VLS-1488 for Advanced Cancer

Recruiting at 13 trial locations

Overseen By Volastra Therapeutics, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Volastra Therapeutics, Inc.

Must not be taking: CYP3A inhibitors, MDR1 inhibitors

Disqualifiers: CNS metastases, Cardiac issues, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests VLS-1488, a new drug for advanced cancers, to find the safest and most effective dose. It targets patients needing new treatment options and checks how the drug interacts with other medications and food.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions restrictions on certain medications that affect liver enzymes and drug transporters. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What is known about the safety of VLS-1488 or similar treatments in humans?

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, which may be similar to VLS-1488, have been associated with risks like bleeding, heart issues, and other serious side effects. However, studies show that these treatments do not significantly increase the risk of fatal adverse events compared to other treatments. ^{1 2 3 4 5}

How is the drug VLS-1488 different from other treatments for advanced cancer?

VLS-1488 is unique because it may act as a vascular disrupting agent (VDA), which means it targets and disrupts the blood vessels that supply the tumor, potentially leading to tumor necrosis (tissue death) and inhibiting tumor growth. This mechanism is different from standard chemotherapy, which typically targets cancer cells directly. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for adults with advanced cancers who've already tried standard treatments. They should be able to perform daily activities with minimal assistance (ECOG ≤ 1), have measurable disease, and take pills without changing them. Not eligible if they have certain genetic mutations, brain metastases, previous KIF18A inhibitor treatment, or recent serious heart issues.

Inclusion Criteria

I have at least one tumor that can be measured on a CT scan or MRI.

I have no other treatment options that would significantly help my cancer.

I am fully active or can carry out light work.

Exclusion Criteria

I haven't had fluid drained from my abdomen or chest in the last 28 days.

I can avoid medications that strongly affect certain liver enzymes and drug transporters.

I have not had a bowel blockage or gut tear in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Examine the safety and tolerability of VLS-1488 in different solid tumor types at various dose levels to identify the Maximum Tolerated Dose (MTD)

28-day cycles

Dose Expansion

Examine the safety, tolerability, Drug Drug Interaction (DDI) risk, Food Effect (FE), and preliminary efficacy of VLS-1488 in different tumor types and/or dose levels

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• VLS-1488

Trial Overview The study tests VLS-1488's safety and early effectiveness in patients with various advanced cancers. It includes two parts: dose escalation to find the right amount of drug and dose expansion to see how well it works at that dose.

Participant Groups

Group I: Dose Expansion: Exploration Cohorts Experimental Treatment 1 Intervention

Subjects with a selected single tumor type will be randomized 1:1 into Exploration Cohorts at two or more dose levels of interest. A subset of subjects will have additional assessments to examine the potential for VLS-1488 to interact with other drugs and the effect of food on VLS-1488 absorption.

Group II: Dose Expansion: Development Cohorts Experimental Treatment 1 Intervention

Subjects with other tumor types will be enrolled at a single dose level of interest. These Development Cohorts will be utilized to examine the preliminary efficacy of VLS-1488 in various tumor types.

Group III: Dose Escalation: Dose Escalation Cohorts Experimental Treatment 1 Intervention

Subjects will be enrolled at various doses and/or schedules of VLS-1488. These Dose Escalation Cohorts will be utilized to identify the MTD and to select dose levels for Dose Expansion.

Group IV: Dose Escalation: Backfill Cohorts Experimental Treatment 1 Intervention

Additional subjects may be enrolled at any dose level that does not meet de-escalation or elimination rules per the BOIN design. These Backfill Cohorts will be utilized to build additional data to support selection of doses and/or tumor types for further study in Dose Expansion.

VLS-1488 is already approved in United States for the following indications:

Approved in United States as VLS-1488 for:

• None approved yet; Fast Track designation for platinum-resistant high-grade serous ovarian cancer

Who Is Running the Clinical Trial?

Volastra Therapeutics, Inc.

Lead Sponsor

Trials

3

Recruited

310+

Findings from Research

Bevacizumab is the only FDA-approved antiangiogenic therapy for advanced non-small-cell lung cancer (NSCLC), but it carries risks such as hemorrhage, venous thromboembolism, hypertension, and proteinuria based on accumulated safety data.

New investigational agents like aflibercept and multitargeted tyrosine kinase inhibitors (TKIs) are being developed to target angiogenesis through different mechanisms, with emerging safety profiles that may offer additional treatment options for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile and tolerability of antiangiogenic agents in non-small-cell lung cancer. Gadgeel, SM.[2022]

In a study of 310 cancer patients, adding mistletoe (Viscum album L.) to targeted therapy significantly reduced the frequency of adverse events (AEs) and treatment discontinuation rates compared to targeted therapy alone.

