vactosertib (TEW-7197) / National OncoVenture, Theragen Etex, Ewha Womans University - LARVOL DELTA

A quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML. (PubMed, Drug Resist Updat) - "However, pretreatment with vactosertib unexpectedly induced complete resistance to cytarabine. Importantly, we found that this drug interaction is not unique to TGFBR1 inhibitors, but extends to other clinically significant kinase inhibitors, such as the FLT3 inhibitor midostaurin. These findings may have important implications for optimizing combination therapies in AML treatment."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • FLT3 • SLC29A1 • TGFB1 • TGFBR1

Antitumor Activity of Vactosertib in Combination With Pembrolizumab in Acral and Mucosal Melanoma Patients Progressed From Prior Immune Check Point Inhibitor (clinicaltrials.gov) - P2 | N=14 | Terminated | Sponsor: Yonsei University | N=30 ➔ 14 | Trial completion date: Dec 2025 ➔ Mar 2025 | Not yet recruiting ➔ Terminated | Trial primary completion date: Jul 2025 ➔ Mar 2025; According to the protocol criteria, during the Phase 1 analysis, the registered participants' imaging evaluation responses did not meet the criteria, leading to an early termination

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • BRAF

MP-VAC-203: Phase 1b/2a, Open-label Study of Vactosertib in Combination with Durvalumab in Advanced NSCLC (clinicaltrials.gov) - P1/2 | N=60 | Completed | Sponsor: MedPacto, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ May 2024

Trial completion • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • UGT1A1

KEYNOTE 900: Vactosertib in Combination with Pembrolizumab in Metastatic Colorectal or Gastric Cancer (clinicaltrials.gov) - P1/2 | N=120 | Completed | Sponsor: MedPacto, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jan 2025 ➔ May 2024

Trial completion • Trial completion date • Colorectal Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation. (PubMed, Neurol Res Int) - "Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • IL1B • TGFB1 • TGFBR1 • TNFA

Preoperative Immunotherapy (Pembrolizumab) for Patients With Colorectal Cancer and Resectable Hepatic Metastases (clinicaltrials.gov) - P2 | N=6 | Active, not recruiting | Sponsor: Chloe Atreya, MD, PhD | Recruiting ➔ Active, not recruiting | N=19 ➔ 6 | Trial completion date: Jan 2027 ➔ Apr 2026 | Trial primary completion date: Jan 2027 ➔ Apr 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MLH1 • MSH2 • MSH6 • PD-L1

MedPacto to launch US phase 2 study for using vactosertib to treat pediatric osteosarcoma (Korea Biomedical Review) - "MedPacto said it will conduct a phase 2 investigator-initiated clinical trial using vactosertib, a TGF-β inhibitor anti-cancer drug, for pediatric osteosarcoma in collaboration with various U.S. medical institutions, including Stanford University and Case Western Reserve University Hospitals...MedPacto highlighted that vactosertib had already demonstrated safety and potential efficacy in inhibiting osteosarcoma cell growth and lung metastasis in preclinical and phase 1 trials, and that the upcoming phase 2 study aims to validate these findings...The trial will be conducted in collaboration with 12 research institutions under the POETIC and is scheduled to begin within the year."

New P2 trial • Osteosarcoma

A phase II double window of opportunity trial evaluating the oral TGF-beta receptor I inhibitor vactosertib in patients undergoing standard of care preoperative therapy for locally advanced esophageal adenocarcinoma. (ASCO-GI 2025) - P2 | "Pre- and post-first window of opportunity treatment biopsies will be obtained for correlative and exploratory analyses. Clinical trial registry number is NCT06044311."

Clinical • Metastases • P2 data • Esophageal Adenocarcinoma • Esophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • TGFB1

Quantification of Vactosertib an Inhibitor of TGFBR1 by LC-MS/MS in Rat Plasma and Its Pharmacokinetic Profiling. (PubMed, Biomed Chromatogr) - "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."

