Table 1.
Completed clinical trials that evaluated TGF-β pathway antagonists in oncology
| Study NCT Registry Number | Agent | Target(s) | Study Population | Number of Patients | Phase | Clinical Efficacy | Most Frequent Adverse Events |
|---|---|---|---|---|---|---|---|
| Small molecule receptor kinase inhibitors | |||||||
| NCT02160106 | Vactosertib | TGF-β RI | Solid tumors | 29 | I | Pharmacokinetics | |
| (TEW-7197) | 35 | I | Dosing model | ||||
| NCT01682187 |
Galunisertib (LY2157299) |
TGF-β RI | Advanced solid tumors | 65 | I | Glioma population ORR 14% | Thrombocytopenia thrombosis, dyspnea |
| NCT01582269 | Galunisertib ± Lomustine | TGF-β RI | Refractory glioma | 180 | II | mOS: Galunisertib 8 m, Lomustine 7 m, Both 6.5 m | Fatigue, nausea, vomiting |
| NCT01220271 |
Temozolomide RT ± Galunisertib |
CT/RT TGF-β RI |
GBM | 75 | Ib/II | mOS 18.2 vs. 17.9 m | Fatigue, nausea constipation |
| NCT01373164 | Galunisertib ± Gemcitabine |
TGF-β RI Chemotherapy |
Inoperable or metastatic pancreatic | 170 | I/II | mOS 8.9 vs. 7.1 m | Neutropenia, thrombocytopenia |
| NCT02154646 | Galunisertib + Gemcitabine | TGF-β RI Chemotherapy | Inoperable or metastatic pancreatic cancer | 9 | I | ORR 0% | Elevated liver enzymes |
| NCT02734160 | Galunisertib + Durvalumab |
TGF-β RI PD-L1 |
Metastatic pancreatic cancer | 32 | I |
ORR 3% mPFS 1.9 |
Elevated liver enzymes neutropenia |
| NCT02240433 | Galunisertib + Sorafenib |
TGF-β RI TKI, Angiogenesis |
Metastatic HCC | 14 | I | ORR 9% |
Hypophosphatemia Hand-foot syndrome |
| NCT01246986 | Galunisertib | TGF-β RI | Metastatic HCC | 147 | II | mPFS: 2.7 m (part A) 4.2 m (part B) | Neutropenia |
| Antibodies | |||||||
| NCT00356460 | Fresolimumab | TGF-β1, β2, β3 |
Advanced melanoma Renal cell cancer |
29 | I |
ORR 3 and 5% mPFS 2.75 m |
Keratoacanthomas hyperkeratosis |
| NCT01472731 |
Fresolimumab RT |
TGF-β1, β2, β3 | Glioma | 23 | II | ORR 0% | Fatigue, anemia keratoacanthomas |
| NCT01646203 | LY3022859 | TGF-β RII | Advanced solid Tumors | 14 | I | Not reported | CRS |
| Ligand Traps | |||||||
| NCT04296942 | Bintrafusp alfa, BN-Brachyury, Entinostat, Adotrastuzumab Emtansine | TGF-β RII and PD-L1 | Advanced Stage Breast cancer | 19 | I | ORR 21% | Bullous pemphigoid increased lipase, colitis |
| NCT03427411 | Bintrafusp alfa | TGF-β RII and PD-L1 | HPV-positive advanced solid tumors | 120 (estimated enrollment) | II | ORR 39% | Colitis, hypokalemia gastroparesis |
| NCT02517398 | Bintrafusp alfa | TGF-β RII and PD-L1 | Pre-treated cervical tumors | 25 | I | ORR 28% | Hypokalemia |
| NCT02517398 | Bintrafusp alfa | TGF-β RII and PD-L1 | Refractory head and neck cancer | 32 | I | ORR 22% | Keratoacanthomas hyperglycemia |
| NCT02517398 | Bintrafusp alfa | TGF-β RII and PD-L1 | Pre-treated NSCLC | 80 | II |
PD-L1 > 1%, ORR 40% PD-L1 > 80%,ORR 71% |
Keratoacanthomas |
| NCT02517398 | Bintrafusp alfa | TGF-β RII and PD-L1 | Pre-treated esophageal adenocarcinoma | 30 | I | ORR 20% | Anemia, pain |
| NCT02517398 | Bintrafusp alfa | TGF-β RII and PD-L1 | Pre-treated gastric cancer | 31 | I | ORR 22% | Anemia, diarrhea, rash |
| NCT02517398 | Bintrafusp alfa | TGF-β RII and PD-L1 | Pre-treated biliary tract cancer | 30 | I | ORR 23% | ILD |
| NCT02517398 | Bintrafusp alfa | TGF-β RII and PD-L1 | Refractory colorectal cancer | 29 | I | ORR 3.4% | Anemia, fatigue enteritis |
| NCT02631070 | Luspatercept | ActRIIb IgG1 | Very low, low or intermediate risk MDS | 229 | III | Transfusion independent > 8 weeks asthenia, nausea, 38% vs. 13% | Fatigue, diarrhea, |
| Antisense nucleotides | |||||||
| NCT00431561 | Trabedersen vs. Temozolomide/ Lomustine | TGF-β2 mRNA | Recurrent/ Refractory glioma | 142 | IIb | 6 m tumor control rate: Trabedersen 10uM: 33% Trabedersen 80uM: 20% Chemotherapy: 27% | Nervous disorders |
| NCT00844064 | Trabedersen | TGF-β2 mRNA | Advanced tumors known to overproduce TGF-β2 | 62 | I | ||
| Vaccines | |||||||
| NCT01058785 | Belagenpumatucel-L | TGF-β2 Inhibition | NSCLC | 75 | II | ORR 15% | Pain, anemia fatigue |
| NCT00676507 | Belagenpumatucel-L | TGF-β2 Inhibition | Inoperable or metastatic NSCLC | 532 | III | mOS 20 vs 17 m | Allergic reactions |
| NCT02574533 | Vigil + Pembrolizumab | Vaccine Anti-PD-1 | Advanced melanoma | 2 | I | ||
Summary of completed clinical trials utilizing TGF-β targeting agents in a variety of treatment refractory metastatic solid tumors including breast, esophageal, gastric, biliary, pancreatic, non-small cell lung cancer, melanoma, GBM and head and neck tumors. Nine trials utilized small molecule inhibitors, three utilized antibodies, ten utilized ligand traps, two utilized ASOs, and three utilized vaccination strategies