Selective TrkA Inhibitor VMD-928 to Treat TrkA Overexpression Driven Solid Tumors or Lymphoma

Study Overview
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Brief Summary
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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 progressed or are non responsive to available therapies and for which no standard or available curative therapy exists

Detailed Description
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This is an open-label, Phase I, FTIH, multiple-dose, dose-escalation and cohort expansion multi-center study conducted in three parts to identify a safe and pharmacologically active dose and regimen for VMD-928 monotherapy, which can be implemented in Phase 2 studies (the RP2D). The regimen will be identified using an adaptive design, multiple-ascending dose study in cancer patients. To conserve patients in the lower dose cohorts, dose escalation will begin with an accelerated titration scheme. A second part of the study will assess antitumor activity at the RP2D. The third part of the study will collect tumor samples before and after treatment to assess biological activity.

Official Title
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An Open-Label, Multiple-Dose, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of VMD-928 in Subjects With Solid Tumors or Lymphoma

Conditions
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Any Solid Tumors Progressed After a Prior Immunotherapy, Cervical Cancer, Adenoid Cystic Carcinoma, Squamous Cell Carcinoma of Head and Neck, Mesothelioma, Gall Bladder Cancer, Thymic Carcinoma, Non-Small Cell Squamous Lung Cancer, Bladder Cancer, Ovarian Cancer, Pancreatic Cancer, Colon Cancer, Leiomyosarcoma, Head and Neck Squamous Cell Carcinoma, Thymoma, Urothelial Carcinoma

Intervention / Treatment
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* Drug: VMD-928 300 mg Tablet (ongoing); 100 mg Capsule (complete)


Participation Criteria
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Eligibility Criteria
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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. Subjects must have a tumor: (i). with TrkA protein overexpression in the validated TrkA IHC assay, OR (ii). with documented NTRK1 gene fusion, or 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: Absolute neutrophil count ≥1.5x10^9/L Hemoglobin ≥9g/dL Platelets ≥100x10^9/L PT/INR, PTT ≤1.5xULN Total bilirubin ≤1.5x ULN AST, ALT ≤2.5xULN Creatinine ≤1.2xULN for age, weight Calculated creatinine clearance or 24h urine creatinine clearance ≥60mL/min Key Exclusion Criteria: Received chemotherapy having delayed toxicity within the last 14 days (six weeks for prior nitrosourea or mitomycin C). Received anticancer therapy with radiation, immunotherapy, and a biologic, surgery and/or tumor embolization within the past 2 weeks. 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. 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. Negative result on TrkA immunohistochemistry (IHC) assay. Known active infections including HIV disease. Patients with a history of chronic viral hepatitis (HBV/HCV) or a history of cirrhotic liver secondary to any etiology (i.e. alcoholism, non-alcoholic steatohepatitis). Currently pregnant, nursing, or planning to become pregnant during the course of the study. QTcF interval ≥ 480 msec. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system. Acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks. Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would compromise the patient's safety or interfere with assessment of the drug. 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. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drug, or excipients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Escalation: Tablet formulation (ongoing); Capsule formulation (complete) Cohort Expansion with RP2D;
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VMD-928 300 mg Tablet (ongoing); 100 mg Capsule (complete)<br> | Drug: VMD-928 300 mg Tablet (ongoing); 100 mg Capsule (complete)<br>* Taken orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and severity of treatment-emergent AEs |  | Within 2 cycles (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) of VMD-928. |  | On Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Peak plasma concentration (Cmax) of VMD-928. |  | On Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Incidence of Dose Limiting Toxicities. |  | During the Cycle 1 (each cycle is 28 days) | 
| Analgesic response as defined by the Brief Pain Inventory (BPI). |  | On Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Change in TrkA protein expression. |  | Pre-dose and at the end of Cycle 2 (each cycle is 28 days) | 
| Correlation between clinical antitumor and AUC. |  | Up to the end of the Cycle 2 (each cycle is 28 days) | 
| Correlation between clinical antitumor and TrkA protein expression. |  | Up to the end of the Cycle 2 (each cycle is 28 days) | 
| Correlation between analgesic response and TrkA protein expression. |  | Up to the end of the Cycle 2 (each cycle is 28 days) | 
| Correlation between analgesic response and AUC. |  | Up to the end of the Cycle 2 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TrkA, NTRK1, Thymic, Mesothelioma, Head and Neck Squamous Cell Carcinoma, Ovarian, Urothelial, Squamous Cell Carcinoma of Lung (squamous NSCLC), Esophageal, Adenoid Cystic Carcinoma, Bladder, Cervical, Gall Bladder, Colon, Progression after anti PD-1/PD-L1 immunotherapy, Progressed after an immunotherapy