VMD-928 for Advanced Cancer

Recruiting at 32 trial locations

Overseen By Krishna Patel; Stephanie Saathoff

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: VM Oncology, LLC

Must not be taking: Acetaminophen, Strong CYP3A4 inhibitors

Disqualifiers: Active infections, Heart failure, others

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

Compensation: Varies

Number of Visits: Unknown

242 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new oral medication, VMD-928, for individuals with advanced solid tumors or lymphoma that have not responded to standard treatments. The study aims to determine if VMD-928, a TrkA inhibitor, can help when other options are ineffective. Participants must have a specific protein (TrkA) present in their tumor, which may indicate the drug's potential effectiveness for them. This trial may suit those who have tried other cancer treatments without success and have a tumor with certain genetic traits. As a Phase 1 trial, this research focuses on understanding how VMD-928 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking Tylenol (acetaminophen) and any strong CYP3A4 inhibitors or inducers during the study.

Is there any evidence suggesting that VMD-928 is likely to be safe for humans?

A previous study examined VMD-928 as a treatment for advanced solid tumors and lymphoma. Current studies do not yet provide specific safety information for VMD-928 in humans. However, similar treatments, known as TRK inhibitors, have generally been well tolerated and usually do not cause serious side effects.

VMD-928 is currently being tested in a Phase 1 trial, marking its first use in humans. The primary goal at this stage is to determine the treatment's safety. Phase 1 involves careful safety evaluation. Although similar treatments have shown safety, each new treatment requires its own testing to confirm this. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about VMD-928 because it offers a new approach to treating advanced cancer by targeting specific cancer cell mechanisms. Unlike traditional treatments like chemotherapy that indiscriminately attack both healthy and cancerous cells, VMD-928 aims to selectively inhibit a pathway crucial for cancer cell survival. This targeted action not only holds the promise of being more effective but also potentially reduces the side effects typically seen with conventional treatments.

What evidence suggests that VMD-928 might be an effective treatment for advanced cancer?

Research has shown that VMD-928 is a promising new treatment for advanced cancers. It targets a protein called TrkA, involved in cancer growth, through both indirect and permanent actions. This unique method aims to stop cancer cells from growing and spreading. Early human studies found that VMD-928 is well-tolerated, and researchers remain hopeful about its potential against cancers unresponsive to other treatments. Although this is an early-stage study, the innovative design of VMD-928 offers a new way to combat difficult-to-treat cancers. ^{1 2 5 6 7}

Who Is on the Research Team?

Clinical Development

Principal Investigator

VM Oncology

Are You a Good Fit for This Trial?

Adults with advanced solid tumors or lymphoma that have no standard curative therapy left. They must have TrkA overexpression, NTRK1 gene fusion, or progression after pan-Trk inhibitor treatment. Participants need to be in good physical condition (ECOG score of 0-1), able to take oral meds, and provide tumor tissue for analysis.

Inclusion Criteria

My cancer is not responding to standard treatments or has worsened after them.

You need to have a sample of your tumor tissue available, or be willing to have a sample taken before starting the study, so that it can be tested for a specific protein called TrkA.

My organs are working well.

Exclusion Criteria

I have not had chemotherapy that causes delayed side effects in the last 14 days.

Known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drug, or excipients

I have a history of chronic hepatitis or liver cirrhosis due to any cause.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation Treatment

Participants receive multiple ascending doses of VMD-928 to identify a safe and pharmacologically active dose

8-12 weeks

Cohort Expansion Treatment

Participants receive VMD-928 at the recommended Phase 2 dose to assess antitumor activity

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• VMD-928

Trial Overview

The trial is testing VMD-928, an oral medication aimed at treating various cancers by targeting the TrkA protein. It's a Phase 1 study where all participants receive the drug to evaluate its safety and effectiveness against their cancer.

How Is the Trial Designed?

Group I: VMD-928 monotherapy Experimental Treatment 1 Intervention

VMD-928 tablet monotherapy

Group II: Combination Therapy Experimental Treatment 1 Intervention

VMD-928 tablet in combination with fixed dose of pembrolizumab 200 mg once-very-21-day (per cycle)

Who Is Running the Clinical Trial?

VM Oncology, LLC

Lead Sponsor

Trials

1

Recruited

80+

Published Research Related to This Trial

The selective pan-NTRK inhibitor AZD7451 significantly inhibited the growth of colorectal cancer cells with an NTRK1 fusion (KM12) at a low concentration of 2 nM, demonstrating its potential as an effective treatment for tumors with NTRK fusions.

In contrast, AZD7451 had no inhibitory effect on the H810 cell line, which expressed low levels of NTRK1-3, suggesting that the efficacy of NTRK inhibitors may depend on the presence of specific NTRK fusions or expressions in lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of neurotrophic tyrosine kinase receptor 1 fusions and neurotrophic tyrosine kinase receptor family expression in non-small-cell lung cancer and sensitivity to AZD7451 in vitro. Tatematsu, T., Sasaki, H., Shimizu, S., et al.[2021]

The study identified a specific genomic rearrangement (TPM3-NTRK1) in the KM12 human colorectal carcinoma cell line, which leads to the expression of an oncogenic protein that makes these cells highly sensitive to TRKA kinase inhibition.

