Vactosertib for Osteosarcoma

Recruiting at 7 trial locations

Overseen By Aarati Rao

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: MedPacto, Inc.

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Cardiovascular disease, Gastrointestinal bleeding, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests vactosertib, an oral medication, to determine its safety and effectiveness in treating osteosarcoma, a type of bone cancer. The researchers aim to assess how well the treatment works for individuals whose cancer has returned or is unresponsive to other treatments. Those with osteosarcoma who have not succeeded with other treatments might be suitable for this trial. Participants must have a confirmed diagnosis of osteosarcoma that has recently worsened. As a Phase 1, Phase 2 trial, this research seeks to understand the treatment's effects in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to early-stage cancer treatment advancements.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you must stop all current medications, but you cannot take certain drugs that affect the CYP450 enzyme system or are substrates for MDR1. A washout period of 5 half-lives is recommended for these drugs before starting the trial. Please consult with the trial team for specific guidance on your medications.

Is there any evidence suggesting that vactosertib is likely to be safe for humans?

Research shows that Vactosertib, a drug being tested for osteosarcoma, has produced promising results in lab and animal studies. It blocks a specific pathway that aids cancer cell growth and spread, potentially stopping tumor growth and enhancing the body's immune response against cancer.

However, detailed safety information for Vactosertib in humans with osteosarcoma remains limited. As this treatment is in early-phase trials, researchers are still gathering safety data. These trials closely monitor how well participants tolerate the drug and identify any side effects.

If Vactosertib had been approved for other conditions, it might provide some safety insights. Since it hasn't, ongoing research is crucial to determine its safety for treating osteosarcoma. Participants in these trials contribute valuable data needed to answer these questions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for osteosarcoma?

Vactosertib is unique because it targets a specific protein involved in cancer growth called TGF-beta, which is different from the typical chemotherapy approach for osteosarcoma. Most treatments for this condition focus on killing rapidly dividing cells, but Vactosertib works by blocking the signals that help cancer cells grow and spread. Researchers are excited about this treatment because it offers a new way to potentially control or shrink tumors, with the hope of fewer side effects compared to traditional chemotherapy.

What evidence suggests that vactosertib might be an effective treatment for osteosarcoma?

Research shows that Vactosertib, a pill, might help treat osteosarcoma by blocking a protein pathway that tumors use to grow. Studies have found that this drug can significantly slow the growth of osteosarcoma cells in lab tests and animals. It also appears to strengthen the body's immune response against these cancer cells. Although limited data from human trials exist, these early findings suggest that Vactosertib could help reduce tumor size. Participants in this trial will receive Vactosertib in a single-arm, open-label study to further evaluate its effects. ^{1 2 3 4 6}

Who Is on the Research Team?

Timothy Allen, MD, PHD

Principal Investigator

MedPacto, Inc.

Are You a Good Fit for This Trial?

This trial is for adolescents and adults aged 14 or older with recurrent, refractory, or progressive osteosarcoma. Participants must have normal organ and marrow function, measurable disease per RECIST 1.1 criteria, and be recovered from prior treatments' acute effects to ≤ Grade 1 toxicity (except certain conditions). They should not have uncontrolled illnesses or be on medications that could interfere with the study.

Inclusion Criteria

I have recovered from previous cancer treatments, except for hair loss, loss of appetite, bone, or tumor pain.

My kidneys work well, I don't have an active infection, and I can do most activities on my own.

My organ and bone marrow functions are normal.

Exclusion Criteria

I do not have any severe ongoing illnesses that my doctor has told me are not under control.

Subjects who have major abnormalities at the Investigator's discretion based on electrocardiogram (ECG)and Doppler ECHO results at screening or within 14 days before screening. QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥450 ms in male and ≥470 ms in female calculated from 12-lead ECGs

I have had heart or aorta surgery in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Dose escalation to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in adults and adolescents

Varies based on dose escalation

Phase II Treatment

Subjects enrolled at the RP2D to evaluate efficacy in a total of 42 adult and adolescent subjects

Until study completion, an average of 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Vactosertib

Trial Overview The MP-VAC-209 study is testing the safety and effectiveness of an oral drug called Vactosertib in treating osteosarcoma that has returned or hasn't responded to treatment. It's a Phase I/II trial where all participants receive Vactosertib twice daily to evaluate its antitumor activity.

How Is the Trial Designed?

