Fostroxacitabine bralpamide (fostrox), an oral prodrug of troxacitabine, has shown promising results in a Phase 1a/1b clinical trial for patients with advanced liver cancers. The study, published in the Journal of Hepatocellular Carcinoma, evaluated the safety, tolerability, and preliminary efficacy of fostrox monotherapy in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and liver metastases from other solid tumors. The trial's findings suggest that fostrox is well-tolerated and exhibits encouraging anti-tumor activity, particularly in HCC patients, warranting further investigation in combination therapies.
The open-label, multi-center trial enrolled 19 patients with advanced liver cancers who had progressed on prior systemic treatments. Patients received escalating doses of fostrox monotherapy, ranging from 3 mg to 70 mg daily for 1-5 days in 21-day cycles. The primary objective was to assess safety and tolerability, while secondary objectives included evaluating pharmacokinetics, liver targeting, and preliminary anti-tumor activity.
Safety and Tolerability
The study found that fostrox monotherapy was generally well-tolerated at doses ≤40 mg daily. The most common treatment-emergent adverse events (TEAEs) were anemia and increased levels of aspartate aminotransferase (AST). Grade 3 treatment-related adverse events (TRAEs) were observed in 53% of patients, with transient neutropenia and thrombocytopenia being the most frequent. No grade 5 adverse events were reported.
Two dose-limiting toxicities (DLTs) occurred during the study: one patient experienced neutropenic sepsis at a dose of 70 mg, and another developed a grade 3 rash at 40 mg. Based on the accumulated safety, tolerability, and pharmacokinetic data, the recommended phase 2 dose (RP2D) was defined as 40 mg for 5 days in a 21-day cycle.
Preliminary Efficacy
Preliminary efficacy results showed a clinical benefit rate (CBR) of 63% in HCC patients, with stable disease observed in 5 patients. Three out of six patients who received fostrox 40 mg daily for 5 days in 21-day cycles exhibited stable disease ongoing at 12 weeks, as measured by RECIST 1.1 criteria. The researchers noted that similar activity was observed in patients with cholangiocarcinoma, while no activity was seen in patients with liver metastases from other tumor types.
Pharmacokinetics and Pharmacodynamics
Pharmacokinetic analysis confirmed that fostrox was rapidly absorbed and eliminated, with maximum plasma concentrations generally observed within 2 hours after administration. Troxacitabine (TRX) was identified as the main analyte in plasma, with a 2-fold accumulation observed after repeated dosing of fostrox. Liver biopsies revealed significantly higher levels (19 to 40-fold) of the alanine metabolite in tumor tissue compared with plasma, confirming liver targeting of the drug.
Pharmacodynamic analysis of liver biopsies showed clear DNA damage in tumor tissue, as measured by pH2AX staining, while adjacent normal liver tissue showed no evidence of DNA damage. This suggests a tumor-selective effect of fostrox.
Clinical Implications
The study's findings suggest that fostroxacitabine bralpamide is a promising therapeutic agent for advanced liver cancers, particularly HCC. The acceptable safety profile and preliminary anti-tumor activity observed in this Phase 1 trial support further clinical development of fostrox in combination with other drugs with different modes of action. The ongoing phase 1b/2a study evaluating fostrox plus lenvatinib or pembrolizumab in locally advanced or metastatic HCC will provide further insights into the potential of this novel therapy.
"The results from the phase 1a/1b monotherapy study with fostrox showed an acceptable tolerability and safety profile together with preliminary efficacy in HCC," the authors concluded. "The next part of this study includes a phase 1b/2a combination with fostrox plus lenvatinib or pembrolizumab in locally advanced or metastatic HCC."
