A first-in-human phase I trial with antibody drug conjugate ADCT-701 in neuroendocrine tumors and carcinomas.

TPS672 Background: Neuroendocrine neoplasms (NENs) consist of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which are rare malignancies found in various anatomical sites, including the gastrointestinal tract, pancreatic islets, lungs, and adrenal glands. Poorly differentiated NECs are classified as high-grade carcinomas that bear resemblance to small-cell lung cancer (SCLC). Treatment for poorly differentiated NECs typically follows small-cell carcinoma guidelines, utilizing platinum-based regimens; however, these patients experience a high risk of relapse and demonstrate a limited response to additional systemic therapies. Adrenocortical carcinoma (ACC) is another rare malignancy associated with a median survival of approximately 14.5 months post-diagnosis, and advanced disease management options show limited efficacy. Currently, no targeted therapies have demonstrated significant effectiveness for this condition. Preclinical investigations have indicated that Delta-like non-canonical notch ligand 1 (DLK1) is expressed in various neuroendocrine neoplasms, including ACC, SCLC, neuroblastoma, pheochromocytoma, and paraganglioma. ADCT-701, a humanized antibody targeting DLK1, has shown potential in suppressing tumor growth and enhancing survival across multiple cancer models expressing this marker. Methods: This Phase I dose escalation study (NCT06041516) aims to enroll adult patients with histologically or cytologically confirmed neuroendocrine neoplasms or malignant ACC with evaluable disease, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants will be part of a dose-finding trial. A 3+3 design is utilized to assess up to ten different dose levels of ADCT-701. Dose escalation continues unless dose-limiting toxicities occur, the maximum tolerated dose (MTD) is reached, or an optimal dose is established. The primary endpoint of the study is to ascertain the recommended phase 2 dose of ADCT-701 in patients with neuroendocrine neoplasms or malignant adrenocortical carcinoma. Secondary endpoints will assess safety, preliminary tumor activity, response rate, overall survival, pharmacokinetics, and the immunogenicity profile of ADCT-701. The trial aims to enroll up to 70 evaluable patients across a maximum of 10 dose levels. For further details, please refer to clinical trial information NCT06041516. Clinical trial information: NCT06041516 .