A phase I/II, two-part, multicenter, first-in-human study of DS-7300a in patients with advanced solid malignant tumors.

TPS3646 Background: B7 homologue 3 (B7-H3) is a protein that is overexpressed in various cancer types, including lung, head and neck squamous cell carcinoma, prostate, esophageal, and breast. B7-H3 overexpression is associated with poor prognosis because it promotes increased invasive and metastatic potential of cancer cells (Dong P, et al. Front Oncol. 2018;8:264). Currently, no B7-H3–targeted cancer therapies are approved. DS-7300a is an antibody-drug conjugate composed of a humanized anti–B7-H3 IgG1 monoclonal antibody (MABX-9001a) conjugated to a drug linker that releases its payload upon internalization by cancer cells. The payload, DXd, is an exatecan derivative that inhibits topoisomerase I, an enzyme that relaxes supercoiled DNA for replication and transcription. DS-7300a induced apoptosis in cancer cells in vitro and showed potent antitumor activity in xenograft models of various types of solid tumors in vivo. Methods: This phase 1/2, multicenter, nonrandomized, open-label, first-in-human study of DS-7300a is ongoing in the United States and Japan in patients with selected advanced solid tumors (NCT04145622). This study has 2 parts: dose escalation (part 1) and dose expansion (part 2). Primary objectives are to evaluate the safety, tolerability, and antitumor activity of DS-7300a and to determine the maximum tolerated dose or recommended dose for the expansion part. Secondary objectives include the pharmacokinetic characterization of DS-7300a, determination of the total levels of anti–B7-H3 antibody and the drug component (DXd), and assessment of the incidence of anti-drug antibodies against DS-7300a. Key inclusion criteria are age ≥ 18 years (United States) or ≥ 20 years (Japan), an ECOG performance status of 0 or 1, ≥ 1 measurable lesion according to RECIST 1.1 as assessed by the investigator, and consent to provide pre- and on-treatment tissue samples (mandatory if clinically allowed and not contraindicated). Key exclusion criteria include prior treatment with orlotamab, enoblituzumab, other B7-H3–targeted agents, or an antibody-drug conjugate that is conjugated with a topoisomerase I inhibitor. Dose expansion will start with 3 cohorts, including patients with selected advanced solid tumors. In both parts, DS-7300a will be administered intravenously on day 1 of each 21-day cycle. During dose escalation, the starting dose of DS-7300a is 0.8 mg/kg. This trial is currently in the dose-escalation part. Clinical trial information: NCT04145622 .