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. 2020 Apr 10;12(4):937. doi: 10.3390/cancers12040937

Table 1.

Published major clinical trials of targeted therapies from January 2017 to December 2019.

Treatment Disease Type Clinical Trial Phase No. of Patients Result (s) Reference
1 Alisertib + RT Recurrent I 17 OS-6: 88.2%; Median survival: 11.1 months; PFS-6: 35.5%. [84]
2 Lomustine + 52 TMZ vs. 52TMZ Primary III 141 Median OS: 48.1 months (32.6—not assessable) vs. 31.4 months (95% CI, 27.7—47.1);
AEs: 59% vs. 51% of patients.		 [85]
3 Disulfiram + copper Recurrent II 21 ORR: 0%; Clinical benefit: 14%; Median PFS: 1.7 months; Median OS: 7.1 months; DLTs: 4%. [86]
4 Ortataxel Recurrent II 40 PFS-6: 11.4%; AEs: Neutropenia and hepatotoxicity (13.2%) and leukopenia (15.8%). [87]
5 Buparlisib Recurrent II 15+50 Reduction of phosphorylated AKT: 42.8%; PFS-6: 8%; Median PFS: 1.7 months (95% CI, 1.4 to 1.8 months); AEs: Lipase elevation (10.8%), fatigue (6.2%), hyperglycemia (4.6%), elevated ALT (4.6%). [88]
6 Regorafenib vs.
2 Lomustine		 Recurrent II 119 Patients died at cut-off: 71% vs 95%;
Median OS: 7.4 months (95% CI, 5.8—12.0) vs. 5.6 months (95% CI, 4.7–7.3); AEs: 56% (hand–foot skin reaction, increased lipase, blood bilirubin) vs. 40% (decreased platelet count, decreased lymphocyte count, neutropenia).		 [89]
52 TMZ + RT → 52 TMZ + 7 irinotecan (CPT-11) Primary II 152 Median OS: 16.9 months vs 13. 7 months (p = 0.03) in historical control; Grade 3/4 hematologic toxicity: 38% vs. 14% in Stupp trial. [90]
8 Valproic acid + 52 TMZ + RT Primary II 6 Late toxicity in long-term survivors: neurological, pain, and blood/bone marrow toxicity (mostly grade 1/2). [91]
52 TMZ + 9 memantine + 10 mefloquine + 11 metformin (adjuvant) Primary I 81 DLTs: Dizziness (memantine), gastrointestinal effects (metformin); AEs: Lymphopenia (66%); Median survival: 21 months; 2-year survival: 43%; MTDs (doublet, triplet, quadruplet): Memantine (20 mg b.i.d., 10 mg b.i.d., 10 mg b.i.d.), mefloquine (250 mg 3 times weekly, 250 mg 3 times weekly, 250 mg 3 times weekly), metformin (850 mg b.i.d., 850 mg b.i.d., 500 mg b.i.d.). [92]
RT + 52 TMZ + 12 bevacizumab (BEV) →
2 CCNU + 12 BEV/
2 CCNU + placebo →
12 BEV/placebo + chemotherapy		 Recurrent II 296 No survival benefit and no safety concerns. [93]
13 ERC1671 + 12 bevacizumab vs. 12 bevacizumab + placebo Recurrent II 9 Median OS: 12 months vs. 7.5 months. [94]
14 Palbociclib (with and without resection) Recurrent II 22 Median PFS: 5.14 weeks (5 days–142 weeks); Median OS: 15.4 weeks (2–274 weeks). [95]
15 Iniparib + RT +
52 TMZ 		Primary II 81 Median OS: 22 months (95% CI, 17-24); 2- and 3-year survival: 38% and 25%; Grade 3 AEs: 27% of patients. [96]
16 Depatuxizumab mafodotin + 52 TMZ Recurrent I 60 AEs: blurred vision (63%), fatigue (38%), and photophobia (35%); Grade 3/4 AEs: Ocular (22%), non-ocular (22%); ORR: 14.3%; PFS-6: 25.2%; OS-6: 69.1%. [97]
