Table 2.
Summary for therapies targeting signaling pathways in clinical trials for HCC
| Signaling path way | Target | Agent | Clinical stage | Setting | Patients | Outcome | Safety | Trial identifier | Refs |
|---|---|---|---|---|---|---|---|---|---|
| PI3K/AKT/mT OR pathway | Pan-class1PI3K | Copanlisib | Phase II | Arm Z1F | Tumor with PIK3CA mutations | ORR of 16% (P5.0341) | Hyperglycemia, fatigue, diarrhea, hypertension, nausea 53% grade 3 toxicities; 3% grade 4 toxicities | NCT02465060 | 236 |
| AKT | MK-2206 | Phase II | Single agent | Advanced liver cancer (biliary cancer) did not respond to previous therapy | No clinical activity | Grade1/2 toxicities (lymphopenia, rash, fatigue, fever, vomiting, diarrhea) | NCT01239355 | 237 | |
| mTOR | RAD001 (everolimus) | Phase I/II | Single agent | Advanced HCC, iCCA | No significant difference | Anemia, Diarrhea, Lymphopenia, Stomatitis, Vomiting, Nausea, Constipation, Pain, Fatigue, et al. | NCT00516165 NCT01035229 NCT00973713 NCT00390195 | 646–648 | |
| mTOR | Sirolimus (rapamycin) | Phase II | Single agent | Liver Transplantation for HCC(immunosuppressive) | Does not decrease HCC recurrence but prolongs OS after L DLT for HCC | Wound complication and dyslipidaemia, acute cellular rejection | NCT01374750 | 238 | |
| mTOR | AZD8055 | Phase I/II | Single agent | Patients With Advanced Stage HCC and With Mild or Moderate Hepatic Impairment | Completed | NA | NCT00999882 | 239 | |
| mTOR | Sirolimus | Phase I | Combined with bevacizumab (target VEGF) | Unresected Liver cancer | No survival benefit over bevacizumab-only treatment | Grade 3 thrombocytopenia and grade 3 mucositis. hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhea (33%) and proteinuria (12.5%) | NCT00467194 | 241 | |
| mTOR | Temsirolimus | Phase II | Combinated with Sorafenib | Advanced Hepatocellular Carcinoma | Acceptable safety but did not achieve the target threshold for efficacy | Grade 3 (hypophosphatemia, thrombocytopenia, and rash) | NCT01687673 | 242 | |
| mTOR | Temsirolimus | Phase I/II | Single agent | HCC | Disease stabilization (defined as CR + PR + SD > 12 weeks) in tumors having high and low pMTOR H-scores to be 70% and 29% respectively (OR 5.667, 95% CI1.129–28.454, p = 0.035) | Grade ≥ 3 that occurred in > 10% of patients included thrombocytopenia (4) and hyponatraemia (4) | NCT00321594 NCT01251458 NCT01567930 | 649 | |
| TORC1/2 | Onatasertib (CC-223) | Phase II | Single agent | HBV-positive advanced HCC;Advanced solid tumor including HCC | Preliminary antitumor activity | Diarrhea (60.38%), hyperglycaemia (60.38%), thrombocytopenia (30.19%), hyperbilirubinaemia (11.32%) | NCT03591965 NCT01177397 | ||
| TGF-β pathway | TGF-βRI | Galunisertib | Phase II | Combined with sorafenib | Advanced HCC and Child-Pugh A liver function without prior systemic therapy | Median OS: 18.8 months;ORR: 4.5% | The most frequent treatment emergent adverse events of any grade: palmar-plantar erythrodysesthesia (56.8%), diarrhea (43.2%), and pruritis (25.0%) | NCT01246986 | 292 |
| TGF-βRI | Galunisertib | Phase I | Combined with stereotactic body radiotherapy | Advanced HCC who progressed on, were intolerant of, or refused sorafenib | Median OS: 9.0 months; median PFS: 3.7-months; ORR: 14.2% | The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%) | NCT02906397 | 187 | |
| TGFβ1/GARP | Livmoniplimab | Phase I/II | Combined with Budigalimab | Locally advanced or metastatic and/ or unresectable HCC | Not reported | Not reported | NCT06109272 | Not available | |
