A phase I trial of AVA6000, a fibroblast activation protein (FAP)-released, tumor microenvironment (TME)-targeted doxorubicin peptide drug conjugate in patients with FAP-positive solid tumors

BackgroundAVA6000 is a peptide drug conjugate, in which doxorubicin (dox) is bound by a linker that is specifically cleaved by FAP, which is overexpressed in the TME of many solid tumors.MethodsThe safety, pharmacokinetics (PK) and preliminary efficacy of AVA6000 was studied in a first-in-human, multicenter dose escalation phase I trial. AVA6000 was administered i.v. q3w or q2w using a 3+3 design in patients with locally advanced or metastatic solid tumors categorized as high or middle range FAP (FAPhigh and FAPmid) based on published data. AUC based dosing was used to calculate maximum safe number of cycles of AVA6000 (equivalent to cumulative dox dose of 550mg/m2).Results48 pts (median age 60 yr, range 30-79), median 3 prior therapy lines (range, 0-7) received AVA6000 doses of 80 to 385mg/m2 i.v. q3w, and a starting dose of 160mg/m2 given q2w. The safety profile was favorable with both schedules, the most frequent grade 3-4 hematologic toxicities were neutropenia (11%), anemia (6%), and thrombocytopenia (5%). Grade 3 non-hematologic toxicities included mucositis, fatigue and hematemesis (n=1). Two DLTs in the q3w arm were grade 2 cardiac failure (120mg/m2) and grade 4 neutropenia/thrombocytopenia (200mg/m2). Compared to conventional dox, PK showed reduced systemic exposure (AUC, 5-77%) and peak concentration (Cmax, 78-93%), without accumulation suggesting q2w dosing may be optimal. The therapeutic index of free dox was significantly increased, with respect to severe neutropenia, AUC and efficacy. No dose-response relationship was seen between troponin levels and AVA6000 dose. Concentrations of free dox in tumor biopsies (n=11) were ∼2 log scale higher than plasma. PK/PD modeling suggested free dox generation in the TME with an increased plasma distribution half-life. Two PR (RECISTv.1.1) and 3 minor responses (-10 to -29%) were observed in 5 pts with FAPhigh tumor types including salivary gland cancer and soft tissue sarcoma.ConclusionsAVA6000 delivers high concentration of free dox to the TME relative to plasma, resulting in antitumor activity in FAPhigh tumor types with reduced systemic dox exposure, resulting in lower toxicity versus conventional dox.Clinical trial identificationNCT04969835.Legal entity responsible for the studyAvacta Group Plc.FundingAvacta Group Plc.DisclosureAll authors have declared no conflicts of interest.