17 Fotemustine (120 or 140 mg/m) Recurrent I/II 37 Toxicity: Grade 3 and 4 thrombocytopenia (4 of 6 patients at 140 mg/m vs. 3 of 31 patients at 120 mg/m); Median PFS: 12.1 (1–40.2) weeks; OS: 19.7 (1–102) weeks. [98]
18 AZD1775 Recurrent 0 20 BBB permeability; Median unbound tumor to plasma concentration ratio: 3.2. [99]
19 Bortezomib +
52 TMZ + RT		 Primary II 24 Median PFS: 6.2 months (95% CI 3.7–8.8); Median OS: 19.1 months (95% CI, 6.7–31.4); no unexpected AEs. [100]
20 Carboxyam-
idotriazole orotate + 52TMZ		 Recurrent/
Primary		 Ib 47 DLTs: none; Recommended phase II dose: 600 mg/day. [101]
12 Bevacizumab + RT vs. RT Primary II 75 Median PFS: 7.6 vs. 4.8 months, p = 0.003; OS: 12.1 vs. 12.2 months, p = 0.77. [102]
21 Interferon β + 52 TMZ + RT vs. 52TMZ + RT Primary II 122 OS: 24.0 vs. 20.3 months; Median PFS: 8.5 vs. 10.1 months; Neutropenia: 20.7 vs. 12.7 % (concomitant) and 9.3% vs. 3.6% (maintenance). [103]
12 Bevacizumab + 52 TMZ Primary II 66 Median OS: 23.9 weeks (95% CI 19–27.6); Median PFS: 15.3 weeks (95% CI, 12.9–19.3); AEs: Grade ≥ 3 hematological events (20%), high blood pressure (24%), venous thromboembolism (4.5%), cerebral hemorrhage (3%), and Intestinal perforation (3%). [104]
3 Disulfiram (with or without copper) + adjuvant 52 TMZ Primary I 18 MTD: Disulfiram 500 mg daily was well tolerated, 1000 mg daily was not;
Median PFS: 4.5 months (95% CI 0.8–8.2); Median OS: 14.0 months (95% CI 8.3–19.6). 		[7]
22 Temsirolimus +
23 sorafenib		 Recurrent I/II 41 MTD (Phase I): sorafenib (200 mg twice daily) and Temsirolimus (20 mg weekly); Median PFS and OS (Phase II): 2.6 months vs. 1.9 months (VEGF inhibitor-naïve vs. prior VEGF inhibitor patients) and 6.3 months vs. 3.9 months (VEGF inhibitor-naïve vs. prior VEGF inhibitor patients). [105]
24 Trebananib vs. 24 trebananib + 12 bevacizumab Recurrent II 48 Trebananib: Well tolerated as monotherapy; Trebananib + Bevacizumab: PFS-6 (24.3%, 95% CI, 12.1%-38.8%), Median OS (9.5 months, 95% CI, 7.5–4.7 months), OS-12 (37.8%, 95% CI, 22.6%–53.0%). [106]
25 Vorinostat +
12 bevacizumab + 52 TMZ		 Recurrent I/II 9+39 MTD (phase I): 400 mg for vorinostat; PFS-6 (phase II): 53.8% (95% CI, 37.2–67.9). [107]
25 Vorinostat +
12 bevacizumab		 Recurrent II 40 PFS-6: 30.0% (95% CI, 16.8%–44.4%); Median OS: 10.4 months (95% CI, 7.6–12.8 months); AEs (grade 2): Lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). AEs (grade 4): Leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). [108]
26 Everolimus + RT + 52 TMZ vs. RT + 52TMZ Primary II 171 Median PFS: 8.2 vs. 10.2 months, p = 0.79); Median OS: 16.5 vs. 21.2 months, p = 0.008) [109]
27 AXL1717 Recurrent I 9 Tumor response: 44%; AEs: Neutropenia. [110]
28 ONC201 Recurrent II 17 Median OS: 41.6 weeks; PFS-6: 11.8%; Drug-related serious AEs: None; Plasma pharmacokinetics (2-h post-dose): 2.6 µg/mL. [111]
29 Nivolumab (with or without 30 ipilimumab) Recurrent I 40 Nivolumab monotherapy better tolerated; AEs: fatigue, and diarrhea; Tumor-cell programmed death ligand-1 expression ≥1% (68%). [112]
