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 pathway (YAP/TAZ–TEAD) and is being developed for malignant mesothelioma and other tumors with Hippo pathway dysregulation (often via NF2 alterations). A first‑in‑human phase 1/2, multicenter, open‑label trial (NCT04665206) began in March 2021 and remains ongoing, with dose‑escalation, expansion, and combination cohorts. In July 2025, the FDA granted orphan drug designation to VT3989 for mesothelioma. (clinicaltrials.ucsf.edu, cdek.pharmacy.purdue.edu, prnewswire.com)

Mechanism of action

• VT3989 binds TEAD family transcription factors and blocks TEAD autopalmitoylation, disrupting YAP/TAZ–TEAD complex formation and downstream transcription. In preclinical models, TEAD inhibitors from this series selectively suppressed proliferation of NF2‑deficient mesothelioma cells and inhibited NF2‑mutant xenograft growth. (aacrjournals.org)
• Additional preclinical data suggest VT3989 can enhance the efficacy and durability of several targeted therapies (e.g., EGFR, MET, KRAS G12C, BRAF/MEK, and mTOR inhibitors), supporting evaluation in combination regimens. (aacrjournals.org)

Efficacy

Phase 1 (dose escalation; updated conference abstracts/news releases)

• Population: 69 patients enrolled in Part 1; 44 with mesothelioma (pleural, peritoneal, pericardial, or bicavitary). Patients were heavily pretreated (median 3 prior regimens; nearly all mesothelioma patients had prior platinum/pemetrexed and immunotherapy). (jto.org, mdanderson.org)
• Responses:
• Mesothelioma: 6 partial responses (5 confirmed, 1 unconfirmed); 3 ongoing up to 21+ months at reporting; all responders with epithelioid histology. NF2 status among responders included both NF2‑mutant and NF2‑wild‑type cases. (jto.org)
• Overall: 7 partial responses among 69 patients with measurable disease; clinical benefit rate in mesothelioma (PR + SD ≥8 weeks, per protocol) reported as 57% in an AACR abstract. (aacrjournals.org)

Ongoing development includes dose/schedule optimization in mesothelioma expansion cohorts and planned combinations (nivolumab/ipilimumab in mesothelioma; osimertinib in EGFR‑mutant NSCLC). Study completion is estimated for June 2027. (clinicaltrials.ucsf.edu, cdek.pharmacy.purdue.edu)

Safety

Across dose levels 25–200 mg once daily (continuous and intermittent schedules):

• No dose‑limiting toxicities were observed; no maximum tolerated dose was reached up to 200 mg. (jto.org, aacrjournals.org)
• Common adverse events (mostly grade 1–2): reversible albuminuria (~54%), peripheral edema (~36%), fatigue (~25%), and nausea (~20%). Notably, albuminuria did not lead to reduced renal function or nephrotic syndrome in reported data. (jto.org, cancertherapyadvisor.com)
• Higher‑grade events: seven possibly treatment‑related grade 3 events (including albuminuria, edema, fatigue, and transaminase elevations) and one possibly related grade 4 cardiomyopathy; no treatment‑related deaths reported. (jto.org, mdanderson.org)

Trial details

• Trial: NCT04665206 (Phase 1/2; multi‑arm). Parts include dose escalation, disease‑specific expansions (mesothelioma with/without NF2 alterations; non‑pleural mesothelioma; NF2‑altered solid tumors), and combinations (nivolumab/ipilimumab; osimertinib). Primary completion estimated December 2026; study completion June 2027. (clinicaltrials.ucsf.edu, cdek.pharmacy.purdue.edu)

Further reading

• First‑in‑human clinical abstracts and reports
• Journal of Thoracic Oncology poster/meeting abstract (mesothelioma subset data): “First‑in‑Human Phase 1 Trial of VT3989…” (2023) https://www.jto.org/article/S1556-0864%2823%2901482-X/fulltext (jto.org)
• AACR Annual Meeting 2023 abstract CT006 (trial overview, clinical benefit rate): https://aacrjournals.org/cancerres/article/83/8_Supplement/CT006/725200 (aacrjournals.org)

• 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)

• Mechanism and preclinical studies

• Tang TT et al. Small Molecule Inhibitors of TEAD Auto‑palmitoylation… Mol Cancer Ther. 2021;20:986‑998. https://aacrjournals.org/mct/article/20/6/986/673270 (aacrjournals.org)

• AACR‑NCI‑EORTC 2023 abstract on combination strategies: https://aacrjournals.org/mct/article/22/12_Supplement/B088/730441 (aacrjournals.org)

• Trial registry and status

• ClinicalTrials.gov (via UCSF listing): https://clinicaltrials.ucsf.edu/trial/NCT04665206 (clinicaltrials.ucsf.edu)

• CDEK summary (timeline/design): https://cdek.pharmacy.purdue.edu/trial/NCT04665206/ (cdek.pharmacy.purdue.edu)

• Regulatory update

• FDA orphan drug designation news (July 30, 2025): https://www.prnewswire.com/news-releases/vivace-therapeutics-announces-receipt-of-orphan-drug-designation-for-vt3989-for-treatment-of-mesothelioma-302516783.html (prnewswire.com)

Notes: Reported clinical data are from early phase 1 presentations (mainly 2023 conference abstracts). As of September 2, 2025, peer‑reviewed, full clinical trial results have not yet been published; expansion and combination cohorts remain ongoing. (clinicaltrials.ucsf.edu, cdek.pharmacy.purdue.edu)

Last updated: Sep 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.