Abstract A131: A phase I trial of FAP-Exd (AVA6103), a Fibroblast Activation Protein (FAP)-enabled pre|CISION® peptide-drug conjugate delivering sustained tumor microenvironment (TME) release of exatecan in patients with FAP-positive solid tumors
Alex I. Spira, Nehal J. Lakhani, Michael M. Song, Judy Wang, Muhammad R. Khawaja, Ruairidh Edwards, Kim H. Paulsen, Curtis Rink, Christiana Nikolova, Dave LiebowitzAbstract
Background:
AVA6103 (FAP-Exd) is a pre|CISION® peptide-drug conjugate (PDC) comprising the potent topoisomerase I inhibitor exatecan (Exd) covalently linked to the pre|CISION® peptide, a dipeptide designed to be selectively cleaved by the enzyme fibroblast activation protein α (FAP), enabling sustained release of Exd within the tumor microenvironment (TME). FAP is a cell-surface serine protease that is highly expressed by cancer-associated fibroblasts (CAFs) in the TME across multiple solid tumors, including pancreatic cancer, with limited expression in most normal adult tissues. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic stroma enriched in FAP-expressing CAFs, with >90% of PDAC patients expressing FAP. AVA6103 aims to directly exploit this stromal biology by releasing exatecan within the TME, enabling bystander cell killing of adjacent tumor cells. In preclinical studies, FAP-Exd demonstrated FAP-dependent activation and robust antitumor activity, including complete tumor regressions in several patient-derived xenograft models spanning a range of FAP-expression levels and tumor types, including pancreatic cancer. Tumor uptake studies demonstrated sustained intratumoral exposure to released exatecan with limited systemic exposure, supporting clinical evaluation in patients with FAP-positive solid tumors. Trial Design: FOCUS-01 (NCT07454642) is a first-in-human, multicentre, phase I dose-escalation and expansion study evaluating AVA6103 in patients with locally advanced or metastatic solid tumors, including pancreatic cancer, that frequently express FAP and have progressed on standard therapy. FAP-Exd is administered intravenously on Q2W or Q3W schedules depending on tumor type, with pancreatic cancer among the indications evaluated using a Q2W regimen. Dose escalation is guided by a Bayesian optimal interval (BOIN) design. Primary objectives are to evaluate safety and tolerability and to determine the recommended dose(s) and schedule(s) for further development. Secondary/exploratory objectives include preliminary antitumor activity per standard response criteria and characterisation of pharmacokinetics, assessment of translational/biomarker endpoints including intratumoral drug concentrations and FAP protein expression. As of 30-March-2026, the study has opened and enrollment is ongoing in the dose-escalation phase.
Citation Format:
Alex I. Spira, Nehal J. Lakhani, Michael M. Song, Judy Wang, Muhammad R. Khawaja, Ruairidh Edwards, Kim H. Paulsen, Curtis Rink, Christiana Nikolova, Dave Liebowitz. A phase I trial of FAP-Exd (AVA6103), a Fibroblast Activation Protein (FAP)-enabled pre|CISION® peptide-drug conjugate delivering sustained tumor microenvironment (TME) release of exatecan in patients with FAP-positive solid tumors [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A131.