Journal • PK/PD data • Preclinical • Oncology • TGFBR1

Unmet Needs in Multiple Myeloma and Potential Solutions: A Systemic Literature Review (ASH 2024) - "Other unmet needs reported were patient and family experience/supportive care (11%), pathophysiology (4%), diagnosis/response assessment (4%), toxicity management/prevention (3%) and poor prognosis (4%).Unmet needs that were reported starting from 2010 [and their proposed solutions] include treatment of high-risk cytogenetic features (4%) [elotuzumab/isatuximab/melflufen/selinexor/anti-BCMA conjugates], treatment of plasma cell leukemia/extramedullary disease (3%) [utilizing MM drugs (daratumumab/boretezemib/melfufen/frontline ASCT etc.)], prevention/management of toxicities (mucositis, neuropathy, nephropathy and GVHD) (1%) [CR4056/amifostine/cannabidiol], treatment/prevention of thromboembolism (1%) [risk assessment model for thromboembolism/studies on anticoagulation], treatment of frail/elderly (1%) [SEA BCMA/melflufen], immune response in MM (<1%) [immunological studies], and measures to assess response to treatment (<1%) [heavy light chain ratio/DW..."

Review • Cardiovascular • Geriatric Disorders • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Mucositis • Multiple Myeloma • Novel Coronavirus Disease • Oncology • Orthopedics • Pain • Renal Disease • Respiratory Diseases

KEYNOTE 900: Vactosertib in Combination with Pembrolizumab in Metastatic Colorectal or Gastric Cancer (clinicaltrials.gov) - P1/2 | N=120 | Active, not recruiting | Sponsor: MedPacto, Inc. | Trial completion date: Aug 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Colorectal Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

The TGFβ Type I Receptor Kinase Inhibitor Vactosertib Improves T-Cell Fitness in Relapsed/Refractory Multiple Myeloma: A Phase 1b Trial (ASH 2024) - P1 | "Vactosertib combined with pomalidomide was well-tolerated at all dose levels, displayed a manageable adverse event profile and induced durable responses. Current studies are focused on defining the antimyeloma effects of vactosertib in combination with immune checkpoint inhibitors, autologous and allogeneic chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers. Accumulating evidence suggests that functional blockade of the TGF pathway offers promise to optimize CAR-T-cell therapy for hematologic and solid tumors, albeit with efficacy anticipated restricted to specific populations."

IO biomarker • P1 data • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • CD8 • TGFB1

TGF-β1-SMAD2 Axis Regulates Hematopoiesis and β-Globin Gene Expression Via Super-Enhancer Associated Chromatin Reorganization (ASH 2024) - "Taken together, faster erythroid differentiation and reduced cell divisions lead to anemia phenotypes. These can be rescued with a novel, clinically useful ALK5 inhibitor, Vactosertib."

Anemia • Aplastic Anemia • Hematological Disorders • Myelodysplastic Syndrome • MYC • SMAD2 • TGFB1 • TGFBR1

Vactosertib with Durvalumab in Urothelial Carcinoma Failing Checkpoint Inhibition (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: MedPacto, Inc. | N=48 ➔ 0 | Not yet recruiting ➔ Withdrawn

Checkpoint inhibition • Enrollment change • Metastases • Trial withdrawal • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

MP-VAC-203: Phase 1b/2a, Open-label Study of Vactosertib in Combination with Durvalumab in Advanced NSCLC (clinicaltrials.gov) - P1/2 | N=60 | Active, not recruiting | Sponsor: MedPacto, Inc. | Phase classification: P1b/2a ➔ P1/2 | Trial completion date: Dec 2022 ➔ Dec 2024 | Trial primary completion date: Oct 2022 ➔ May 2024

Combination therapy • Metastases • Phase classification • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • UGT1A1

MP-VAC-205: Vactosertib in Combination with Pembrolizumab for PD-L1 Positive Non-small Cell Lung Cancer (NSCLC) Subjects (clinicaltrials.gov) - P2 | N=11 | Terminated | Sponsor: 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.

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • PD-L1 • ROS1

MP-VAC-206: Vactosertib and Imatinib Combination in Patients with Advanced Desmoid Tumor/aggressive Fibromatosis (DT/AF) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: MedPacto, Inc. | N=76 ➔ 0 | Initiation date: Nov 2021 ➔ Jun 2021 | Recruiting ➔ Withdrawn

Enrollment change • Metastases • Monotherapy • Trial initiation date • Trial withdrawal • Desmoid Tumors • Fibrosis • Oncology • Sarcoma • Solid Tumor

TEW-7197 with Paclitaxel for the Treatment of Metastatic Gastric Cancer (clinicaltrials.gov) - P1/2 | N=62 | Completed | Sponsor: MedPacto, Inc. | Active, not recruiting ➔ Completed

Metastases • Trial completion • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • HER-2

Harnessing the Engineered Probiotic-Nanosystem to Remodulate Tumor Extracellular Matrix and Regulate Tumor-Colonizing Bacteria for Improving Pancreatic Cancer Chemo-Immunotherapy. (PubMed, Small) - "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..."

