VMD-928 for Advanced Cancer

Recruiting in Palo Alto (17 mi)

+16 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: VM Oncology, LLC

Must not be taking: Acetaminophen, Strong CYP3A4 inhibitors

Disqualifiers: Active infections, Heart failure, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

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 and understand how the drug affects cancer cells.

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.

What data supports the effectiveness of the drug VMD-928 for advanced cancer?

Research on similar drugs, like entrectinib, shows that targeting TRKA (a protein involved in cancer growth) can shrink tumors in certain cancers, such as colorectal and lung cancer, by blocking the activity of the NTRK1 gene, which is often altered in these cancers. ^{1 2 3 4 5}

Is VMD-928 safe for humans?

The research articles do not provide specific safety data for VMD-928 in humans, but they discuss similar TRK inhibitors like larotrectinib and entrectinib, which are generally well tolerated with some side effects. These drugs are used for cancers with NTRK fusions and have shown good safety profiles in clinical trials. ^{3 4 6 7 8}

What makes the drug VMD-928 unique for treating advanced cancer?

VMD-928 is unique because it specifically targets and inhibits TRKA (a protein involved in cancer growth), which is particularly effective in tumors with NTRK1 gene fusions. This targeted approach may offer benefits for patients whose cancers are driven by these specific genetic changes, unlike more general cancer treatments. ^{2 3 4 6 9}

Research Team

Clinical Development

Principal Investigator

VM Oncology

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• VMD-928 (Small Molecule Inhibitor)

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.

Participant Groups

Group I: VMD-928 300 mg Tablet (ongoing); 100 mg Capsule (complete) Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

VM Oncology, LLC

Lead Sponsor

Trials

1

Recruited

80+

Findings from Research

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]

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]

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 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]

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]

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]

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 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]

References

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

Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. [2022]

2. United States 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. [2021]

3. France 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. [2021]

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

Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer. [2023]

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

Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. [2018]

6. France pubmed.ncbi.nlm.nih.gov

Design, synthesis, and Structure-Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Targeting TRK: A fast-tracked application of precision oncology and future directions. [2021]

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

NTRK fusion-positive cancers and TRK inhibitor therapy. [2021]

9. England 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. [2021]