Patients receiving the combination therapy had a 70% lower probability of discontinuing their oncological treatment due to AEs, highlighting the potential of mistletoe as a supportive treatment in cancer care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients. Thronicke, A., Oei, SL., Merkle, A., et al.[2020]

In a study involving 12,520 patients from 23 randomized controlled trials, VEGFR-TKIs significantly improved progression-free survival (PFS), objective response rates (ORR), and disease control rates (DCR) in advanced non-small cell lung cancer (NSCLC) patients, but did not significantly affect overall survival (OS).

Patients treated with VEGFR-TKIs experienced a higher incidence of adverse events, including serious conditions like neutropenia and hypertension, indicating that while these drugs can be effective, they also come with increased risks of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer? Wang, S., Yang, Z., Wang, Z.[2022]

In a systematic review of 17 randomized controlled trials involving 6,982 patients with solid tumors, VEGFR2-targeted agents were found to have an overall incidence of fatal adverse events (FAEs) of only 1.7%.

The study concluded that the use of VEGFR2-targeted agents did not significantly increase the risk of FAEs compared to control treatments, indicating a favorable safety profile for these cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and Risk of Fatal Adverse Events in Cancer Patients Treated With Vascular Endothelial Growth Factor Receptor 2-Targeted Agents: A Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials. Zhao, B., Zhao, H., Zhao, J.[2020]

A meta-analysis of 10 randomized controlled trials involving 4,679 cancer patients found that vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are associated with a 1.5% incidence of fatal adverse events (FAEs), which is significantly higher than in control patients.

The relative risk of experiencing FAEs for patients treated with VEGFR TKIs was 2.23, indicating more than double the risk compared to those not receiving these treatments, highlighting the need for careful monitoring of patients on these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. Schutz, FA., Je, Y., Richards, CJ., et al.[2022]

In a phase II trial involving 104 patients with advanced non-small-cell lung cancer (NSCLC), the addition of the vascular disrupting agent ASA404 to standard chemotherapy showed numerical improvements in tumor response, time to disease progression, and overall survival without significantly increasing side effects.

The study supports the potential of combining VDAs like ASA404 with standard chemotherapy, as they target different aspects of tumor biology, and further trials are ongoing to explore this combination's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trials of vascular disrupting agents in advanced non--small-cell lung cancer. McKeage, MJ.[2012]

The combination of vandetanib and bicalutamide in patients with metastatic castration-resistant prostate cancer did not show superior efficacy compared to bicalutamide alone, with similar PSA response rates of 18% for the combination and 19% for bicalutamide alone.

Patients receiving the combination therapy experienced significantly higher rates of treatment discontinuation due to adverse events (42% vs. 5%), indicating that the combination is associated with considerable toxicity and is not recommended for further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer. Azad, AA., Beardsley, EK., Hotte, SJ., et al.[2022]

The maximum tolerated dose (MTD) of motesanib when combined with gemcitabine and erlotinib was determined to be 100 mg once daily, indicating a safe dosage for further studies.

Among the 56 patients treated, motesanib showed tolerable safety with common side effects like diarrhea and nausea, and resulted in one confirmed partial response and 26 patients with stable disease, suggesting potential efficacy in treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study. Kotasek, D., Tebbutt, N., Desai, J., et al.[2022]

In a clinical trial involving 276 patients with HER2-negative metastatic breast cancer, treatment with motesanib plus paclitaxel did not show a significant improvement in objective response rate compared to placebo plus paclitaxel, with response rates of 49% and 41% respectively.

Motesanib was associated with a higher incidence of serious adverse events, particularly gastrointestinal issues, compared to the placebo and bevacizumab groups, leading to the conclusion that further investigation of motesanib at this dose and schedule is not supported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Martin, M., Roche, H., Pinter, T., et al.[2022]

Cediranib, when combined with standard chemotherapy (cisplatin and gemcitabine), showed promising anti-tumor activity in advanced non-small cell lung cancer, with a response rate of 26.7% among all patients and 33.3% among those evaluable.

The study found that cediranib can be safely administered at a daily dose of 30 mg without dose-limiting toxicities, although some manageable side effects like fatigue and diarrhea were noted, indicating its potential for further development in phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. Goss, G., Shepherd, FA., Laurie, S., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Safety profile and tolerability of antiangiogenic agents in non-small-cell lung cancer. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer? [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Incidence and Risk of Fatal Adverse Events in Cancer Patients Treated With Vascular Endothelial Growth Factor Receptor 2-Targeted Agents: A Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical trials of vascular disrupting agents in advanced non--small-cell lung cancer. [2012]

7. United States pubmed.ncbi.nlm.nih.gov

A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. [2022]

10. England pubmed.ncbi.nlm.nih.gov

A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. [2022]