Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study

Jung, Su Young; Hwang, Sun-Jin; Clarke, Jeffery M; Bauer, Todd M.; Keedy, Vicki L.; Lee, Hukeun; Park, Neunggyu; Kim, Seong‐Jin; Lee, Jangik I.

doi:10.1007/s10637-019-00835-y

Cited by 39 publications

(28 citation statements)

References 24 publications

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“…219,220 Phase 1 clinical trial investigation of this inhibitor for patients with refractory multiple myeloma/metastatic CRC/ metastatic PDAC and phase 2 study for patients with metastatic gastric cancer/CRC/urothelial carcinoma/ NSCLC/myeloproliferative neoplasm/advanced desmoid tumors are ongoing. [221][222][223][224] LY3200882 is a next-generation highly selective potent ATPcompetitive TβRI inhibitor that showed antitumor efficacy in a preclinical mouse model of TNBC cancer. 225 The phase 1 clinical trial results showed that LY3200882 had a tolerable safety profile and early signs of antitumor efficacy for patients with advanced or metastatic cancers (NCT04031872).…”

Section: Neutralizing Antibodiesmentioning

confidence: 99%

Targeting TGFβ signal transduction for cancer therapy

Liu

Ren

Dijke

2021

Sig Transduct Target Ther

224

173

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Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

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Section: Neutralizing Antibodiesmentioning

confidence: 99%

Targeting TGFβ signal transduction for cancer therapy

Liu

Ren

Dijke

2021

Sig Transduct Target Ther

224

173

View full text Add to dashboard Cite

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“…A first-in-human phase I dose escalation study investigated the safety, tolerability and pharmacokinetics of Vactosertib in patients with advanced, refractory solid tumors (NCT02160106) [70,71]. Vactosertib pharmacokinetics were dose proportional when administered once daily for five days.…”

Section: Small Molecule Inhibitors Of Tgf-β Receptor Kinase Activitymentioning

confidence: 99%

“…Based upon a relatively short halflife, it was postulated that Vactosertib should be administered twice or thrice daily to maintain a concentration above a minimum effective level over dosing interval. A two-compartment linear model with first-order absorption and absorption lag time adequately described the population pharmacokinetics [70].…”

Section: Small Molecule Inhibitors Of Tgf-β Receptor Kinase Activitymentioning

confidence: 99%

Novel therapies emerging in oncology to target the TGF-β pathway

et al. 2021

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The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.

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“…This study determined once-a-day administration of vactosertib was rapidly absorbed with a median time to maximum concentration of 1.2 hours. It was, therefore determined that vactosertib treatment benefits from two to three times daily dosing schedules in order to maintain its concentration in the blood [61].…”

Section: Tgfβ Small Molecule Inhibitorsmentioning

confidence: 99%

The Role of TGFβ in Clinical Cancer Response

Gillman¹,

Nemunaitis²,

Creeden³

et al. 2020

COR

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A B S T R A C TThe role of transforming growth factor beta (TGFβ) is context dependent. Even within the specific context of cancer, the functional significance of TGFβ varies according to environmental conditions. Therapies targeting TGFβ capitalize upon recent discoveries in canonical SMAD-dependent biochemical signaling networks as well as non-canonical SMAD-independent biochemical signal transduction pathways and mechanobiological signal transduction pathways. TGFβ clinical trials utilizing vaccine, small molecule inhibitor, antibody, and aptamer strategies support TGFβ as a viable anticancer target for a variety of cancer diagnoses. Combination therapies incorporating TGFβ inhibition and immune checkpoint blockade provide additional avenues for future TGFβ-based clinical intervention.

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Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study

Cited by 39 publications

References 24 publications

Targeting TGFβ signal transduction for cancer therapy

Targeting TGFβ signal transduction for cancer therapy

Novel therapies emerging in oncology to target the TGF-β pathway

The Role of TGFβ in Clinical Cancer Response

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