Group I: Single Arm Experimental Treatment 1 Intervention

Single arm, open-label, no blinding or randomization procedure will be involved.

Who Is Running the Clinical Trial?

MedPacto, Inc.

Lead Sponsor

Trials

11

Recruited

370+

Published Research Related to This Trial

In a study of 41 patients with advanced osteosarcoma, apatinib treatment showed potential adverse events, with the most common severe side effects being pneumothorax (16.22%) and wound dehiscence (10.81%).

Certain adverse events like hypertension and anorexia were associated with better outcomes, indicating they may serve as markers for clinical benefit in patients treated with apatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anorexia, Hypertension, Pneumothorax, and Hypothyroidism: Potential Signs of Improved Clinical Outcome Following Apatinib in Advanced Osteosarcoma. Xie, L., Xu, J., Sun, X., et al.[2022]

Regorafenib is an effective treatment for patients with metastatic colorectal cancer who have previously undergone multiple chemotherapy regimens, showing a significant improvement in overall survival compared to placebo (6.4 months vs 4 months).

The treatment is associated with manageable side effects, with the most common severe adverse events being hand-foot syndrome (17%) and asthenia (10%), indicating that while it is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Regorafenib approved in Metastatic Colorectal cancer]. André, T., Dumont, SN.[2022]

TAS-115, a new receptor tyrosine kinase inhibitor, has shown promise in suppressing tumor growth and lung metastasis in a mouse model of osteosarcoma, indicating its potential as a treatment for this aggressive cancer.

The mechanism of action involves inhibiting key signaling pathways related to platelet-derived growth factor receptor alpha, AXL, and Fms-like tyrosine kinase 3, which are activated in various human osteosarcoma cell lines and contribute to cancer cell proliferation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TAS-115 inhibits PDGFRα/AXL/FLT-3 signaling and suppresses lung metastasis of osteosarcoma. Yasuda, N., Takenaka, S., Nakai, S., et al.[2022]

VS-5584 effectively inhibits the growth of human osteosarcoma cells (U2OS and MG-63) by inducing cell cycle arrest in the G1 phase, which is linked to the regulation of key proteins like p21 and p27.

The treatment with VS-5584 not only suppresses cell growth but also reduces cell migration and tube formation in endothelial cells, indicating its potential as an anticancer agent by targeting the PI3K/mTOR signaling pathway and down-regulating HIF-1α and VEGF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways. Sun, JY., Hou, YJ., Cui, HJ., et al.[2021]

Blocking TGF-β1 signaling with the inhibitor Vactosertib significantly reduces osteosarcoma (OS) cell proliferation both in laboratory settings and in animal models, indicating its potential as a novel treatment.

Vactosertib not only decreases the expression of the cancer-promoting protein c-Myc but also enhances immune responses by increasing immune effector cells while reducing immune suppressors in the tumor environment, suggesting a comprehensive approach to combat OS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral TGF-βR1 inhibitor Vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity. Choi, SH., Myers, J., Tomchuck, S., et al.[2023]

In a phase 1b study involving relapsed and/or refractory multiple myeloma patients, the TGF-β inhibitor vactosertib combined with pomalidomide showed a high safety profile and resulted in 80% progression-free survival at 6 months, compared to only 20% with pomalidomide alone.

Vactosertib not only improved patient outcomes but also reduced PD-1 expression on CD8+ T-cells and CD138+ cells, enhancing the anti-myeloma activity of T-cells, indicating its potential to reinvigorate T-cell function in the treatment of multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vactosertib, a novel TGF-β1 type I receptor kinase inhibitor, improves T-cell fitness: a single-arm, phase 1b trial in relapsed/refractory multiple myeloma. Malek, E., Rana, PS., Swamydas, M., et al.[2023]

Osteosarcoma, the most common primary bone cancer in children and adolescents, is often linked to genetic mutations, particularly in the TP53 gene, and is associated with several syndromes that increase cancer risk.

Current treatments primarily involve chemotherapy and surgery, but new targeted therapies like cabozantinib, sorafenib, and pazopanib are being studied for their safety and efficacy in treating osteosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Biology of Osteosarcoma. Czarnecka, AM., Synoradzki, K., Firlej, W., et al.[2020]

The combination of pazopanib and trametinib shows synergistic antitumor activity in advanced osteosarcoma by inducing apoptosis and inhibiting key signaling pathways (ERK1/2 and Akt), which are crucial for cancer cell survival.