A novel TRKA inhibitor, NMS-P626, was found to effectively suppress tumor growth in mice with KM12 tumors, suggesting that patients with the TPM3-NTRK1 rearrangement in colorectal cancer may benefit from targeted TRKA inhibitor therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Ardini, E., Bosotti, R., Borgia, AL., et al.[2021]

NTRK gene fusions are significant drivers of various tumors, and first-generation TRK inhibitors like larotrectinib and entrectinib show over 75% response rates in treating NTRK fusion-positive cancers, regardless of tumor type.

While first-generation TRK inhibitors are generally well tolerated, resistance can develop in advanced cases, but second-generation TRK inhibitors like LOXO-195 and TPX-0005 may effectively target these resistant mutations, offering hope for continued treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NTRK fusion-positive cancers and TRK inhibitor therapy. Cocco, E., Scaltriti, M., Drilon, A.[2021]

The TPR-NTRK1 fusion kinase promotes rapid tumor growth in mouse models of pancreatic and lung cancers, and these tumors are highly sensitive to treatment with entrectinib, a TRKA inhibitor.

Combining entrectinib with the MEK1/2 inhibitor cobimetinib can significantly delay the development of drug resistance in NTRK1-driven tumors, suggesting a promising strategy for improving long-term treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer. Vaishnavi, A., Scherzer, MT., Kinsey, CG., et al.[2023]

A novel TRK kinase inhibitor, compound 34 (IHMT-TRK-284), was developed with impressive potency, showing IC50 values of 10.5 nM, 0.7 nM, and 2.6 nM against TRKA, B, and C respectively, indicating strong potential for treating cancers driven by fused NTRK genes.

This compound demonstrated the ability to overcome drug-resistant mutations and showed good pharmacokinetic profiles and antitumor efficacy in various animal models, suggesting it could be a promising new treatment for TRK fusion or mutant-driven cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants. Wang, B., Zhang, W., Liu, X., et al.[2021]

Larotrectinib and entrectinib are effective first-generation TRK inhibitors that have shown significant and durable responses in patients with tumors containing NTRK gene fusions, leading to FDA approvals for these drugs regardless of cancer type.

To address the issue of acquired resistance to these treatments, second-generation TRK inhibitors like selitrectinib and repotrectinib have been developed to enhance efficacy against resistant cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting TRK: A fast-tracked application of precision oncology and future directions. Kojadinovic, A., Laderian, B., Mundi, PS.[2021]

A new series of 3-vinylindazole derivatives, particularly compound 7mb, has been developed as potent Trk inhibitors, showing low nanomolar binding affinities and effective suppression of TrkA/B/C kinase functions.

Compound 7mb is effective against NTRK fusion-driven tumors and demonstrates strong activity against Larotrectinib-resistant mutations, making it a promising lead for further drug development despite its low oral bioavailability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis, and Structure-Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors. Duan, Y., Wang, J., Zhu, S., et al.[2021]

A novel LMNA-NTRK1 gene rearrangement was identified in a metastatic colorectal cancer patient, leading to abnormal TRKA protein expression and sensitivity to the pan-TRK inhibitor entrectinib.

Treatment with entrectinib resulted in a partial response, significantly reducing the size of liver metastases, marking the first clinical evidence of TRKA inhibition efficacy in solid tumors and highlighting a genomic-driven approach for targeting specific colorectal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. Sartore-Bianchi, A., Ardini, E., Bosotti, R., et al.[2018]

Researchers discovered new gene fusions involving the NTRK1 gene in 3.3% of lung cancer patients, which lead to the activation of the TRKA protein, promoting cancer growth.

Inhibiting TRKA kinase activity in cells with these NTRK1 fusions effectively reduced cell growth and autophosphorylation, suggesting a potential therapeutic target for treating this subset of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Vaishnavi, A., Capelletti, M., Le, AT., et al.[2022]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03556228

NCT03556228 | Selective TrkA Inhibitor VMD-928 to Treat ...

This is a multicenter, open-label, Phase 1 study of orally administered VMD-928 in adult subjects with advanced solid tumors or lymphoma

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.3081

First-time in-human study of VMD-928, an oral allosteric ...

This is an open label, Phase 1 study investigating oral VMD-928 in adults with advanced solid tumors or lymphoma.

3.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.TPS3146

First-time in-human study of VMD-928, an allosteric and ...

VMD-928 is the first oral small-molecule TrkA (NTRK1) selective inhibitor with dual allosteric and irreversible mechanisms of action.

4.

withpower.com

withpower.com/trial/phase-1-squamous-cell-carcinoma-of-head-and-neck-5-2018-d7952

VMD-928 for Advanced Cancer

This trial tests VMD-928, an oral drug, in adults with advanced cancers that don't respond to other treatments. It aims to find a safe and effective dose ...

5.

trial.medpath.com

trial.medpath.com/clinical-trial/263404c5d757ef90

Selective TrkA Inhibitor VMD-928 to Treat TrkA ... - MedPath

This is a multicenter, open-label, Phase 1 study of orally administered VMD-928 in adult subjects with advanced solid tumors or lymphoma that have ...

6.

npcf.us

npcf.us/clinical-trials/selective-trka-inhibitor-vmd-928-to-treat-trka-overexpression-driven-solid-tumors-or-lymphoma/

Selective TrkA Inhibitor VMD-928 To Treat ...

This is a multicenter, open-label, Phase 1 study of orally administered VMD-928 in adult subjects with advanced solid tumors or lymphoma that have ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10842066/

Safety of current treatment options for NTRK fusion-positive ...

TRKi have histology-agnostic activity against tumors with NTRK gene fusions. TRKi are generally well tolerated with a side effect profile that compares ...