Phase I/II, Multi-Center, Open-Label Study of VT3989, Alone or in Combination, in Patients With Locally Advanced or Metastatic Solid Tumors

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.

More details:

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 two 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).

Overview

VT3989 is an oral, first‑in‑class inhibitor of TEAD autopalmitoylation that targets the Hippo–YAP/TEAD transcriptional pathway. It is being developed by Vivace Therapeutics for mesothelioma and other solid tumors, including those with NF2 alterations. In July 2025, the FDA granted VT3989 orphan drug designation for mesothelioma. (aacrjournals.org)

Active clinical development includes a first‑in‑human, multi‑center Phase 1/2 study (NCT04665206) with dose‑escalation, expansion, and combination cohorts (with nivolumab/ipilimumab and with osimertinib). The trial began in March 2021 and remains ongoing; recent postings list it as recruiting with an estimated completion in 2027. (clinicaltrials.ucsf.edu)

Mechanism of action

TEAD transcription factors require autopalmitoylation for optimal activity and for interaction with YAP/TAZ. VT3989 inhibits TEAD autopalmitoylation, thereby disrupting YAP/TEAD‑driven transcriptional programs implicated in NF2‑deficient and other Hippo‑pathway‑dysregulated cancers. (aacrjournals.org)

Efficacy

Early clinical activity has been observed in the ongoing Phase 1 study:

• Across 69 evaluable patients (advanced mesothelioma and other solid tumors), 7 achieved RECIST v1.1 partial responses (~10%); 34 had stable disease. Responses included mesothelioma and an NF2‑mutant sarcoma, with durability up to 21+ months in some patients. (mdanderson.org)
• In an analysis focused on mesothelioma (44 patients), 6 partial responses were reported (5 confirmed; ~14% of the mesothelioma cohort), with several ongoing beyond 21 months; all responders had epithelioid histology. (jto.org)

Note: These are early, single‑arm results from dose‑escalation/optimization cohorts; randomized efficacy data are not yet available. (aacrjournals.org)

Safety

Across dose levels up to 200 mg once daily, no dose‑limiting toxicities or maximum tolerated dose were identified in early cohorts. The most frequent adverse events have been reversible albuminuria/proteinuria and peripheral edema; other common events include fatigue and nausea. Reported higher‑grade events have been uncommon (isolated grade 3 events such as fatigue, transaminase elevations, edema, and a single possibly related grade 4 cardiomyopathy). No nephrotic syndrome or sustained decline in renal function has been reported to date. (aacrjournals.org)

Ongoing trials and combinations

NCT04665206 includes expansion in mesothelioma (with and without NF2 mutations) and NF2‑altered solid tumors, plus combination cohorts with nivolumab/ipilimumab in mesothelioma and with osimertinib in EGFR‑mutant NSCLC. Site listings indicate active recruitment as of August 2025, with an estimated study completion in June 2027. (clinicaltrials.ucsf.edu)

Further reading

• AACR 2023 abstract (CT006): First‑in‑human VT3989 in advanced solid tumors/mesothelioma (efficacy and safety details) — https://aacrjournals.org/cancerres/article/83/8_Supplement/CT006/725200/Abstract-CT006-First-in-class-first-in-human-phase (aacrjournals.org)
• Journal of Thoracic Oncology meeting abstract: Phase 1 VT3989 in advanced mesothelioma — https://www.jto.org/article/S1556-0864%2823%2901482-X/fulltext (jto.org)
• Clinical trial record (NCT04665206) — UCSF overview: https://clinicaltrials.ucsf.edu/trial/NCT04665206; additional registry summary: https://cdek.pharmacy.purdue.edu/trial/NCT04665206/ (clinicaltrials.ucsf.edu)
• MD Anderson news release summarizing AACR 2023 presentation — https://www.mdanderson.org/newsroom/yap-tead-inhibitor-shows-encouraging-early-results.h00-159617856.html (mdanderson.org)
• FDA orphan drug designation coverage — https://www.onclive.com/view/vt3989-receives-fda-orphan-drug-designation-for-mesothelioma and company release: https://www.prnewswire.com/news-releases/vivace-therapeutics-announces-receipt-of-orphan-drug-designation-for-vt3989-for-treatment-of-mesothelioma-302516783.html (onclive.com)

Notes - Data are from conference abstracts, institutional news releases, and trial listings; a peer‑reviewed, full clinical report has not yet been published as of October 7, 2025. (jto.org)

Last updated: Oct 2025

Inclusion Criteria:

* Part 1: Patients with pathologically diagnosed metastatic solid tumor or mesothelioma who have 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 Expansion Cohorts 1 and 2: In mesothelioma cohorts, patients with pathologically diagnosed advanced malignant mesothelioma with or without NF2 mutations, who have 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 Expansion Cohort 3: Only non-pleural mesothelioma patients with epithelioid histology, who have relapsed from or are refractory to prior platinum-based chemotherapy and immunotherapy.

* Part 2 Expansion Cohort 4: in the solid tumor cohort, patients with pathologically diagnosed metastatic or locally advanced solid tumor with clearly inactivating NF2 mutations/alterations or YAP/TAZ gene rearrangements, who have progressed on or after approved therapies of known clinical benefit except if the patient refuses or is not a candidate for such therapy.

* Part 2 Expansion Cohort 5: Patients with pathologically diagnosed advanced malignant pleural mesothelioma with epithelioid histology, who have progressed on or after licensed immunotherapy, chemotherapy or combined chemoimmunotherapy, except if the patient refuses or is not a candidate for such therapy.

* 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 1: Evaluable or measurable disease per RECIST v1.1 or mRECIST

* Part 2 and 3: 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

* Corrected QT (QTcF) interval \> 470 msec (using Fridericia's correction formula); except for Part 2 Expansion Cohort 3, the QTcF interval criteria is \> 450 msec).

* Additional active malignancy that may confound the assessment of the study endpoints

* Women who are pregnant or breastfeeding

* Prior treatment with TEAD inhibitor, except for EHE patients.