yet (NCT03175224)

KIT

DCC-2618

Advanced malignancies, including glioma

I

Determine safety, MTD, ORR, and DCR, no results yet (NCT02571036)

VEGFR

Anlotinib

(multi-targeted agent)

Recurrent GBM/HGG [74]

I/II

PFS, no results yet (NCT04004975; NCT04822805)

AXL

Bemcentinib (BGB324)

Recurrent GBM undergoing surgery

I

Determine the PK and PD parameters, no results yet (NCT03965494)