31 Cabozantinib Recurrent II 70 ORR: 4.3%; Median duration of response: 4.2 months; PFS-6: 8.5%; Median PFS: 2.3 months; Median OS: 4.6 months. AEs: Fatigue, diarrhea, increased alanine aminotransferase, headache, hypertension, and nausea. 48.6% resulted in dose reductions (140 mg/day to 100 mg/day). [113]
31 Cabozantinib (140 mg/day vs. 100 mg/day) Recurrent II 152 ORR: 17.6% vs. 14.5%; PFS-6: 22.3% vs. 27.8%; Median PFS: 3.7 months in both; Median OS: 7.7 vs. 10.4 months; AEs (grade 3/4): 79.4% vs. 84.7%; Dose reduction due to AEs: 61.8% vs. 72.0%. [114]
25 Vorinostat + 52 TMZ + RT Primary I/II 15+107 MTD: 300 mg/day; DLTs: Grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence; Phase II OS-15 months: 55.1% (median OS 16.1 month); Phase II toxicities: Lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). [115]
23 Sorafenib + 32 tipifarnib Recurrent I 24 Study stopped because of excessive toxicities. Last dose reached: 200 mg and 100 mg twice a day for sorafenib and tipifarnib, respectively. [116]
33 Axitinib vs. 33 axitinib +
2 lomustine 		Recurrent II 79 ORR: 28% vs. 38%; PFS-6: 26% (95% CI, 14–38) vs. 17% (95% CI, 2–32); Median OS: 29 weeks (95% CI, 20–38) vs. 27.4 weeks (95% CI 18.4–36.5); Toxicities: Grade ¾ neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). [117]
34 Rindopepimut + 52 TMZ vs. 52 TMZ Primary III 745 OS for patients with MRD: 20.1 months (95% CI, 18.5–22.1) vs. 20.0 months (18.1–21.9); Grade 3/4 AEs: Thrombocytopenia (9% vs. 6%), fatigue (2% vs. 5%), brain edema (2% vs. 3%), seizure (2% vs. 2%), and headache (2% vs. 3%); Mortality by AEs: 4% vs. 3%. [118]
12 Bevacizumab + 52 TMZ Recurrent II 30 ORR: 51 weeks; PFS-6: 52%; Median time to tumor progression: 5.5 months. [119]
52 TMZ (150–200 mg/m2/day) +
RT (60 Gy in 5 days)		 Primary II 35 OS: 22 months; Hematologic toxicities: ≤grade 2. [120]
35 Lapatinib + 52TMZ + RT Primary II 12 Higher dose correlates to lymphopenia; Common AEs: fatigue, rashes, and diarrhea [121]
36 Dacomitinib Recurrent II 30 + 19 PFS-6: 10.6%; Median PFS: 2.7 months; Median OS: 7.4; Best overall response: 4.1%; Common AEs: Diarrhea and rash; Drug-related AEs: 40.8% (grade 3/4). [122]
37 HER2-CAR VSTs (HER2 specific CAR-modified virus-specific T cells) Recurrent I 17+7 No dose-limiting toxic effects; Presence in peripheral blood: up to 12 months; Stable disease: 7 out of 16 patients for 8 weeks to 29 months; Disease progression: 8 out of 16 patients; Median OS: 11.1 months (95% CI, 4.1–27.2 months) after infusion. [123]
38 Irinotecan liposome injection (nal-IRI) Recurrent I 16 + 18 MTD: 120 mg/m2 (WT cohort), 150 mg/m2 (HT cohort); DLTs: Diarrhea, dehydration and/or fatigue. [124]
39 CpGODN→RT + 52 TMZ vs. RT + 52 TMZ Primary II 81 2 years OS: 31% vs. 26%; Median PFS: 9 vs. 8.5 months. [125]
40 Aflibercept + RT + 52 TMZ→
52 TMZ		 Primary I 59 MTD: 4 mg/kg for 2 weeks; DLTs: G3 deep vein thrombosis, G4 neutropenia, G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia; Treatment discontinuation: disease progression (47%), toxicities (36%), others (14%), full course (3%). [126]
