A phase Ia/Ib trial of FAP-Dox (AVA6000), a fibroblast activation protein (FAP)–released doxorubicin peptide drug conjugate in patients with FAP-positive solid tumors and activity against salivary gland cancers.

Abstract

e15113 Background: Faridoxorubicin (faridox, AVA6000) is a cleavable peptide drug conjugate (PDC) comprised of doxorubicin (dox) bound to a peptide by a linker that is specifically cleaved by FAP, which is overexpressed in the tumor microenvironment (TME) of many solid tumors. This PDC technology utilizes a mask and release technology to concentrate released payload in the TME. Methods: The safety, pharmacokinetics (PK) and preliminary efficacy of faridox were established in a first-in-human, multicenter Phase 1a and 1b trial with faridox administered i.v. q3w or q2w using a 3+3 design in patients with locally advanced or metastatic solid tumors. The Phase 1b expansion portion enrolled patients with salivary gland cancer (SGC), soft tissue sarcoma (STS) and triple negative breast cancer (TNBC) patients at the Phase 1a RP2D of 310 mg/m 2 Q3W. AUC based dosing was initially utilized to calculate maximum safe number of cycles of AVA6000, equivalent to a cumulative dox dose of 550 mg/m 2 ; this lifetime limit was lifted during Phase 1b based on absence of cardiac toxicity. Results: Results of the faridox Phase 1a escalation in 63 patients were previously reported (Lahu et al, ESMO 2025). In the Phase Ib expansion portion, an additional 27 patients with SGC, TNBC or STS have been dosed as of the data cutoff (median age 62 yr, range 32-81; 44% male; 63% ECOG 0). The safety profile in Phase Ib was favorable and consistent with Ph Ia observations; the most frequent AEs being fatigue (56%), alopecia (52%), nausea (44%), anemia (26%), and neutropenia (22%). Grade 3-4 hematologic toxicities included neutropenia (11%) and lymphopenia (4%). No grade 3 or 4 cardiac events or clinically relevant changes in left ventricular ejection fraction were observed despite faridoxorubicin being dosed to dox exposures associated with a cumulative dose of 550 mg/m 2 . Based on the favorable cardiac safety data, the lifetime maximum dox exposure was lifted during the trial. Compared to conventional dox, PK showed reduced systemic exposure (AUC, up to 77% reduction), reduced volume of distribution and higher tumor concentrations (median 117:1 ratio of tumor to plasma exposure of released dox). In the 30 patients with SGC treated across Phase 1a and 1b (n = 11 and 19), 2 pts with partial responses and 25 pts with stable disease were observed for a disease control rate of 90%. Median PFS in the SGC cohort has not been reached with median follow up exceeding 5 mos in the combined cohort (9 mos in Ph Ia). Efficient dox production was observed in the TME with FAP IHC levels ranging from 1+-3+ by immunohistochemistry in SGC. Conclusions: Faridox is active in SGC and well tolerated, delivering high concentration of free dox to the TME relative to plasma. Responses were observed and prolonged disease stabilization in patients with SGC indicating activity of the PDC. Clinical trial information: NCT04969835 .