vactosertib (TEW-7197)

The method demonstrated a sensitivity of 1.0 ng/mL, linearity ranging from 1.0 to 1000.0 ng/mL, an r2 of 0.999, accuracy ranged between 91.60% and 100.70%, and the drug was found to be stable across all freeze-thaw cycles. The results indicated that the method was selective, accurate, and validated for quantification of vactosertib in biological fluids and pharmacokinetic profiling of vactosertib.

P1/2, N=120, Active, not recruiting, MedPacto, Inc. | Trial completion date: Aug 2024 --> Jan 2025

P2, N=0, Withdrawn, MedPacto, Inc. | N=76 --> 0 | Initiation date: Nov 2021 --> Jun 2021 | Recruiting --> Withdrawn

P2, N=11, Terminated, MedPacto, Inc. | N=55 --> 11 | Trial completion date: Dec 2025 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2022 --> Aug 2024; This is because Medpacto decided to modify its development strategy as the business and development environment changed.

P2, N=0, Withdrawn, MedPacto, Inc. | N=48 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=62, Completed, MedPacto, Inc. | Active, not recruiting --> Completed

P1/2, N=60, Active, not recruiting, MedPacto, Inc. | Phase classification: P1b/2a --> P1/2 | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Oct 2022 --> May 2024

Particularly, vactosertib (VAC, a transforming growth factor-β1 receptor inhibitor) is delivered by probiotic-nanosystem to silence the active pancreatic stellate cells (PSCs) for inhibiting the development of ECM, resulting in a loosened ECM and providing a golden opportunity for the deep penetration of chemotherapy drugs and immune cells. Subsequently, gemcitabine (GEM) is efficiently delivered into the core of tumors via probiotic-nanosystem, achieving an enhanced chemotherapy efficacy. Noteworthily, CB can alleviate γ-proteobacteria-mediated GEM degradation through competitively reducing the contents of γ-proteobacteria and promoting the amounts of tumor-inhibiting bacteria, thereby significantly potentiating the therapeutic effect of GEM. The engineered probiotic-nanosystem can not only enhance the GEM-induced immunogenic cell death (ICD) of a pancreatic tumor to activate antitumor immune responses but also markedly increase the tumor-infiltration of effector immune cells to heighten tumoricidal immunity, offering a promising strategy for chemo-immunotherapy of pancreatic cancer.

P2, N=2, Terminated, Weill Medical College of Cornell University | N=37 --> 2 | Trial completion date: Sep 2025 --> Jul 2024 | Recruiting --> Terminated; Low accrual

P2, N=19, Recruiting, Chloe Atreya, MD, PhD | Trial completion date: Jun 2024 --> Jan 2027 | Trial primary completion date: Jun 2024 --> Jan 2027

In human RPE cells (ARPE-19), TGF-β administration suppressed mRNA and protein levels of LRAT; and vactosertib, a selective inhibitor of TGF-β receptor kinase type 1, reversed the effect of TGF-β. These findings suggest that hypertension-induced retinal neurodegeneration involves inflammation, apoptosis, necroptosis, and disrupted retinoid metabolism, providing potential therapeutic targets for hypertensive retinopathy.

Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

No abstract available

In 2D and 2.5D cultures, treatment with β-estradiol with or without EGF or TGF-β decreased CGN expression and the epithelial permeability barrier and enhanced cell migration, and pretreatment with EW7197+AG1478, U0126 or an anti-IL-6 antibody prevented this. In conclusion, CGN, with tTJ proteins might suppress the malignancy of human EEC and its complex proteins are sensitive to estrogen and growth factors derived from stromal cells.

P1/2, N=120, Active, not recruiting, MedPacto, Inc. | Phase classification: P1b/2a --> P1/2 | N=67 --> 120 | Trial completion date: Aug 2023 --> Aug 2024 | Trial primary completion date: Jun 2021 --> May 2024

SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFβR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis.

Vactosertib and imatinib combination was well-tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-β inhibitor, in this rare and difficult-to-treat desmoid tumor.

P2, N=76, Recruiting, MedPacto, Inc.

P1/2, N=48, Recruiting, MedPacto, Inc. | Not yet recruiting --> Recruiting

EW-7197 (a TGF-β receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-β and EGF in 2D and 2.5D cultures. In conclusion, TGF-β and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer.

One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

P2, N=37, Recruiting, Weill Medical College of Cornell University | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients.

