First-in-human, phase 1, open-label, dose-escalation, dose-expansion study of ADCT-901 as monotherapy in patients with select advanced solid tumors.

TPS3157 Background: Kidney associated antigen 1 (KAAG1) is highly and selectively expressed on tumor cell surface, such as ovarian, prostate, and triple negative breast cancers (TNBC), and is rapidly internalized and co-localized with a lysosomal marker, making an ideal candidate for an antibody-drug conjugate (ADC) target. ADCT-901 is an ADC composed of a humanized monoclonal antibody IgG1 against KAAG1, conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In mouse xenograft models of human-derived TNBC, ovarian, and renal cancers significant tumor reduction was observed after a single dose of ADCT-901, providing the rationale for clinical development of a PBD-based ADC to treat KAAG1 expressing tumors (Zammarchi et al, AACR 2019). This study aims to identify the recommended dose and schedule for expansion and to characterize safety and tolerability of ADCT-901 in patients (pts) with selected advanced solid tumors that generally express KAAG1. Methods: ADCT-901-101 is a phase 1, multicenter, 2-part, open-label study that will enroll ̃70 pts (NCT04972981). Part 1: pts will receive escalating doses of ADCT-901 guided by a 3+3 design (1st dose: 15 µg/kg every 3 weeks [Q3W]; highest dose: 290 µg/kg Q3W). Dose escalation will be evaluated by administering the lowest dose to first 3 pts, then increasing/decreasing the dose based on dose-limiting toxicity (DLT) experienced by pts. The dose and schedule of ADCT-901 identified in part 1 will be tested in part 2 to characterize safety, tolerability, and preliminary efficacy of ADCT-901. Primary endpoints include incidence of DLTs (part 1 only), frequency/severity of adverse events (AE) and serious AE, clinically significant changes in vitals, laboratory values, overall tolerability, and frequency of dose interruptions and reductions. Secondary endpoints include overall response rate, duration of response, progression-free and overall survival, pharmacokinetic parameters of ADCT-901 total antibody, PBD-conjugated antibody, unconjugated SG3199 in serum, and frequency of confirmed positive antidrug antibody responses. Exploratory endpoints include tumor modulation and potential pharmacodynamic changes. Key inclusion criteria: pathologic diagnosis of selected solid tumor (cholangiocarcinoma, renal cell carcinoma, ovarian/fallopian tube and prostate cancers, TNBC) locally advanced or metastatic at time of screening, pts refractory or intolerant to existing therapy, tissue biopsy or available tissue sample, ECOG of 0-2, and adequate organ function based on predefined laboratory parameters. Pts with symptomatic CNS metastases and clinically significant third space fluid accumulation will be excluded. The study opened for recruitment in September 2021; enrollment is ongoing. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group. Clinical trial information: NCT04972981.