Sponsor: VM Oncology, LLC (industry)
Phase: 1
Start date: June 8, 2018
Planned enrollment: 82
VMD-928 is an investigational small molecule drug developed by VM Oncology, LLC, designed to target cancers characterized by TrkA overexpression or NTRK1 gene fusions. (mycancergenome.org)
VMD-928 functions as a selective inhibitor of tropomyosin receptor kinase A (TrkA), also known as neurotrophic tyrosine receptor kinase 1 (NTRK1). By binding to TrkA, VMD-928 inhibits the interaction between neurotrophins and TrkA, preventing receptor activation. This inhibition disrupts downstream signaling pathways essential for tumor cell growth, survival, invasion, and resistance to treatment. (mycancergenome.org)
VMD-928 is currently being evaluated in a Phase 1, open-label, dose-escalation study (NCT03556228) involving adult patients with advanced solid tumors or lymphoma that have progressed or are unresponsive to standard therapies. The study aims to determine the safety, pharmacokinetics, and pharmacodynamics of VMD-928, as well as to identify a recommended Phase 2 dose. (ichgcp.net)
As of April 2025, detailed efficacy and safety results from the ongoing Phase 1 trial have not been published. The trial is designed to assess the antitumor activity of VMD-928 at the recommended Phase 2 dose and to collect tumor samples before and after treatment to evaluate biological activity. (ichgcp.net)
Last updated: Apr 2025
Goal: The trial aims to determine the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of VMD-928, an oral selective TrkA inhibitor, in patients with advanced solid tumors or lymphoma that are refractory to standard therapies.
Patients: Adult patients with histologically or cytologically confirmed advanced solid tumors or lymphoma that are non-responsive to, or have progressed following, available therapies and for which no standard or curative therapy exists. Subjects are required to have good performance status (ECOG 0-1), adequate organ function, and tumors either overexpressing TrkA or harboring an NTRK1 gene fusion. Patients with active infections, significant comorbidities, or impaired drug absorption are excluded.
Design: This is a multicenter, open-label, first-in-human phase 1 study employing a multiple-dose, dose-escalation and expansion cohort design. Dose escalation uses an adaptive, accelerated titration scheme, followed by cohort expansion at the recommended phase 2 dose with collection of pre- and post-treatment tumor biopsies for correlative studies.
Treatments: The study investigates oral VMD-928, an investigational small molecule that irreversibly and allosterically inhibits TrkA by acting as a molecular glue to dimerize and inactivate the protein. VMD-928 is highly selective for TrkA, distinguishing it from current ATP-competitive pan-TRK inhibitors. Early phase results identified a recommended phase 2 dose of 600 mg twice daily, with dose-limiting toxicities including elevated liver enzymes and manageable adverse events such as dark stool and gastrointestinal symptoms. Preliminary evidence shows prolonged stable disease in at least one patient with adenoid cystic carcinoma. Expansion cohorts target tumors with high TrkA expression.
Outcomes: Primary outcome measures include the number and severity of treatment-emergent adverse events and dose-limiting toxicities. Secondary outcomes assess pharmacokinetics (AUC, Cmax), pharmacodynamics (change in TrkA expression), and exploratory correlations between TrkA expression, plasma exposure, analgesic response, and antitumor activity through two cycles of therapy.
Burden on patient: Patient burden is moderate to high. Phase 1 trials require frequent clinic visits for safety assessment, regular blood draws for pharmacokinetic sampling, and additional tumor biopsies both pre-treatment and after two cycles for pharmacodynamic studies. Analgesic response and clinical outcomes are closely monitored, and patients with advanced disease may experience increased travel and procedural burdens.
Key Inclusion Criteria:
* Histologically or cytologically confirmed diagnosis of any type of solid tumor malignancy or lymphoma that is not responsive to standard therapies or had progressed following standard therapy and for which there is no approved or curative therapy. Additionally, patients must not be candidates for or have exhausted regimens known to provide clinical benefit, including hematopoietic stem cell transplantation in lymphoma patients if they are deemed transplant eligible.
* ECOG score of 0 or 1.
* Able to swallow and retain oral medication.
* Adequate organ system function.