To probe the tumor intrinsic anti-myeloma activity of vactosertib, we first determined the relative effect of vactosertib compared to the IMiDs pomalidomide and lenalidomide (Fig. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, Vactosertib reduced TGFβ in patient bone marrow and suppressed PD-1 expression on CD8+ T-cells and lead to reduction of PD-L1/PD-L2 expression on CD138+ cells and enhanced autologous T-cell cytotoxicity. Taken together, our results support the safety and efficacy of vactosertib to treat RRMM and revealed that vactosertib modulates the T-cell immunophenotype and reinvigorates T-cell fitness.

P2, N=19, Recruiting, Chloe Atreya, MD, PhD | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P2, N=25, Not yet recruiting, Jennifer Eva Selfridge

Using an orally bioavailable inhibitor of the Activin A pathway to attenuate oral cancer cell migration and invasion, we further demonstrate the targetability of this signaling axis. Our study highlights the oncogenic role of ΔNp63 - Activin A - SMAD2/3 signaling and provides a basis for targeting this oncogenic pathway in oral cancers.

Patients were simultaneously treated with pomalidomide (POM; 4 mg po qd) on days 1–21 of each cycle. Vactosertib + POM is a well-tolerated, steroid-free regimen with a promising response rate in heavily pretreated patients. Our results support the safety and efficacy of vactosertib to treat RRMM, a population with limited remaining treatment options. Vactosertib modulates the T-cell immunophenotype and reinvigorates T-cell fitness to revert T-cell exhaustion.

Methods Eligible patients were >18 years old with ECOG performance status 0-1 and who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan. Conclusions Vactosertib combined with pembrolizumab showed anti-tumor activity, prolonged overall survival and manageable safety profiles in patients with MSS mCRC. The phase 2 part is still ongoing.

P1, N=12, Recruiting, Jennifer Eva Selfridge | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

Our results indicate a high risk of death in tumor |stroma expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.

Therefore, our findings demonstrate that vactosertib synergistically increased the antitumor activity of gemcitabine via inhibition of ECM component production by inhibiting the TGF-β/Smad2 signaling pathway. This suggests that the combination of vactosertib and gemcitabine may be a potential treatment option for patients with pancreatic cancer.

The EGF receptor tyrosine kinase inhibitor AG1478 prevented the increase of claudin-2 expression induced by EGF in A549 cells. EW-7197 prevented the increase of epithelial permeability of FITC-4kD dextran induced by TGF-β1 in 2.5D culture of normal HLE cells. In conclusion, downregulation of angulin-1/LSR induces malignancy via EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma.

The restored level of ICAM-1 and VCAM-1 at 1 μM TU2218 was equivalent to the activity of combined treatment of 1 μM Vactosertib (ALK5 inhibitor) and 25 μg/ml Ramucirumab (VEGFR2 inhibitor). We conclude that TU2218 leads not only to the enhancement of T cell-traffic toward TME, but also to the conversion of immune balance favorable to anti-PD1 therapy. The Phase 1b trial of TU2218 combined with pembrolizumab is underway for advanced solid cancers (NCT05204862).

RNA sequencing analysis of mouse tumors revealed that the combination of T1-44 and vactosertib significantly altered the expression of genes involved in cancer progression, such as cell migration, extracellular matrix, and apoptotic processes. These data demonstrate that the combination therapy of T1-44 with vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer.

Ectopic overexpression of Btg2 inhibited the EMT response, blocking cell migration, and promoted cancer cell death. These data demonstrate that the combination therapy of T1-44 with Vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer.

This phase Ib open-label study evaluates the safety and persistence (primary objectives), and the clinical and biological activity and trafficking (secondary objectives) of our novel NK cell therapy in combination with IL-2 (aldesleukin) and TGFβ receptor 1 inhibitor vactosertib...Pts will undergo low-dose lymphodepletion with fludarabine and cyclophosphamide followed by 2 infusions of NK cells, administered 14 days apart...The trial is currently open to enrollment, with 1 pt accrued at time of submission. Clinical trial information: NCT05400122.

Moreover, we selected the combination treatment comprising TGF-β inhibitor, vactosertib, and imatinib. (4) We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.

We have identified a highly metastatic subpopulation of TICs marked by LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in PDAC patients. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker.

No abstract available

However, combination therapy with vactosertib not only inhibits these radiation-induced markers and properties by blocking TGF-β signaling, but also enhances the anticancer effect of radiation by reducing the volume of breast cancer. Therefore, these data suggest that vactosertib can effectively reduce radiation fibrosis and resistance in breast cancer treatment by inhibiting radiation-induced TGF-β signaling and oxidative stress, fibrosis, and CSC.