Purpose:To evaluate safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics, of fostroxacitabine bralpamide (fostrox, MIV-818), a novel oral troxacitabine nucleotide prodrug designed to direct exposure to the liver, while minimizing systemic toxicity. Patients and Methods:Fostrox monotherapy was administered in an open-label, single-arm, first-in-human, phase 1a/1b study, in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, or solid tumor liver metastases. The first part (1a) consisted of intra/inter-patient escalating doses (3 mg to 70 mg) QD for up to 5 days, and the second part (1b), doses of 40 mg QD for 5 days, in 21-day cycles. Safety and tolerability were evaluated by the Safety Review Committee, and efficacy was assessed every 6 weeks with CT or MRI using RECIST 1.1 and mRECIST. Results:Nineteen patients were treated with fostrox. Most common adverse events (AEs) were hematological and increased AST. Grade 3 treatment related AEs (TRAE) were seen in 53% of the patients, with transient neutropenia and thrombocytopenia as the most common. No grade 5 AE was observed. Recommended Phase 2 dose of fostrox was 40 mg QD for 5 days in 21-day cycles. Preliminary efficacy showed a clinical benefit rate in the liver of 53% and stable disease (SD) as best response in 10 patients. Liver targeting with fostrox was confirmed with higher exposure of troxacitabine and its metabolites in liver compared to plasma. Systemic exposure of fostrox was generally low with troxacitabine as main analyte. Biopsies demonstrated tumor-selective, drug-induced DNA damage. Conclusion:The phase 1a/1b monotherapy study of fostrox, in patients with liver tumors, showed a tumor selective effect in the liver and that 40 mg QD for 5 days in 21-day cycles is safe and tolerable. Safety and preliminary efficacy in patients with advanced HCC supports clinical development of fostrox in combination with other modes of action in HCC.

476 Background: Fostrox is an orally administered troxacitabine-based nucleotide prodrug in clinical development in combination with lenvatinib (NCT03781934). Fostrox is rapidly metabolized by human hepatocytes, directing high levels of the active metabolite to the liver. Phase I fostrox monotherapy demonstrated selective intra-tumoral activity in on-treatment liver biopsies. The anti-angiogenic activity of lenvatinib has the potential to synergize with fostrox by hypoxia-induced increase in the enzymatic generation of the active metabolite of fostrox in the tumor. Methods: In a phase Ib/IIa study with an inter-patient dose escalation 3+3 cohort design followed by a dose expansion phase, fostrox was administered orally QD for 5 days in 21-day cycles in combination with lenvatinib according to local prescription information. Patients (pts) with <2 prior lines systemic treatment for advanced, unresectable HCC were recruited at 10 sites in Spain, South Korea and UK. Pts with histologically, radiologically, or cytologically confirmed HCC, Child-Pugh A, ≥18 years, ECOG PS ≤ 1 and adequate organ function were eligible. The primary objective was to assess safety and tolerability. Key secondary endpoints were ORR based on RECIST 1.1 and mRECIST. Exploratory endpoints included pharmacokinetics (PK) and pharmacodynamic effects of fostrox in combination with lenvatinib. Results: At interim data cut-off 18 pts (6 pts in Ib and 12 pts in IIa) were enrolled at fostrox QD doses of 20mg (3 pts) and 30mg (15 pts) in combination with lenvatinib. Median age was 63 years (range: 42-82). No DLTs and only 1 discontinuation of fostrox due to AEs with a median FU of 3.8 months, were observed. Most common grade 3/4 AEs were transient neutrophil count decrease, platelet count decrease and hypertension. No febrile neutropenia, bleeding events or proteinuria were reported. The safety profile was consistent with each individual agent. In phase Ib, central independent review based on RECIST 1.1 showed SD in 5/6 pts, while mRECIST showed CR in 1 pt, PR in 2 pts and SD in 2 pts. Updated phase Ib data and efficacy data from phase IIa by central independent review, together with PK for fostrox and lenvatinib, and liver biopsy biomarker data, will be presented. Conclusions: Fostrox in combination with lenvatinib, in pts with HCC who progressed on previous systemic treatment, had an acceptable safety and tolerability profile with promising interim efficacy results from the completely enrolled phase Ib/IIa study. Clinical trial information: NCT03781934 .

The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and upregulation in TP63ΔN (p40) network. Adenosquamous histology can be observed. This study assessed immunohistochemical p40 expression in fine needle biopsy (FNB) samples with PDAC and association with cytomorphological features of squamous differentiation and clinical data. 106 EUS FNBs with PDAC were assessed for eight cytomorphological features of squamous differentiation. P40 H-score (intensity 0–3 × percentage positive nuclei) was analysed for association with morphological features, patient age, gender, operability, chemotherapy and survival. P40 H-score in 14 paired FNBs and resections was compared. P40 h-score was 1–3 in 31%, 4–30 in 16% and > 30 in 13% of FNBs. It was significantly associated with intercellular bridges, elongated cell shape, sharp cell borders, angular nuclei with homogenous chromatin (p < 0.001) and dense cytoplasm (p = 0.002). Keratinisation was not seen. Inoperable patients (n = 81) had a shorter median survival for h-score > 30 (n = 9, 1.8 months) than for h-score ≤ 30 (n = 66, 6.7 months) not quite reaching statistical significance (p = 0.08). P40 was significantly associated with squamous morphology in FNBs with PDAC. P40 H-score > 30 showed a trend towards shorter survival in inoperable patients. Squamous differentiation may be a treatment target in PDAC.