SKB264 ADC: A first-in-human study of SKB264 in patients with locally advanced unresectable/metastatic solid tumors who are refractory to available standard therapies.

TPS3659 Background: Elevated expression of trophoblast antigen 2 (TROP2) is often associated with invasion/aggression, progression, and metastasis of many different tumor types. Efficacies of anti-TROP2 ADC have been demonstrated both pre-clinically and in the clinical trials. SKB264 is being developed as a further optimized TROP2-targeting ADC with a proprietary cytotoxic, belotecan-derived payload and novel stable conjugation chemistry to achieve average DAR (Drug Antibody Ratio) of 7.4. Release of payload upon SKB264 internalization is in a TROP2 expression dependent manner. Extensive preclinical studies demonstrated antitumor activity of SKB264 in vitro, in xenograft and patient-derived xenograft (PDX) animal models. In addition, safety studies have demonstrated a good safety profile to allow SKB264 to be studied in clinical trials. Methods: SKB264-01 is a global open label multicenter study. The study is divided into 2 parts, the phase I is to determine the safety profile, define MTD and/or the RP2D, and characterize DLTs of SKB264. Dose escalation and MTD identification will be directed using a Bayesian logistic regression model (BLRM) with overdose control. The phase II is to evaluate efficacy and obtain clinical activity data of SKB264 as a monotherapeutic agent at the RP2D in each of the designated Phase II cohorts and overall (n = 16 per cohort; n = 48 for entire Phase II part). Objective response rate (ORR) will be continuously evaluated in each cohort using a Bayesian hierarchical model. TROP2 assessments will not be performed prior to enrollment but it will be assessed retrospectively. Confirmation of TROP2 expression by immunohistology or other methods is not required, but the Sponsor will request tissue specimens from archived materials for determination of TROP2 expression. The patient must have, in the judgment of the investigator, historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types: i. ovarian epithelial cancer, ii. gastric adenocarcinoma, iii. pancreatic adenocarcinoma, iv. triple negative breast cancer, v. bladder cancer. Patient will receive study drug as a single IV infusion at the prescribed dose level at each administration. Cycles will continue until disease progression or unacceptable toxicity. Adverse Events (AE) will be graded according to CTCAE V.5.0. Responses will be evaluated according to RECIST V1.1. The enrollment will began in Mar 2020 in USA sites. Clinical trial information: NCT04152499 .