Table 2 Clinical studies of recent targeted combinatorial therapies in GBM. (Data from http://clinicaltrials.gov was searched until Nov 2023)

VEGF, PD-1

Bevacizumab + Nivolumab

2

GBM

NCT03452579

(Active, not recruiting)

-

Yes

Unreported

OS-1: 46.2% for standard bevacizumab, 37.7% for low dose bevacizumab

VEGF, PD-1

Bevacizumab + Nivolumab

2

GBM

NCT03743662

(Active, not recruiting)

-

Yes

Ongoing

Ongoing

VEGF, PD-1

Bevacizumab + Camrelizumab

2

rGBM

NCT04952571

(Suspended, non-drug related)

-

No

Suspended

Suspended

VEGF, PD-1

Bevacizumab + Pembrolizumab

2

rGBM

NCT03661723

(Active, not recruited)

-

Yes

Median: 4 months

PFS-6: 10.6%

Median: 8.6 months

OS-6: 56.7%

OS-12: 16.6%

VEGF, PD-1

Bevacizumab + Tislelizumab

2

rGBM

NCT05540275

(Not yet recruiting)

-

Yes

Ongoing

Ongoing

VEGF, PD-1

Bevacizumab + Sintilimab

2

rGBM

NCT05502991

(Not yet recruiting)

-

Yes

Ongoing

Ongoing

VEGF, PD-1

Bevacizumab + Durvalumab

2

rGBM

NCT02336165

(Completed)

-

Yes

Median: 16 weeks

PFS-6: 15.2%

Median: 19.3 weeks

OS-6: 36.4%

VEGF, T-cell

Bevacizumab + GX-17

2

rGBM

NCT05191784

(Active, not recruiting)

-

Yes

Ongoing

Ongoing

VEGF, endoglin

Bevacizumab + TRC105

2

GBM

NCT01564914

(Completed)

-

Yes

Median: 1.81 months

Median: 5.75 months

VEGF, endoglin

Bevacizumab + TRC105

1/2

rGBM

NCT01648348

(Completed)

Tolerable, MTD: 10 mg/kg bevacizumab + 10 mg/kg TRC105

Yes

Median: 2.9 months

PFS-6: 25%

Median: 9.7%

VEGF, PI3K

Bevacizumab + BKM120

1/2

rGBM

NCT01349660

(Completed)

Tolerable at 60 mg/day BKM120

Yes

Median: 2.8 months for prior bevacizumab, 5.3 months for bevacizumab naïve

Median: 6.6 months for prior bevacizumab, 10.8 months for bevacizumab naïve

VEGF, mTOR

Bevacizumab + Everolimus

2

GBM

NCT00805961

(Completed)

-

Yes

Median: 11.3 months

Median: 13.9 months

VEGF, mTOR

Bevacizumab + nab-sirolimus

2

ndGBM

NCT03463265

(Completed)

-

Yes

Median: 3.1 months

PFS-6: 37.5%

PFS-12: 12.5%

Median: 6.8 months

OS-12: 25%

VEGF, mTOR

Bevacizumab + Sapanisertib

1

rGBM

NCT02142803

(Active, not recruiting)

MTD/RP2D: 5 mg/day

-

-

-

VEGF, angiopoietin1/2

Bevacizumab + Trebananib

1/2

rGBM

NCT01290263

(Completed)

Tolerable

Yes

Median: 285 days

PFS-6: 24.3%

Median: 108 days

VEGF, angiopoietin1/2

Bevacizumab + Trebananib

2

rGBM

NCT01609790

(Completed)

-

Yes

Median: 4.2 months

PFS-6: 22.6%

Median: 7.5 months

VEGF, proteasome

Bevacizumab + Marizomib

1/2

GBM

NCT02330562

(Completed)

Tolerable, RP2D: MRZ 0.8 mg/m²

Yes

Median: 3.9 months

Median: 10.4 months

VEGF, CDK4/6

Bevacizumab + Abemaciclib

1

rGBM

NCT04074785

(Active, not recruiting)

Ongoing

-

-

-

VEGF, multi-kinases

Bevacizumab + Ponatinib

2

rGBM

NCT02478164

(Completed)

-

Yes

Median: 28 days

PFS-3: 0%

Median: 98 days

VEGF, FASN

Bevacizumab + ASC40

3

rGBM

NCT05118776

(Recruiting)

-

Yes

Ongoing

Ongoing

VEGF, topoisomerase I

Bevacizumab + Irinotecan

1

rGBM

NCT05201326

(Recruiting)

Ongoing

-

-

-

VEGF, angiogenesis

Bevacizumab + VB-111

3

rGBM

NCT02511405

(Completed)

-

Yes

Median: 3.4 months

Median: 6.8 months

EGFR, glucose

Osimertinib + Fludeoxyglucose F-18

2

rGBM

NCT03732352

(Active, not recruiting)

-

Yes

Ongoing

Ongoing

EGFR, Osmolality

Cetuximab + Mannitol

1/2

GBM

NCT02861898

(Recruiting)

Ongoing

Yes

Ongoing

Ongoing

EGFR, multi-kinases

Erlotinib + Sorafenib

2

rGBM

NCT00445588

(Completed)

-

No

PFS-6: 14%

Median: 5.7 months

PI3K, c-MET

Buparlisib + INC280

1/2

rGBM

NCT01870726

(Terminated, no clear activity)

RP2D not declared due to drug-drug interactions

Yes

Combination arms not initiated

Combination arms not initiated

PI3K

Buparlisib + Carboplatin / Lomustine

1

rGBM

NCT01934361

(Completed)

