Phase 1 trial of GD2-SADA:Lu-177-DOTA drug complex in patients with recurrent or refractory metastatic solid tumors known to express GD2 including small cell lung cancer (SCLC), sarcoma, and malignant melanoma

TPS3162 Background: GD2 is a disialoganglioside with high expression in small cell lung cancers (SCLC), sarcomas and melanomas and limited expression in normal tissues. The SADA platform represents a 2-step pretargeted radioimmunotherapy approach developed to optimize tumor targeting and reduce normal tissue irradiation. The GD2-SADA molecule is composed of a non-radioactive, bispecific antibody (anti-GD2 x anti-DOTA) linked to a tetramerization sequence from the p53 protein. In the first step, the GD2-SADA molecule is administered in a tetrameric form with a high affinity to the GD2 tumor target. In preclinical research, any unbound GD2-SADA molecule will disassemble to monomers and has shown to clear via the kidneys. In the second step, the radioactive payload 177 Lu-DOTA is administered, which binds to the anti-DOTA part of the GD2-SADA and leads to radiation-induced damage at the target and has shown limited exposure to non-target tissues in preclinical research. This pre-targeting approach supports the concept of highly focused irradiation of the tumor target with the potential of administering higher radioactivity doses. Methods: Trial 1001 (NCT05130255) is a first-in-human, dose-escalation, single-arm, open-label, non-randomized, multicenter phase 1 trial with the purpose of evaluating safety and tolerability of GD2-SADA: 177 Lu-DOTA. The trial is composed of 3 parts: Part A is dose escalation of the GD2-SADA dose and testing of different intervals between GD2-SADA and 177 Lu-DOTA. Part B is dose escalation of the 177 Lu-DOTA radioactivity dose to establish its maximum tolerated dose (MTD). Part C involves repeated dosing to assess the safety profile and determine the Recommended Phase 2 Dose (RP2D). Parts B and C may only begin upon completion of dose-limiting toxicity (DLT) observation period of Parts A and B, respectively. Escalation is based on classical 3+3 design. Parts A, B, and C will include 18, 12, and 32 patients, respectively. Patients can only be assigned to one part of the trial. The trial will include adult/adolescent patients with either SCLC, sarcoma, or melanoma with radiographical relapse/progression on standard therapies. The patients must be in ECOG performance status 0-1 and have adequate hematological, renal, and liver function. The patients must have measurable disease according to RECIST 1.1. Patients with active CNS metastases are ineligible. Safety endpoints (DLTs and adverse events) will be summarized by trial part and cohort. Objective response according to RECIST 1.1 and disease control rates at 6, 12 and 24 months will be presented with exact 95% CI. PFS, OS, and duration of response will be estimated using Kaplan-Meier methods. Additional objectives include dosimetry, PK, and immunogenicity data. The study is actively enrolling at US sites. Clinical trial information: NCT05130255 .