| Wnt/β-catenin pathway | PORCN | CGX1321 | Phase Ib | With Pembrolizumab or Encorafenib + Cetuximab | Advanced GI Tumors | Unkwown | NA | NCT02675946 | |
| PORCN | CGX1321 | Phase I | Dose Expansion | Advanced GI Tumors | Unkwown | NA | NCT03507998 | ||
| Wnt ligands | OMP-54F28 | Phase Ib | Combined with sorafenib | HCC patients | Completed | NA | NCT02069145 | ||
| DKK1 | DKN-01, (humanized monoclonal antibody) | Phase I | Combined with gemcitabine and cisplatin | Carcinoma to Primary to the Intra-or Extra-Hepatic Biliary System or Gallbladder | No additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. | Neutropenia (60%), thrombocytopenia (34%), and anemia (23%) | NCT02375880 | 328 | |
| β-catenin-CBP | E7386 | Phase Ib/II | Combined with pembrolizumab or pembrolizumab+lenvatinib | Previously Treated Subjects With Selected Solid Tumors, including HCC | Recruiting | NA | NCT05091346 | ||
| β-catenin-CBP | E7386 | Phase Ib | Combined with lenvatinib | Solid tumor including HCC | Recruiting | NA | NCT04008797 | ||
| β-catenin-CBP | E7386 | Phase I | Single agent | Solid tumor | Recruiting | NA | NCT03264664 | ||
| JAK/STAT pathway | JAK1 | Itacitinib | Phase Ib | Single agent | Advanced HCC | Ongoing | NA | NCT04358185 | |
| STAT3 | OPB-111077 | Phase I | Single agent | Advanced HCC | Limited preliminary efficacy outcomes | Thrombocytopenia (6%), fatigue (3%), and dizziness (3%) | NCT01942083 | 276 | |
| STAT3 | OPB-31121 | PhaseI/II | Single agent | Advanced HCC | Insufficient antitumor activity for HCC | Peripheral nervous system-related toxicities | NCT01406574 | 650 | |
| STAT3 | Napanucasin(BBI608) | PhaseI/II | Combined with sorafenib | Advanced HCC | No additional effect | No dose-limiting toxicities, diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%) | NCT02279719 NCT02358395 | 651 | |
| STAT3 | AZD9150 | Phase I/Ib | Single agent | Advanced/Metastatic HCC | Completed | Abdominal pain; Hepatorenal failure | NCT01839604 | ||
| Hedgehog pathway | Gli | Arsenic trioxide (ATO) | Phase II | Single agent | Unresectable metastatic liver cancer | Completed | NA | NCT00128596 | |
| Gli | Arsenic trioxide (ATO) | Phase II | Single agent | Advanced liver cancer | Terminated | NA | NCT00582400 | ||
| Smo | Vismodegib | Phase I | Single agent | Advanced solid malignancies (include HCC) and hepatic impairment | Completed | Four patients experienced dose-limiting toxicity of hyperbilirubinemia on study: one in the moderate cohort and three in the severe cohort. | NCT01546519 | 363 | |
| Hedgehog | LDE225 | Phase Ib | Single agent | Advanced or metastatic HCC and Child-Pugh A/B7 Cirrhosis | Completed | NA | NCT02151864 | ||
| Hippo pathway | TEAD | IK-930 | Phase I | Single agent | Solid tumors with or without YAP1/ TAZ Fusion Genes or NF2 deficient | Recruiting | NA | NCT05228015 | |
| Notch pathway | γ-Secretase | Ginsenoside (RG3) | Phase I | Combined with TACE | HCC with high expression of Notch1 (n = 320) | Completed | NA | NCT02724358 | |
| Telomere regulation | TERT | Telomelysin (OBP-301) | Phase I | Evaluate the Safety and Efficacy, non-comparative | HCC | Improved local control in patients with advanced HCC (SD78%) | Influenza-like illness, pyrexia, fatigue, decreased platelet count, 46 abdominal distension, and anemia | NCT02293850 | 446 |
| Epigenetics | Class I, class IIa and IV HDAC | Resminostat | Phase I/II | Alone or combined with sorafenib | Advanced HCC | Resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy | Gastrointestinal disorders, thrombocytopenia and fatigue | NCT02400788 NCT00943449 | 466,467 |