In vivo studies in osteosarcoma-bearing mice demonstrated that this drug combination effectively down-regulates specific receptors (EphA2 and IL-7R) associated with tumor growth, although the up-regulation of MEK6 may contribute to potential drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights. Chiabotto, G., Grignani, G., Todorovic, M., et al.[2020]

A total of 3120 adverse event cases related to avapritinib were reported to the FDA, with 44% occurring within the first 30 days of treatment, highlighting the importance of monitoring patients closely during this period.

The study found that elderly male patients are at a higher risk for serious adverse events, indicating that clinicians should exercise caution when prescribing avapritinib to this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. Rong, L., Xie, M., Jiang, M., et al.[2023]

Regorafenib, a multikinase inhibitor used for advanced solid tumors, was associated with a range of adverse events (AEs) in a meta-analysis of 2,065 patients, with the most common being hand-foot skin reaction (54%), diarrhea (33%), and fatigue (32%).

The analysis revealed that regorafenib significantly increases the risk of developing AEs compared to placebo, highlighting the importance of monitoring these effects to improve patient safety and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events risk associated with regorafenib in the treatment of advanced solid tumors: meta-analysis of randomized controlled trials. Yin, X., Yin, Y., Shen, C., et al.[2022]

Despite efforts to enhance treatment for osteosarcoma over the past 30 years, survival rates have not improved, highlighting the need for new therapeutic strategies.

Recent studies have uncovered significant genomic instability and complexity in osteosarcoma, suggesting that targeted and immune-mediated therapies could be promising avenues for future treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of osteosarcoma. Bishop, MW., Janeway, KA., Gorlick, R.[2022]

Adverse events (AEs) related to regorafenib are significantly more common in patients under 65 years old and are strongly correlated with the higher starting dose of 160 mg, suggesting that younger patients may be at greater risk.

Lowering the regorafenib dose to 120 mg may reduce the incidence of AEs while maintaining efficacy, as 57% of patients recovered from AEs after dose adjustments, indicating the importance of monitoring and managing side effects for continued treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-Analysis of Regorafenib-Associated Adverse Events and Their Management in Colorectal and Gastrointestinal Stromal Cancers. Xie, G., Gong, Y., Wu, S., et al.[2020]

In a study of 29 patients with refractory osteosarcoma, off-label use of targeted therapies (TTs) showed that sirolimus was particularly effective, resulting in a median progression-free survival (PFS) of 3 months, which was significantly better than other TTs.

The overall survival (OS) for patients was 6.8 months, with no reported toxic deaths, indicating that these treatments, especially sirolimus, have an acceptable safety profile even in younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-label use of targeted therapies in osteosarcomas: data from the French registry OUTC'S (Observatoire de l'Utilisation des Thérapies Ciblées dans les Sarcomes). Penel-Page, M., Ray-Coquard, I., Larcade, J., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10104208/

Oral TGF-βR1 inhibitor Vactosertib promotes osteosarcoma ... Here we show that blocking TGF-β1 signaling using TGF-βR1 inhibitor, Vactosertib, significantly inhibited OS proliferation in vitro and in vivo.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05588648

NCT05588648 | Study to Assess Safety and Efficacy of ... Study to Assess Safety and Efficacy of Vactosertib in Adolescents and Adults With Recurrent, Refractory or Progressive Osteosarcoma. ClinicalTrials.gov ID ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11337916/

Oral transforming growth factor‐beta receptor 1 inhibitor ... Oral TGF-βR1 inhibitor Vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity.

4. withpower.com withpower.com/trial/phase-2-osteosarcoma-2023-7262a

Vactosertib for Osteosarcoma The available research does not provide specific data on the effectiveness of Vactosertib for treating osteosarcoma. Instead, it discusses other drugs like ...

5. pharmaceutical-technology.com pharmaceutical-technology.com/data-insights/vactosertib-medpacto-osteosarcoma-likelihood-of-approval/

Vactosertib by MedPacto for Osteosarcoma: Likelihood of ... According to GlobalData, Phase II drugs for Osteosarcoma have a 13% phase transition success rate (PTSR) indication benchmark for progressing into Phase III.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02160106?term=TEW-7197&viewType=Table&rank=4

First in Human Dose Escalation Study of Vactosertib (TEW ... A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to ...