Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors Enriched for Tumors With NF2 Gene Mutations

Study Overview
=================
Brief Summary
-----------------
This is an open-label, dose escalation and expansion study to evaluate the safety, tolerability, PK, and biological activity of VT3989 administered in patients with mesothelioma and/or metastatic solid tumors that are resistant or refractory to standard therapy or for which no effective standard therapy is available.

Detailed Description
-----------------
Dose Escalation will employ a traditional 3 + 3 design to assess safety of VT3989 in patients with refractory metastatic solid tumors or mesothelioma until until the MTD or recommended phase 2 dose(s) and schedule(s) are determined. The recommended phase 2 dose(s) and schedule(s) may be less than the MTD depending on the type and severity of AEs that occur during and after the first cycle. Dose Expansion patients will be enrolled into up to 4 cohorts: Cohorts 1 and 2 will both enroll mesothelioma patients with or without an NF2 mutation that have progressed following standard therapy. The cohorts will differ by either the dose and/or schedule of VT3989, as recommended by the SRC. If a 3rd expansion cohort for mesothelioma patients is enrolled, it will employ a different regimen than the initial 2 expansion cohorts. If an NF2m solid tumor cohort is evaluated, it will use one of the regimens evaluated in the mesothelioma expansion cohorts.

Official Title
-----------------
Phase 1, Multi-Center, Open-Label, Study to Evaluate the Safety, Tolerability, and PK of VT3989 in Patients With Refractory Locally Advanced or Metastatic Solid Tumors Enriched for Tumors Harboring Mutations of the NF2 Gene

Conditions
-----------------
Solid Tumor, Adult, Mesothelioma

Intervention / Treatment
-----------------
* Drug: VT3989


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part 1: pathologically diagnosed metastatic solid tumor or mesothelioma that has progressed on or after all approved therapies of known clinical benefit except if the patient refuses or is not a candidate for such therapy; Part 2: In mesothelioma cohorts, pathologically diagnosed advanced malignant mesothelioma with or without NF2 mutations, that has progressed on or after all approved therapies of known clinical benefit except if the patient refuses or is not a candidate for such therapy. In the solid tumor cohort, pathologically diagnosed solid tumor with documented NF2 mutations. Measurable disease per RECIST v1.1 for non-pleural mesothelioma or other solid tumors (solid tumor expansion cohort) or modified RECIST v1.1 for malignant pleural mesothelioma. ECOG: 0-1 Exclusion Criteria: Active brain metastases History of leptomeningeal metastases Active or chronic, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy HIV positive or active Hepatitis B or Hepatitis C Clinically significant cardiovascular disease Additional active malignancy that may confound the assessment of the study endpoints Women who are pregnant or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 dose escalation: 3 + 3 design Part 2 dose expansion: up to 4 cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VT3989 Dose Escalation<br>VT3989 dosed orally in 21 or 28 day cycles. Patients will be enrolled into escalating dose levels during the Dose Escalation Phase | Drug: VT3989<br>* 25 or 100 mg capsules for oral administration.<br>|
| Experimental: Dose Expansion<br>VT3989 dosed in 21 or 28 day cycles in patients with refractory metastatic solid tumors or mesothelioma, with or without NF2 mutant tumors. | Drug: VT3989<br>* 25 or 100 mg capsules for oral administration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Dose Limiting Toxicity | Incidence of Adverse and Serious Adverse Events | over the first 21 days of dosing | 
| Occurrence of General Toxicity | Incidence of Adverse and Serious Adverse Events, Discontinuations due to Adverse Events and general safety Evaluations | through study completion, an average of 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Determined by RECIST v1.1 or modified RECIST v1.1 | through study completion, an average of 30 months | 
| Pharmacokinetic Evaluation - Cmax | Peak plasma concentration of VT3989 | over first 21 days of dosing | 
| Pharmacokinetic Evaluation - Tmax | Time to reach peak plasma concentration of VT3989 | over first 21 days of dosing | 
| Pharmacokinetic Evaluation - Half-life | Time required for the plasma concentration of VT3989 to reduce by half after reaching peak | over first 21 days of dosing |