41 Onartuzumab + 12 bevacizumab vs. placebo + 12 bevacizumab Recurrent II 129 Median PFS: 3.9 vs. 2.9 months; Median OS: 8.8 vs. 12.6 months; AEs (G ≥ 3): 38.5% vs. 35.9%. [127]
42 Tivozanib Recurrent II 10 Progressive disease: 80%; Median PFS: 2.3 months; Median OS: 8.1 months. [128]
43 MEDI-575 Recurrent II 56 PFS-6: 15.4% (90% CI 8.1–24.9 months); Stable disease: 41.1%; Median PFS: 1.4 months (90% CI 1.4–1.8); Median OS: 9.7 months (90% CI, 6.5–11.8); Treatment-related AEs: Diarrhea (16%), nausea (13%), and fatigue (13%). [129]
44 Bortezomib + 52 TMZ + 12 bevacizumab Recurrent I 12 MTD: 75 mg/m2 for TMZ; PFS: 3.27 months: Mean OS: 20.75 months. [130]
45 Nimustine + 52 TMZ Recurrent I/II 15 + 40 MTD: TMZ (150 mg/m2), nimustine (40 mg/m2); ORS: 11%; Stable disease: 68%; PFS-6 and PFS-12: 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%); Median PFS: 13 months (95% CI, 9.2–17.2 months); OS-6 and OS-12: 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%); Median OS: 11.8 months (95% CI, 8.2–14.5 months). [131]
46 Tandutinib Recurrent I/II 19+30 MTD: 600 mg twice daily; Phase II terminated as PFS-6 not achieved. [132]
47 Imatinib + RT vs. 47 imatinib +
re-irradation		 Recurrent II 51 Median OS: 5.0 months (95% CI, 0-24.1 months) vs. 6.5 months (95% CI 0–32.5 months; Median PFS: 2.8 months (95% CI 0–8.7 months) vs. 2.1 months (95% CI 0–11.8 months). [133]
48 BKM120 + 12 bevacizumab Recurrent I/II 88 MTD: 60 mg PO (orally) daily; PFS-6: 36.5%; ORR: 26%; TRTs: 57%. [134]
49 Perifosine Recurrent II 30 PFS-6: 0%; PFS: 1.58 months (95% CI, 1.08–1.84 months); Median OS: 3.68 months (95% CI, 2.50–7.79 months). [135]
50 Dovitinib (naïve vs. progressed on prior antiangiogenic therapy) Recurrent II 19+14 PFS-6: 12% vs. 0%; TTP: median 1.8 months vs. 0.7–1.8 months. [136]
51 Nimotuzumab + 52 TMZ + RT Primary II 39 ORR: 72.2%; Median OS: 24.5 months; Median PFS: 11.9 months. [137]
53 Ponatinib Recurrent II 15 PFS-3: 0; Median PFS: 28 days (95% CI, 27–30); Median OS: 98 days (95% CI 56–257). [138]
2 Lomustine + 52 TMZ vs. 52 TMZ Primary III 129 Health-related quality of life: No significant differences; Neurocognitive function: Mini-mental state examination (favors the TMZ group); Neurocognitive test battery: No significant differences. [139]
54Vistusertib + 52TMZ Recurrent I 15 Tolerability: Vistusertib 125 mg b.i.d. + TMZ 150 mg/m2 for 5 days; PFS-6: 26.6%; AEs: G1/G2. [140]
55 Ascorbate + RT + 52 TMZ Primary I 11 DLTs: None; AEs: Dry mouth and chills; Median PFS: 9.4 months; Median OS: 18 months. [141]
56 Plerixafor Primary I/II 9+20 Tolerability: No drug-attributable G3 toxicities; Median OS: 21.3 months (95% CI, 15.9-NA); PFS: 14.5 months (95% CI, 11.9-NA). [142]
16 Depatux-M (+52 TMZ) vs. 52 TMZ/
2 lomustine		 Recurrent II 260 Efficacy: Monotherapy is comparable to control (hazard ratio: 1.04, 95% CI, 0.73–1.48); Toxicities: Reversible corneal epitheliopathy; AEs: G3–G4 (25–30%) [143]
57 VB-111 +
