212 Pb Pb-MP0712 in patients with small cell lung cancer and other Delta-like ligand 3–expressing solid tumors: A phase 1/2a study to assess safety, tolerability, and efficacy.

TPS3176 Background: 212 PbPb-MP0712 is a novel radiopharmaceutical comprising a Designed Ankyrin Repeat Protein (DARPin) that binds with high affinity to DLL3 and carries the alpha-emitting isotope lead-212 ( 212 Pb) for targeted delivery of high linear energy transfer radiation. DLL3 is highly expressed in SCLC, large cell neuroendocrine carcinoma (LC-NEC) of the lung, and extrapulmonary NEC (epNEC), while its expression in healthy tissue is virtually absent. In preclinical studies, 212 PbPb-MP0712 selectively accumulates in DLL3-positive tumors, exhibits an adequate biodistribution profile, and induces complete and durable tumor regression with prolonged survival and a favorable safety profile (Croset et al. AACR 2025). Initial human imaging data from a patient who received 203 PbPb-MP0712 in a Named Patient Access Program under the legal framework for compassionate care in South Africa indicate its specific uptake in tumor (Steiner et al. TRP EU 2025). Methods: This first-in-human Phase 1/2a study evaluates the safety, biodistribution, dosimetry, and preliminary antitumor efficacy of 212 PbPb-MP0712 (NCT07278479). Key inclusion criteria are SCLC and progression or recurrence following ≥2 prior lines of systemic therapy, or lung LC-NEC or epNEC with progression or recurrence following ≥1 prior line of systemic therapy, and measurable disease by RECIST v1.1. Patients with clinically stable central nervous system metastasis or prior DLL3-targeted therapy are eligible. Key exclusion criteria are Merkel cell carcinoma, neuroendocrine prostate cancer, interstitial lung disease, and active non-infectious pneumonitis. This study has two parts, a dose escalation (Part 1) and an expansion (Part 2). Primary objectives of Part 1 are to evaluate safety and tolerability of 212 PbPb-MP0712, and to determine the maximum tolerated dose and recommended phase 2 dose (RP2D). Primary objective of Part 2 is to assess preliminary antitumor activity of 212 PbPb-MP0712. All patients will receive a single dose of 203 PbPb-MP0712 as intravenous (IV) injection at 185 MBq to evaluate DLL3-expressing tumor lesions, pharmacokinetics, biodistribution and dosimetry using single-photon emission computerized tomography (SPECT)/CT, followed by 212 PbPb-MP0712 treatment. In study Part 1, for SCLC/lung LC-NEC cohorts, treatment proceeds regardless of imaging results; for epNEC cohorts, a DLL3-positive SPECT/CT is required. Patients will be enrolled in sequential cohorts to receive escalating doses of 212 PbPb-MP0712 as IV injection on Day 1 of each 28-day cycle for up to six cycles. The dose escalation will be guided by an adaptive Bayesian Logistic Regression Model. Upon completion of Part 1, Part 2 will enroll two groups of patients with DLL3-positive SCLC/lung LC-NEC or epNEC at the RP2D. Clinical trial information: NCT07278479 .