First-in-human study of OBI-999: A globo H-targeting antibody-drug conjugate in patients with advanced solid tumors.

Abstract

3029 Background: OBI-999 is a novel antibody-drug conjugate, composed of a humanized monoclonal IgG1 antibody which targets the tumor-associated carbohydrate antigen Globo H, conjugated with monomethyl auristatin E (MMAE, vedotin). Upon binding to Globo H, OBI-999 is internalized into the tumor cell, and the linker (Thiobridge) connecting MMAE (an ultrapotent antimitotic agent) to the monoclonal antibody is cleaved by cathepsin B to release MMAE, thereby causing cell cycle arrest by inhibiting tubulin polymerization. We conducted a first-in-human, phase 1, dose-escalation study of OBI-999 monotherapy in patients with advanced cancer (NTC04084366). Methods: OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg on Day 1 of a 21-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 15 adult patients were treated. OBI-999 administered on Day 1 of each 21-day cycle was well tolerated up to 1.2 mg/kg, the maximum tolerated dose (MTD). Treatment-related AEs (TRAEs) were noted in 40% (6/15) of patients. TRAEs ≥Grade 3 were noted in 27% (4/15) of patients; of whom 3 had neutropenia and 2 had anemia. OBI-999 exhibited non-linear pharmacokinetics from 0.4 mg/kg to 1.6 mg/kg, with lower clearance at higher doses. A retrospective validated automated immunohistochemistry assessment indicated 50% of patients with advanced solid tumors had high Globo H staining (H-score cutoff ≥100). Of 3 patients treated at the 1.6 mg/kg dose level; 2 developed Grade 4 neutropenia during Cycle 1 and the third developed Grade 4 neutropenia on Cycle 2 Day 15. One patient (1.6 mg/kg) with Grade 4 neutropenia also developed Grade 4 renal insufficiency and died from progressive disease (direct bilirubin, 3.5 mg/dL). Five (33.3%) patients had stable disease (SD), including 1 patient with adenoid cystic carcinoma of the oropharynx (SD for 13 cycles); 1 patient with gastroesophageal junction adenocarcinoma (SD for 8 cycles), and 3 patients with other tumor types (SD for 4, 2, and 2 cycles). Conclusions: We completed the dose-escalation portion of the study. OBI-999 was well tolerated. The recommended phase 2 dose was determined to be 1.2 mg/kg once every 3 weeks. Dose-dependent, non-cumulative neutropenia was dose limiting. We are currently enrolling patients with high Globo H expressing solid tumors (H-score ≥100) in the expansion phase of the study, which includes pancreatic, colorectal, and cancers of other histologic subtypes. Clinical trial information: NTC04084366.