Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors

Official title

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

Overview

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.

Detailed description

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).

Interventions

• Drug VT3989
  25, 50, 100, 150 or 200 mg capsules for oral administration.
• Drug Nivolumab & Ipilimumab
  Nivolumab infusion - 360 mg every 3 weeks, 30-minute intravenous infusion Ipilimumab infusion - 1 mg/kg every 6 weeks, 30-minute intravenous infusion
• Drug Osimertinib
  40 or 80 mg tablets for oral administration
• Drug Pemetrexed/Carboplatin
  Pemetrexed infusion: 500 mg/m2 intravenous infusion Carboplatin infusion: AUC 5.0 intravenous infusion

Primary outcome measures

• Occurrence of Dose Limiting Toxicity [Time frame: over the first 21 days of dosing]
• Occurrence of General Toxicity [Time frame: through study completion, an average of 30 months]

Secondary outcome measures (7)

• Tumor Response [Time frame: through study completion, an average of 30 months]
• Pharmacokinetic Evaluation - Cmax [Time frame: for first 6 cycles]
• Pharmacokinetic Evaluation - Tmax [Time frame: for first 6 cycles]
• Pharmacokinetic Evaluation - Half-life [Time frame: for first 6 cycles]
• Overall survival [Time frame: At 6, 12, 18 and 24 months]
• Progression free survival [Time frame: At 6, 12, 18 and 24 months]
• Quality of life assessment (Part 2, expansion cohort 3, 4, and 5) [Time frame: Through study completion, an average of 30 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 9 centers

• UCSF Helen Diller Family Comprehensive Cancer Center — San Francisco
• University of Chicago Medical Center — Chicago
• Massachusetts General Hospital — Boston
• Dana-Farber Cancer Institute — Boston
• M Health Fairview University of Minnesota Medical Center — Minneapolis
• Memorial Sloan Kettering Cancer Center — New York
• MD Anderson Cancer Center — Houston
• NEXT Oncology — San Antonio
• … and 1 more center

Australia · 3 centers

• Monash Health — Clayton
• Peter MacCullum Cancer Centre — Melbourne
• Linear Clinical Research — Nedlands

Publications

• Yap TA, Kwiatkowski DJ, Dagogo-Jack I, Offin M, Zauderer MG, Kratzke R, Desai J, Body A, Millward M, Tolcher AW, Raghav KPS, Thurston A, Post L, Dorr FA, Tang TT, Li Y, Sharma N, Kindler HL. YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. Nat Med. 2025 Dec;31(12):4281-4290. doi: 10.1038/s41591-025-04029-3. Epub 2025 Oct 19. PMID 41111090

Identifiers

NCT: NCT04665206 · VT3989-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