12 bevacizumab vs. 12 bevacizumab		 Recurrent III 256 Median OS: 6.8 months (combination) vs. 7.9 months (control); ORR: 27.3% (combination) vs. 21.9% (control); AEs (G3–G5): 67% (combination) vs. 40% (control). [144]

1 Aurora kinase inhibitor; 2 Nitrosourea, also known as CCNU; 3 Proteasome inhibitor; 4 Taxane-derived antineoplastic agent; 5 Pan-class I phosphoinositide 3-kinase inhibitor; 6 Receptor tyrosine kinase inhibitor; 7 Topoisomerase I inhibitor; 8 Histone deacetylase inhibitor; 9 NMDA receptor inhibitor; 10 Phospholipid-interacting antimalarial drug; 11 Anti-diabetic drug 12 Anti-angiogenic agent; 13 Allogeneic/Autologous vaccine; 14 CDK4/6 inhibitor; 15 Poly ADP ribose polymerase (PARP) inhibitor; 16 Antibody–drug conjugate; 17 Third-generation nitrosourea; 18 Wee1 inhibitor; 19 Proteasome inhibitor; 20 Non-voltage-dependent calcium channel inhibitor; 21 Interferon-binding protein; 22 Rapamycin (mTOR) inhibitor; 23 Raf kinase and vascular endothelial growth factor receptor 2 inhibitor; 24 Angiopoietin blocking peptibody; 25 Histone deacetylase (HDAC) inhibitor; 26 Rapamycin (mTOR) inhibitor; 27 IGF-1R pathway modulator; 28 G protein-coupled receptor DRD2 antagonist; 29, 30 Monoclonal antibody; 31 Tyrosine kinase inhibitor; 32Farnesyltransferase inhibitor; 33 Tyrosine kinase inhibitor; 34 Vaccine; 35 Epidermal growth factor receptor (EGFR) inhibitor; 36 Pan-human EGRF tyrosine kinase inhibitor; 37 Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs); 38 Topoisomerase I inhibitor; 39 Oligodeoxynucleotide-containing unmethylated cytosine-guanosine motifs (CpG-ODN); 40 Recombinant human fusion protein; 41 Monovalent mesenchymal epithelial transition factor (MET) inhibitor; 42 Pan-VEGF receptor tyrosine kinase inhibitor; 43 Anti platelet-derived growth factor-α antibody; 44 Proteasome inhibitor; 45 Nitrosourea; 46 Platelet-derived growth factor receptor-β tyrosine kinase inhibitor; 47 Tyrosine kinase inhibitor; 48 Oral PI3K inhibitor; 49 AKT inhibitor; 50 Inhibitor of fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR); 51 Humanized anti-epidermal growth factor receptor (EGFR) antibody; 52 Alkylating agent; 53 Tyrosine kinase inhibitor; 54Dual mTORC1/2 inhibitor; 55 Causes oxidative stress; 56 Reversible C-X-C chemokine receptor type 4 (CXCR4) inhibitor; 57 Non-replicating adenovirus, also known as Ofranergene obadenovec. Abbreviations: RT: radiotherapy; CI: confidence Interval; OS: overall survival; OS-6: overall survival at 6 months; OS-12: overall survival at 12 months; AEs: adverse events; median PFS: median progression-free survival; PFS-3: progression-free survival at 3 months; PFS-6: progression-free survival at 6 months; ALT: alanine aminotransferase; ORR: overall response rate; DLTs: dose-limiting toxicity; MTD: maximum tolerated dose; b.i.d.: twice a day; MRD: minimal residual disease; TMZ: temozolomide; G1: grade 1; G2: grade 2; G3: grade 3; G4: grade 4; TRTs: treatment-related toxicities; TTP: time to progression; BBB: blood–brain barrier.