Endocrine Abstracts

Background: Despite the introduction of Lutathera, there remains an unmet medical need for new front-line therapies for advanced NETs. In this Phase I study, [²¹²Pb]VMT-α-NET, a novel targeted alpha radionuclide therapy (TAT) to SSTR2, is being investigated for safety and efficacy in PRRT-naïve patients with SSTR2 expressing tumors. Here we present initial results from the first two dose escalation cohorts.

Methods: This is a first-in-human dose-escalation study to determine the safety, pharmacokinetics, and preliminary efficacy of [²¹²Pb]VMT-α-NET in adult NETs of any grade, Small Cell Lung Cancer, Pheochromocytoma and Paraganglioma with progressive disease as assessed by RECIST 1.1. (NCT05636618). The Phase 1 of the trial includes four escalating cohorts and follows a Bayesian modified toxicity probability interval (mTPI-2) design. The first two cohorts incorporate dosimetry evaluations with the therapeutic surrogate [²⁰³Pb]VMT-a-NET prior to receiving up to 4 treatment cycles of [²¹²Pb]VMT-a-NET with injected activity of 92.5 MBq (2.5 mCi) or 185 MBq (5 mCi) for Cohort 1 or 2, respectively. Reno-protective amino acids are co-administered with [²¹²Pb]VMT-a-NET. DLT assessment period is defined as the first 6 weeks of cycle 1. Safety is assessed weekly during cycle 1 and bi-weekly for subsequent cycles. The total in-trial follow-up period will be 18 months following the final administration. Efficacy will be assessed by RECIST 1.1 criteria. The primary objective is to evaluate the tolerability of [²¹²Pb]VMT-a-NET, collection and measurement of radioactive blood and urine PK samples at specific timepoints, and determination of the recommended phase 2 dose of [²¹²Pb]VMT-a-NET in PRRT naïve participants with NETs.

Results: A total of 9 patients were enrolled (2 in cohort 1 and 7 cohort in 2). There were no DLTs or grade 3 AEs for Cohort 1 (92.5 MBq (2.5 mCi). 4/33 TEAEs were grade 2 AEs (elevated Amylase, fatigue, nausea and urinary tract infection). Cohort 2 Safety Monitoring Committee (SMC) meeting was held on July 17^th, 2024, with no DLTs. There were 2 grade 3 AEs (diarrhea, syncope), 4 grade 2 AEs (fatigue, nausea, presyncope and weight loss). The most frequent TEAE were in descending order: nausea, alopecia, diarrhea and fatigue. No nephrotoxicity was reported in either cohort. One patient discontinued due to progressive disease.

Conclusions: [²¹²Pb]VMT-α-NET is safe up to 185 MBq (5 mCi) dose level, and the SMC supported dose escalate to cohort 3 at 277.5 MBq (7.5 mCi) following a mandatory FDA review in fall. Cohort 2 remains open for dose level expansion.

ABSTRACT ID28690