Table 1.
Clinical Trials Targeting Metabolism Pathways Related to Head and Neck Carcinoma
| Strategies | Key Molecules/Targets | Inhibitors/Drugs | NCT Number | Main Results |
|---|---|---|---|---|
| Inhibition of Glycolysis | Glycolysis/ Glucose analog | 2-DG | NCT00096707 |
11 pts (32%) had SD, 1 pts (3%) PR and 22 pts (66%) PD as best response RD of 2DG with weekly docetaxel 63 mg/kg/day [119] |
| Anaerobic glycolysis | Dichloroacetate | NCT01386632 |
No significant differences in Gr 3/4 AE rates between dichloroacetate and placebo CR rates were higher in the dichloroacetate group [120] |
|
| Modulating Fatty Acid Metabolism | CD36 | ABT-510 | NCT00113334 |
2 pts had SD, 1 pt had PD |
| 3-hydroxy-3-methyl glutaryl coenzyme A reductase | Atorvastatin | NCT04915183 | No results posted | |
| NCT02022293 | Enrollment target could not be achieved | |||
| Inhibition of Amino Acid Metabolism | IDO | Epacadostat | NCT02318277 | Phase 2 ORR 12.0%, higher in CPI-naive (16.1%) vs. previous CPI (4.1%) [123] |
| NCT02178722 | 84% pts (n = 52) experienced TRAEs, Gr 3/4 TRAEs reported in 24% pts, and 100 mg Epacadostat twice per day plus 200 mg pembrolizumab every 3 weeks recommended for phase II evaluation [124] | |||
| NCT02327078 | For pts on Epacadostat 300 mg, preliminary DCR was 70%, and 48% pts (n = 42) reported TRAEs [125, 126] | |||
| BMS-986205 | NCT03854032 | Higher pTE in radiographic responders vs. non-responders (85% vs. 5%), and higher pTE in responders in the lymph node compartment (73% vs. 23%), while CR demonstrated in 6/16 (38%) pts [127, 128] | ||
| Targeting Nucleotide Metabolism | PARP | Olaparib | NCT02882308 | Olaparib treatment modulates DNA damage response network and exerts extra antitumor effect by elevating oxidative stress in HNSCC patients [129] |
| A2aR | NIR178 | NCT03207867 | For HNSCC pts with NIR178 160 mg twice daily plus PDR001 with no immuno-oncology therapy ORR 13.3 [130] | |
| Modulating Glucose and Fatty Acid Metabolism | PI3K | Buparlisib (BKM120) | NCT02113878 | 1 of 7 pts experienced Gr 4 rash on DL1, DLTs observed (4 of 6 pts) on DL2, and 5 pts respond to buparlisib monotherapy [131] |
| NCT01816984 | Gr3 AEs reported in 10 pts, and no DLTs during dose escalation, while PR (n = 1) and SD (n = 4) reported [132] | |||
| Copanlisib | NCT02822482 | 2 of 3 pts experienced DLT on 45 mg DL, and no DLT was reported on 30 mg DL. Median PFS 2.66 months, and median OS 6.01 months [133] | ||
| Alpelisib (BYL719) | NCT02537223 | No DLT observed at 200 mg, 2 of 2 pts reported DLTs at 250 mg, and RP2D declared at 200 mg. 3-year PFS and OS rate both 77.8% [134] | ||
| NCT01602315 | 1 PR, 3 unconfirmed PRs and 5 SDs at 300 mg, and 1 PD and 1 SD at 400 mg. RP2D declared as 300 mg QD (whole tablets) [135] | |||
| Bimiralisib | NCT03740100 | ORR 17%, median PFS 5 months and median OS 7 months. 62.5% pts (n = 5) experienced 14 severe AEs [136, 137] | ||
| mTOR | Sirolimus(rapamycin) | NCT01195922 | 1 pt had a pathologic CR, while 25% pts (n = 4) reported response (1 CR, 3 PRs, 12 SDs) [138] | |
| Temsirolimus (TORISEL) | NCT01016769 | OR rate 43% (n = 13) with 1 CR, 10 confirmed PRs, and 2 unconfirmed PRs. OS 12.9 months [139] | ||
| NCT01172769 | Median PFS 56 days, median OS 152 days, and PFR 40% at 12 weeks. 87.5% pts (n = 35) experienced at least two AEs [140] | |||
| Everolimus (RAD001) | NCT01333085 | No DLT in phase I, and everolimus RD declared at 50 mg/w, while 2.6% pts experienced a CR (n = 1), 76.3% PR (n = 28), and 21% SD (n = 8). OR rate 79% [141] | ||
| NCT01051791 | CBR 28%, median PFS 1.5 months, and median OS 4.5 months. 2 SDs observed (5.5 and 4.5 months) [142] | |||
| CC-115 | NCT01353625 | 22% pts reported Gr 3 drug-related AEs. SD observed 53% [143] | ||
| EGFR | Cetuximab | NCT01252628 | Median PFS 80 days, no CR found, and 7 PR confirmed. Median OS 211 days vs. 256 days (cetuximab plus PX-866 vs. cetuximab alone) [144] | |
| NCT01256385 |
Median PFS both 3.5 months. (cetuximab plus Temsirolimus vs. Temsirolimus alone) Median OS 177 days vs. 176 days and OR rate 12.5% vs. 2.5% [145] |
|||
| Duligotuzumab | NCT01577173 | PFS 4.2 months vs. 4.0 months (duligotuzumab vs. cetuximab), OS 7.2 months vs. 8.7 months, and OR rate 12% vs. 14.5% [146] | ||
| Erlotinib | NCT00942734 |
OR rate 2.8% at 12 weeks, median PFS 11.9 weeks and median OS 10.25 months 8% pts (n = 3) achieved PR at 4 weeks [147] |
||
| Targeting Oral Microbiome | Oral microbiome | N-Acetyl Cysteine | NCT03982537 | Concept is withdrawn and a different concept will be submitted the near future |
| Oral microbiome |
Probiotic Lozenge (ProDentis Lozenge) |
NCT04925700 | No results posted | |
| Oral microbiome | MET-4 | NCT03838601 | No results posted |
Abbreviations: ORR Objective response rate, PI3K Phosphoinositide 3-kinase, CPI Immune checkpoint inhibitor, pts Patients, Gr Grade, Trp Tryptophan, Kyn Kynurenine, DCR Disease control rate, TRAE Treatment-related adverse event, pTE Pathologic treatment effect, CR Complete response, HNSCC Head and neck squamous cell carcinoma, PFR Progression-free survival rate, DL Dose level, DLT Dose limiting toxicity, AE Adverse event, PR Partial response, SD Stable disease, CI Confidence interval, PFS Progression free survival, OS Overall survival, RP2D Recommended phase 2 dose, PD Progressive disease, RD Recommended dose, OR Overall response, CBR Clinical benefit rate