A Phase 2/3, Multicenter, Randomized Open-Label Study of Zanzalintinib vs Everolimus in Participants With Previously Treated, Unresectable, Locally Advanced or Metastatic Neuroendocrine Tumors

Trial Details

Sponsor: Exelixis (industry)

Phase: 2/3

Start date: April 24, 2025

Planned enrollment: 440

Trial ID: NCT06943755

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More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: Zanzalintinib (XL092)

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Goal: To determine whether zanzalintinib improves progression-free survival compared with everolimus in patients with previously treated, unresectable, locally advanced or metastatic neuroendocrine tumors (NETs).

Patients: Adults with histologically confirmed, well-differentiated (Grade 1–3) pancreatic or extra-pancreatic NETs that are unresectable or metastatic, with radiographic progression by RECIST 1.1 within 12 months and measurable disease. Key exclusions include neuroendocrine carcinomas (e.g., small cell), medullary thyroid cancer, pheochromocytoma, paraganglioma, Merkel cell carcinoma, MiNEN, and prior exposure to VEGFR-targeting TKIs or mTOR inhibitors. Recent chemotherapy, liver-directed/ablative therapy, radionuclide therapy, or recent radiation within protocol-defined windows are not allowed.

Design: Phase 2/3, multicenter, randomized, open-label, active-controlled study comparing zanzalintinib versus everolimus. Allocation is randomized with blinded independent central review for radiographic endpoints. Planned enrollment is 440 participants.

Treatments: Zanzalintinib oral tablets once daily, up to 14 months. Zanzalintinib (XL092) is an investigational oral multi-kinase inhibitor targeting VEGFR2, MET, and TAM kinases (TYRO3, AXL, MER), inhibiting tumor angiogenesis, growth, and immunosuppressive signaling; it has a 16–22 hour half-life supporting once-daily dosing. Early-phase data in heavily pretreated clear cell renal cell carcinoma showed an objective response rate around 38% and median PFS of approximately 9 months, with manageable class-consistent toxicities such as diarrhea, hypertension, asthenia, decreased appetite, and proteinuria. Everolimus oral tablets once daily, up to 14 months, serve as an active comparator standard option in advanced NETs via mTOR pathway inhibition.

Outcomes: Primary: Progression-free survival by RECIST 1.1 per blinded independent central review. Secondary: Investigator-assessed PFS; objective response rate by BICR and investigator; overall survival; duration of response; disease control rate; patient-reported outcomes using EORTC QLQ-C30 and QLQ-GI.NET21; and safety/tolerability (adverse events). Follow-up for efficacy endpoints extends up to 48 months for PFS/response and up to 60 months for OS.

Burden on patient: Burden is moderate and aligned with typical phase 2/3 oral therapy trials. Treatment is oral with clinic visits for safety assessments, laboratory monitoring, and imaging at standard intervals (e.g., every 8–12 weeks) for RECIST evaluation. Archival tumor tissue submission is requested; a fresh biopsy may be needed if archival tissue is unavailable and feasible, which adds procedure-related burden. No intensive pharmacokinetic sampling is described. Recent prior therapies must be washed out, and exclusion of recent radiation or radionuclide therapy may necessitate scheduling adjustments. Overall, travel and testing requirements are comparable to standard care for advanced NETs, with additional centralized imaging review not impacting patient visit frequency.

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