* Subjects must either have available archival tumor tissue samples, or consent to tumor tissue sampling prior to the first dose, that is sufficient for IHC analysis of TrkA expression, except with prior documented NTRK+.
* Subjects must have a tumor:
(i). with TrkA protein overexpression (TrkA+) in the validated TrkA IHC assay, OR (ii). with documented NTRK1 gene fusion (NTRK1+) including a tumor which has progressed due to NTRK1 mutation after treatment of a pan-Trk inhibitor (e.g. larotrectinib or entrectinib)
* Adequate organ system function as defined as follows:
1. Absolute neutrophil count ≥1.5x10\^9/L
2. Hemoglobin ≥9g/dL
3. Platelets ≥100x10\^9/L
4. PT/INR, PTT ≤1.5xULN
5. Total bilirubin ≤1.5x ULN
6. AST, ALT ≤2.5xULN
7. Creatinine ≤1.2xULN for age, weight
8. Calculated creatinine clearance or 24h urine creatinine clearance ≥60mL/min
Key Exclusion Criteria:
1. Received chemotherapy having delayed toxicity within the last 14 days (six weeks for prior nitrosourea or mitomycin C).
2. Received anticancer therapy with radiation, immunotherapy, and a biologic, surgery and/or tumor embolization within the past 2 weeks.
3. Received an investigational anticancer drug within 14 days or 5 half-lives of the investigational agent, whichever is longer, prior to the first dose of VMD-928. Any exceptions to the above must be approved by the Sponsor Medical Monitor.
4. Unresolved toxicity from previous anticancer therapy \> CTCAE Grade 1 (except alopecia or anemia) unless agreed to by both the Sponsor Medical Monitor and the Investigator.
5. Negative result on TrkA immunohistochemistry (IHC) assay (if enrolled in dose expansion cohorts).
6. Known active infections including HIV disease.
7. Patients with a history of chronic viral hepatitis (HBV/HCV), even if treated, or a history of cirrhotic liver secondary to any etiology (i.e. alcoholism, non-alcoholic steatohepatitis).
8. Currently pregnant, nursing, or planning to become pregnant during the course of the study.
9. QTcF interval ≥ 480 msec.
10. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
11. Acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.
12. Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would compromise the patient's safety or interfere with assessment of the drug.
13. Psychological, familial, sociological, geographical, or other concurrent conditions that would interfere with safety evaluation, limit the patient's ability to follow the procedures in the protocol or otherwise jeopardize compliance with the protocol. Patients with uncontrolled major depression, bipolar disorder, or severe anxiety disorder are excluded.
14. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drug, or excipients.
15. Patient has had or is currently having other malignant tumors within 3 years.
16. Patients have multiple factors that affect their oral medication.
17. Patients have long-term unhealed wounds or fractures.
18. Patients have uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage.
19. Patients are taking the following drugs and can't stop them during the study:
* Tylenol or medicine containing acetaminophen (paracetamol).
* Strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.
San Juan, 00935, Puerto Rico
[email protected] / (787) 407-3333
Status: Recruiting
Santa Rosa, California, 95403, United States
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Hartford, Connecticut, 06102, United States
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Washington, District of Columbia, 20037, United States
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Pembroke Pines, Florida, 33028, United States
[email protected] / 954-844-9917
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Fort Lauderdale, Florida, 33308, United States
[email protected] / 954-542-7748
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Florham Park, New Jersey, 07932, United States
[email protected] / 973-436-1755
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Morristown, New Jersey, 07962, United States
[email protected] / 973-971-6373
Status: Recruiting
Englewood, New Jersey, 07631, United States
[email protected] / 201-608-2572
Status: Recruiting
Albuquerque, New Mexico, 87110, United States
[email protected] / 505-559-6089
Status: Recruiting
New York, New York, 10065, United States
[email protected] / 646-962-6091
Status: Recruiting
Maumee, Ohio, 43537, United States
[email protected] / 567.402.4502
Status: Recruiting
York, Pennsylvania, 17403, United States
[email protected] / 1-717-741-9229
Status: Recruiting
Houston, Texas, 77030, United States
[email protected] / 713-563-2169
Status: Recruiting
Salt Lake City, Utah, 84106, United States
[email protected] / 801-269-0231
Status: Recruiting