Journal • Colorectal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • MMP2 • TGFB1

Vactosertib, a TGF-β signaling inhibitor, in combination with durvalumab increased mOS in ≥2L treatment of patients with PD-L1-positive advanced NSCLC (SITC 2024) - P1b/2a | "Vincent's Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).View this table:View inline View popup Download powerpoint Abstract 605 Table 1 Antitumor activity by treatment group for patients with advanced NSCLC. [Abbreviation] TGF-β; Targeting transforming growth factor-β, TME; tumor microenvironment, ICI; immune checkpoint inhibitors, NSCLC; non-small lung cancer, ORR; objective response rate, mDOR; median duration of response, mTTR; median time to objective response, mPFS; median progression-free survival, mOS; median overall survival, TEAEs; treatment-emergent adverse events"

Clinical • Combination therapy • IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1 • TGFB1

Oral TGF-beta Receptor I Inhibitor Vactosertib in SOC Chemoradiotherapy for Esophageal Adenocarcinoma (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Jennifer Eva Selfridge, MD | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients (clinicaltrials.gov) - P2 | N=2 | Terminated | Sponsor: Weill Medical College of Cornell University | N=37 ➔ 2 | Trial completion date: Sep 2025 ➔ Jul 2024 | Recruiting ➔ Terminated; Low accrual

Enrollment change • Trial completion date • Trial termination • Myeloproliferative Neoplasm • Oncology

Surface-engineered mesenchymal stem cell for refractory asthma therapy: Reversing airway remodeling. (PubMed, J Control Release) - "Herein, we constructed surface-engineered mesenchymal stem cells (MSCs/PVLA) via the bioconjugation of MSCs and reactive oxygen species-responsive polymeric micelles loaded with vactosertib (VST) and linifanib (LFN) for treating refractory asthma through reversing airway remodeling. Meanwhile, MSCs reduced inflammatory cell infiltration and cytokine secretion to regulate the pathological microenvironment. Our results suggested that MSCs/PVLA could serve as a promising candidate to prevent disease exacerbations and treat refractory asthma."

Journal • Asthma • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Response of canine and human osteosarcoma cell lines to targeted agents compared to clinically relevant exposure (EORTC-NCI-AACR 2024) - "Dead cells were identified by green-fluorescent YOYO-1 dye incorporation.DrugPutative TargetTested Range (ng/ml)CRD (ng/ml)AlisertibAurora A Kinase50-1500292AlpelisibPI3K15-500454CabozantinibMET, VEGFR 1, 2 and 3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, TIE-2100-25001458CrizotinibALK, c-MET, RON2.5-200188DasatinibBCR-ABL, SRC, c-KIT, EPHA2, PDGFR-b5-15012DefactinibFAK100-4000222OnvansertibPolo-Like Kinase 110-600233PalbociclibCDK 4/65-30073SapitinibErbB1, B2, B325-1000718SorafenibRAF1, BRAF, VEGFR 1, 2 and 3, PDGFR, KIT, FLT3, FGFR1, RET25-50004500VactosertibTGFBR150-1500625VenetoclaxBCL-250-2000633 Screening 12 targeted agents against 13 cOSA cell lines identified 6 agents that inhibited cell growth rate by at least 50% at less than 2-fold the calculated CRD... The results from this limited drug screen identified 6 targeted agents with activity in OSA cell lines at the CRD for further study."

Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • AURKA • AXL • BRAF • CDK4 • FGFR1 • FLT1 • KIT • MET • NTRK2 • PLK1 • ROS1 • TGFBR1

Evaluation of the novel ALK5 inhibitor EW-7197 on therapeutic efficacy in renal fibrosis using a three-dimensional chip model. (PubMed, Kidney Res Clin Pract) - "In a cisplatin-induced renal fibrosis mouse model, blood urea nitrogen levels, TGF-β, and Smad 2/3 were determined, and renal fibrosis was assessed with Masson's trichrome stain. EW-7197 attenuated the TGF-β1-induced fibrotic cellular response in the 3D chip model and animal model. These findings indicate the potential effect of EW-7197 in attenuating renal fibrosis."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • IL1B • IL6 • KDR • KRT8 • SMAD2 • TGFB1 • TGFBR1