A phase I, first-in-human, open-label, dose escalation and expansion study of PT886 in adult patients with advanced gastric, gastroesophageal junction, and pancreatic adenocarcinomas.

Abstract

TPS765 Background: PT886 is a novel bispecific antibody that targets Claudin 18.2 (CLDN18.2) and CD47. CLDN18.2 is overexpressed in a significant proportion of gastric and pancreatic adenocarcinomas and its restricted expression makes it a promising therapeutic target for the treatment of these carcinomas. Moreover, studies have found that immunoglobulin superfamily CD47 is overexpressed widely across tumor types, and CD47 plays an important role in suppressing phagocytes activity through binding to the transmembrane protein SIRPα in phagocytic cells. Hence, by targeting both pathways, one can direct macrophage-mediated phagocytotic activity to tumor cells by blocking the “don’t eat me” signal mediated by CD47/ SIRPα interaction, potentially offering a better safety profile than anti-CD47 monoclonal antibodies. Additionally, PT886 utilizes IgG1 to enhance antibody-dependent cellular cytotoxicity (ADCC) by NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages and thus increases the antitumor activity. The combined cancer killing effects by the above mechanisms therefore represent a novel approach in treating CLDN18.2-positive malignancies. Methods: This is an open label, Phase I study to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PT886 in subjects with unresectable or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC) for which there is no available standard therapy. Approximately 34-58 patients will be enrolled. The study consists of 2 parts: Dose Escalation, and Dose Expansion. The dose escalation study of PT886 will be guided by a standard 3+3 dose escalation study design to determine the maximum tolerated dose (MTD) and/or the optimal biological doses for expansion. The MTD or the optimal biological dose and a lower dose level will be further evaluated in a dose expansion cohort to determine a recommended phase II dose (RP2D). Each enrolled patient will receive PT886 as a monotherapy (0.1, 0.3, 1, 3 or 6 mg/kg QW) as an intravenous infusion continuously (over 60 minutes) in 28-day cycles. The primary endpoints are Dose Limiting Toxicity (DLT) and MTD, if reached, and RP2D of PT886 as a single agent. PD markers of PT886 biological activity will be measured, including T-cell receptor sequencing on circulating T cells, T-cell activation studies, serum cytokines and assessing CLDN18.2 expression in tumor tissues. PT886, which was recently granted orphan drug designation by the FDA for the treatment of pancreatic cancer, has the potential to be a new treatment option for pancreatic and gastric cancer patients whose current standard of care is limited. Preliminary safety and efficacy data are anticipated in the second quarter of 2023. Clinical trial information: NCT02178241 .

Constructing immune and prognostic features associated with ADCP in hepatocellular carcinoma and pan-cancer based on scRNA-seq and bulk RNA-seq

“…CLDN18.2 is overexpressed in the majority of gastric adenocarcinomas and pancreatic cancers. Antibodies targeting CLDN18.2 could redirect macrophage-mediated phagocytic activity towards tumor cells, thereby enhancing anti-tumor activity ( 24 ). Our study also confirmed the role of CLDN18 in regulating ADCP in LIHC, underscoring the validity and potential translational value of our research.…”

ILUSTRO: Phase II Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2–Positive Gastric or Gastroesophageal Junction Adenocarcinoma

“…A humanized immunoglobulin G1 monoclonal antibody against CLDN18.2 and an anti-CLDN18.2 antibody-drug conjugate have also shown promising antitumor activity and acceptable safety profiles in early phase studies of patients with gastrointestinal cancers ( 29, 30 ). Studies assessing safety and antitumor activity of a novel bispecific antibody against CLDN18.2 and a novel CLDN18.2-targeted CAR-T therapy in patients with solid tumors, including gastrointestinal tumors, are underway ( 31, 32 ). These therapeutic strategies have the potential to enhance the treatment landscape for patients with CLDN18.2-positive gastrointestinal cancers.…”

Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma

“…CLDN18.2 will remain a target of interest for further drug development and is currently undergoing many exploration trials [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Additional CLDN18.2 monoclonal antibodies are under investigation in solid tumor trials, including AB011, MIL93, and TST001 (osemitamab) [29][30][31][32].…”

“…For those with CLDN18.2-positive GAC and GEJ patients, ORR was 75%, with a disease control rate of 100%. PT886, a bispecific antibody that targets CLDN18.2 CD47, is under phase 1 investigation for advanced GAC, GEJ, and pancreatic adenocarcinoma patients [34]. Additionally, CLDN18.2 is under investigation as a potential chimeric antigen receptor T (CART) therapy with NCT03874897, NCT05277987, NCT04404595, and NCT03159819; its potential is currently being explored in CLDN18.2-positive patients [24][25][26][27].…”