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

Dose escalation (Part 1) will employ a traditional 3 + 3 design to assess safety of VT3989 in patients with metastatic solid tumors or mesothelioma. The 3 + 3 design will be implemented until the MTD or recommended phase 2 dose(s) and schedule(s) are determined. The MTD is defined as the highest dose level at which < 33% of patients experience a dose limiting toxicity (DLT) during the first cycle of the study (Cycle 1).

Dose Expansion (Part 2) will further evaluate the safety and assess preliminary antitumor activity at the recommended phase 2 dose(s) and schedule(s) with up to 6 cohorts. Expansion cohorts 1 and 2 will enroll patients with mesothelioma of any site origin with or without NF2 mutations. Expansion cohort 3 will enroll non-pleural mesothelioma patients. Expansion cohort 4 will enroll solid tumor patients with clearly inactivating NF2 mutations/alterations or YAP/TAZ gene rearrangements. Cohort 5 will enroll pleural mesothelioma patients.

Combination part (Part 3) includes three cohorts. Cohort A will enroll mesothelioma patients who will receive VT3989 in combination with immunotherapy (nivolumab plus ipilimumab). Cohort B will enroll NSCLC patients whose tumors have exon 19 deletion or exon 21 L858R mutation and will receive VT3989 in combination with targeted therapy (Osimertinib). Cohort C will enroll mesothelioma patients who will receive VT3989 in combination with chemotherapy (pemetrexed plus carboplatin).

Inclusion Criteria:

• Part 3 Combination Cohort A: Patients with pathologically diagnosed, metastatic or unresectable malignant mesothelioma (including both pleural and non-pleural) who have not received systemic therapy.
• Part 3 Combination Cohort B: Patients with pathologically diagnosed incurable locally advanced (inoperable or recurrent), or metastatic NSCLC with exon 19 deletions or exon 21 L858R mutations, with or without prior treatment with Osimertinib.
• Part 3 Combination Cohort C: Patients with pathologically diagnosed metastatic or unresectable malignant pleural mesothelioma who have not received systemic chemotherapy.
• Measurable disease per RECIST v1.1 for non-pleural mesothelioma or other solid tumors or modified RECIST v1.1 for malignant pleural mesothelioma. mRECIST may be used for pleural extension of non-pleural mesothelioma or for mixed pleural and peritoneal (or other) mesothelioma.
• 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).
• Additional active malignancy that may confound the assessment of the study endpoints
• Women who are pregnant or breastfeeding
• Prior treatment with TEAD inhibitor.