| Pan-HDAC | Belinostat | Phase I/II | Single agent | Unresected Liver cancer | Tumor stabilization, well tolerated | Abdominal pain, hyperbilirubinemia, increased ALT, anemia, and vomiting, grade 4 anemia | NCT00321594 | 652 | |
| Pan-HDAC | Panobinostat | Phase I | Combined with sorafenib | Advanced HCC,Metastatic and/or unresectable Liver cancer | Terminated | NA | NCT00823290 NCT00873002 | ||
| Pan-HDAC | Vorinostat | Phase I | Combined with sorafenib; combined with chemotherapy | Advanced liver cancer | Ten patients (77%) had stable disease (SD), The median treatment duration was 4.7 months for response-evaluable patients. | Anorexia, dehydration, dysgeusia, fatigue, lymphocytopenia, nausea, and thrombocytopenia | NCT01075113 NCT00537121 | 465 | |
| HDAC | Tefinostat | Phase I/II | Dose escalation | HCC | Completed | NA | NCT02759601 | ||
| DNMT | Decitabine | Phase I/II | Combined with Chemo- or immunotherapy | Patients with Refractory and/or Chemotherapy Resistant Solid Tumorsor B Cell Lymphomas | The lower-dose decitabine treatment resulted in beneficial clinical response and favorable toxicity profiles(The disease control rate (CR + SD rate) was up to 46.67%. The treatment prolonged PFS and OS to 4 and 11 months) | Generally well tolerated. The most commonly reported Aes were hematologic toxicity and gastrointestinal symptoms. | NCT01799083 | 463 | |
| DNMT | Guadecitabine (SGI-110) | Phase II | After failure of prior sorafenib | Advanced HCC | Median OS: 245(148–303); Median PFS:82.5(57–113) | Pain in extremity, Abdominal pain, Febrile neutropenia | NCT01752933 | 653 | |
| DNMT | Guadecitabine(SGI-110) | Phase Ib | Combined with durvalumab | Digestive tumors including HCC | Active, not recruiting | NA | NCT03257761 | 654 | |
| P53 signaling | MDM2 | ASTX295 | Phase I | Dose escalation | Solid tumors with wild-type p53 | Active, not recruiting | NA | NCT03975387 | |
| MDM2 | HDM201 | Phase II | Different matched targeted therapy | Primary tumor or metastatic lesio solid tumors with specific oncoge advanced/metastatic solid tumors | Recruiting | NA | NCT04116541 | ||
| MDM2 | Idasanutlin MT | Phase II | Tumor-agnostic precision immuno-oncology and somatic targeting rational for you (TAPISTRY) platform study | Solid tumors with specific oncogenic genomic alterations or TMB | Recruiting | NA | NCT04589845 | ||
| MDM2 | Milademetan | Phase II | Single agent | Advanced/ metastatic solid Tumors | Terminated | NA | NCT05012397 | ||
| TP53 Y220C | PC14586 | Phase I/II | Alone and combined with pembrolizumab | Solid tumors with p53 Y220C mutation | Recruiting | NA | NCT04585750 | ||
| Mutant p53 | Arsenic trioxide | Phase II | Single agent | Refractory solid tumors with rescuable p53 mutation | Unknown status | NA | NCT04869475 | ||
| WT p53 | Ad-p53 | Phase II | Combined with immune checkpoint inhibitors | Solid tumor approved for anti-PD-1 or anti-PD-L1 Therapy | Unknown status | NA | NCT03544723 | ||
| Bcl-2 | Navitoclax | Phase I | Combined with Sorafenib | Solid tumor with HCC expansion cohort | This combination was tolerable but had limited efficacy in the HCC expansion cohort, with stable disease as best response in 6 (40%) HCC patients. | Thrombo7cytopenia, increased AST, fatigue, increased ALT, diarrhea, increased alkaline phosphatase, and rash. | NCT01364051 | 503 | |
| CDK 4/6 | Palbociclib(PD-0332991) | Phase II | Single agent | Advanced HCC | Ongoing | NA | NCT01356628 | ||
| CDK 4/6 | Ribociclib(LEE011) | Phase II | Combined with chemoembolization | Locally advanced HCC | Completed | NA | NCT02524119 | ||
| CDK 4/6 | Abemaciclib | Phase II | Combined with Nivolumab | HCC | Completed | NA | NCT03781960 |