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.

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.