A Phase 3 Trial in Advanced Epithelioid Mesothelioma

Approximately 350 participants will be randomized 1:1 to VT3989 (Arm A) or Investigator's choice chemotherapy with gemcitabine or vinorelbine (Arm B).

VT3989 will be administered orally at 100 mg once daily for 2 weeks on treatment followed by 2 weeks off treatment in each 4-week cycle. Comparator treatment will be gemcitabine or vinorelbine using the protocol-specified regimen or local prescribing/institutional practice.

The trial includes screening, treatment, safety follow-up, and survival follow-up periods. A QTc Sub-Study will evaluate cardiac repolarization using time-matched pharmacokinetic samples and ECGs in approximately 25 Arm A participants. Overall survival is the primary endpoint; BICR-assessed progression-free survival is the key secondary endpoint.

• VT3989 (Drug): • 100 mg orally once daily for 2 weeks on treatment followed by 2 weeks off treatment (2W/2W) in each 4-week cycle
• gemcitabine (Drug): • 1,000 mg/m2 IV on Days 1 and 8 of each 3-week cycle, or per local prescribing information/institutional practice
• Vinorelbine (Drug): • 25-30 mg/m2 IV on Days 1 and 8 of each 3-week cycle, or per local prescribing information/institutional practice

Primary outcomes

• Overall Survival (OS) [Approximately 32-35 months after first randomization]: Time from randomization to death from any cause. Participants without an observed death will be censored at the last date known alive or the analysis cut-off date, whichever is earlier.

Secondary outcomes

• Progression-Free Survival by BICR [From randomization through radiologic progression, death, up to approximately 3 years or more]: Time from randomization to the first BICR-assessed radiologic progressive disease or death, using protocol-defined censoring rules.
• Treatment-Emergent Adverse Events and Serious Adverse Events [From first dose through the safety follow-up visit, (28 days after the last dose), up to approximately 3 years or more.]: Incidence and severity of Treatment-Emergent Adverse Events and Serious Adverse Events
• Disease-related symptoms and health-related quality of life outcomes [Baseline through treatment and protocol-specified follow-up; up to approximately 3 years or more]: Disease-related symptoms, treatment side effects, functioning, and health-related quality of life outcomes and time to deterioration.
• Overall Response Rate by BICR [Tumor assessments during treatment and applicable follow-up; up to approximately 3 years or more]: Overall Response Rate by BICR Proportion with best overall response of complete response or partial response by RECIST v1.1 and/or modified RECIST v1.1, assessed by BICR.
• Duration of Response [From first documented response through progression, death, or analysis cut-off; up to approximately 3 years or more]: Among participants with a complete or partial response, time from first documented response to progressive disease or death, with protocol-defined censoring.
• Disease Control Rate by BICR [Tumor assessments during treatment and applicable follow-up; up to approximately 3 years or more]: Proportion with best overall response of complete response, partial response, or stable disease by RECIST v1.1 and/or modified RECIST v1.1, assessed by BICR.
• Time to Response [From randomization to first documented response; up to approximately 3 years or more]: Time from randomization to the first documented complete or partial response by RECIST v1.1 and/or modified RECIST v1.1.
• EORTC QLQ-LC13 [Baseline through treatment and protocol-specified follow-up; up to approximately 3 years or more]: Lung cancer- and treatment-related symptoms using the EORTC Quality of Life Questionnaire Lung Cancer Module 13.
• EQ-5D-5L [Baseline through treatment and protocol-specified follow-up; up to approximately 3 years or more]: Health status and health-related quality of life using the EuroQol 5 Dimension-5 Levels instrument.
• Time to Deterioration [From baseline/randomization through protocol-defined deterioration; up to approximately 3 years or more]: Time to protocol-defined deterioration in disease-related symptoms and health-related quality of life; detailed definition will be specified in the Statistical Analysis Plan.

Other outcomes

• Pharmacokinetic Evaluation - Cmax [Up to Cycle 9 (each cycle is 28 days)]: Peak plasma concentration of VT3989
• Pharmacokinetic Evaluation - AUC [Up to Cycle 9 (each cycle is 28 days)]: Area under the plasma concentration versus time curve (AUC)
• Correlation between VT3989 exposure [Up to Cycle 9 (each cycle is 28 days)]: Correlation between VT3989 exposure

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male or female, age 18 years or older at informed consent.
* Pathologically confirmed advanced epithelioid pleural mesothelioma previously treated with platinum-based systemic chemotherapy and immunotherapy, given sequentially or concurrently.
* Radiologically measurable disease by modified RECIST v1.1 or RECIST v1.1.
* ECOG: 0-1.
* Adequate organ functions, including the liver, kidneys, and hematopoietic system.

Exclusion Criteria:

* Active brain metastases or primary CNS (central nervous system) tumors.
* History of leptomeningeal metastases
* Active or chronic, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
* Known HIV positive or active Hepatitis B or Hepatitis C
* Clinically significant cardiovascular disease and prior exposure to cardiotoxic agents
* Corrected QT (QTcF) interval > 470 msec (using Fridericia's correction formula).
* Women who are pregnant or breastfeeding
* Non-pleural mesothelioma at initial diagnosis or an aggressive histologic type such as sarcomatoid or biphasic mesothelioma.
* Prior treatment with a TEAD inhibitor, including VT3989 or another agent targeting the same molecular pathway.
* Prior receipt of both comparator treatments, gemcitabine and vinorelbine, alone or in combination, or known hypersensitivity to both. A participant who received only one comparator may enroll but must not be assigned to that same comparator.