MTD: 100 mg/day with carboplatin, not determined with lomustine

-

-

-

PI3K

Paxalisib + Metformin + Ketogenic diet

2

rGBM and unmethylated ndGBM

NCT05183204

(Recruiting)

-

Yes

Ongoing

Ongoing

PI3K, PD-1

Pictilisib + MK-3475

1/2

GBM

NCT02430363

(Unknown status)

Unreported

No

Unreported

Unreported

AKT, mTORC1

Perifosine + Temsirolimus

1

rGBM

NCT02238496

(Completed)

Tolerable at 115 mg/week temsirolimus with 100 mg/day perifosine

-

-

-

AKT, PD-L1

Ipatasertib + Atezolizumab

1/2

GBM

NCT03673787

(Unknown status)

RP2D: 400 mg/day ipatasertib with 1200 mg atezolizumab every 3 weeks

No

Unreported

Unreported

mTORC1, CDK4/6

Everolimus + Ribociclib

Early 1

rGBM

NCT03834740

(Completed)

Unreported

Yes

Unreported

Unreported

mTORC1, CDK4/6

Everolimus + Ribociclib

1

Glioma

NCT03355794

(Completed)

Tolerable, RP2D: 120mg/m² ribociclib with 1.2mg/m² everolimus

-

-

-

mTORC1, VEGF

Everolimus + Bevacizumab + TMZ

2

GBM

NCT00805961

(Completed)

-

Yes

Median: 11.3 months

Median: 13.9 months

mTORC1, EGFR

Temsirolimus + Erlotinib

1/2

Glioma

NCT00112736

(Completed)

MTD: 15 mg temsirolimus with 150 mg erlotinib

Yes

PFS-6: 13.95%

Unreported

mTORC1, EGFR

Sirolimus + Erlotinib

2

rGBM

NCT00672243

(Completed)

-

Yes

Median: 6.9 weeks

PFS-6: 3.1%

Median: 33.8 weeks

mTORC1, multi-kinases

Everolimus + Gefitinib

1/2

GBM

NCT00085566

(Completed)

Unreported

No

Unreported

Unreported

mTORC1, multi-kinases

Temsirolimus + Sorafenib

1/2

rGBM

NCT00329719

(Completed)

Considerable grade 3 + toxicity

MTD: 200 mg sorafenib twice daily with 20 mg temsirolimus weekly

Yes

Median: 2.6 months for VEGFi-naïve group, 1.9 months for VEGFi-treated group

Median: 17.1% for VEGFi-naïve group, 9.8% for VEGFi-treated group

Median: 6.3 months for VEGFi-naïve group, 3.9 months for VEGFi-treated group

mTORC1, multikinase

Sirolimus + Vandetanib

1

rGBM

NCT00821080

(Completed)

Tolerable, MTD: 200 mg vandetanib with 2 mg sirolimus

-

PFS-6: 15.8%

-

mTORC1, BCR-ABL tyrosine kinase, ribonucleotide reductase

Everolimus + Imatinib + Hydroxyurea

1

rGBM

NCT00613132

(Completed)

Unreported

-

-

-

mTORC1, AKT, 𝛾-secretase

Ridaforolimus + MK-2206 + MK-0752

1

rGBM

NCT01295632

(Completed)

Unreported

-

-

-

mTOR, proteasome

Nab-sirolimus + Marizomib

2

ndGBM

NCT03463265

(Completed)

-

Yes

Median: 1.7 months

PFS-6: 10%

PFS-12: 0%

Median: 6.7 months

OS-12: 0%

Proteasome, VEGF

Bortezomib + Bevacizumab

2

rGBM

NCT00611325

(Completed)

-

Yes

Median: 2 months for EIAED arm, 2.5 months for non-EIAED arm

PFS-6: 25% for EIAED arm, 28.6% for non-EIAED arm

Median: 8 months for EIAED arm, 6 months for non-EIAED arm

Proteasome, VEGF

Bortezomib + Bevacizumab + TMZ

1

rGBM

NCT01435395

(Completed)

Unreported

-

-

-

Proteasome, histone deacetylases

Bortezomib + Vorinostat

2

rGBM

NCT00641706

(Completed)

-

Yes

Median: 1.5 months for no surgery arm, 4.2 months for surgery arm

PFS-6: 0% for no surgery arm, 29% for surgery arm

Median: 3.2 months for no surgery arm, 8.7 months for surgery arm

Proteasome

Disulfiram + Copper + TMZ + Lomustine + PCV

2/3

rGBM

NCT02678975

(Completed)

-

Yes

Median: 2.3 months

Median: 5.5 months

OS-6: 44%

PARP

Talazoparib + Carboplatin

2

rGBM

NCT04740190

(Unknown status)

-

Yes

Unreported

Unreported

NSC

5-FU

1

rGBM

NCT01172964

(Completed)

Tolerable

-

-

-

NSC

5-FU, Leucovorin

1

rGBM

NCT02015819

(Completed)

Tolerable, RP2D: 150 × 10⁶ CD-NSCs

-

-

-

NSC

Irinotecan Hydrochloride

1

rGBM

NCT02192359

(Active, not recruiting)

Unreported

-

-

-

NSC

Adenovirus, TMZ

1

ndGBM

NCT03072134

(Completed)

Tolerable, RP2D: 1.50 × 10⁸ NSCs loading 1.875 × 10¹¹ viral particles

Yes

Median: 9.1 months

Median: 18.4 months

MSC

5-FU

1/2

rGBM

NCT04657315

(Completed)

Tolerable

Yes

Median: >4 months

Median: not reached

MSC

Adenovirus

1

rGBM

NCT03896568

(Recruiting)

Ongoing

-

-

-