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Clinical Trial
. 2024 Oct 24:11:2033-2047.
doi: 10.2147/JHC.S481410. eCollection 2024.

A Phase 1a/1b Study of Fostroxacitabine Bralpamide (Fostrox) Monotherapy in Hepatocellular Carcinoma and Solid Tumor Liver Metastases

Ruth Plummer  1 , Alastair Greystoke  1 , Gregory Naylor  2 , Debashis Sarker  3   4 , A N M Kaiser Anam  4 , Hans Prenen  5 , Laure-Anne Teuwen  5 , Eric Van Cutsem  6 , Jeroen Dekervel  6 , Beate Haugk  1 , Thomas Ness  1 , Sujata Bhoi  7 , Malene Jensen  7 , Tom Morris  7 , Pia Baumann  7 , Niclas Sjögren  8 , Karin Tunblad  7 , Hans Wallberg  7 , Fredrik Öberg  7 , Thomas R Jeffry Evans  2
Affiliations
Clinical Trial

A Phase 1a/1b Study of Fostroxacitabine Bralpamide (Fostrox) Monotherapy in Hepatocellular Carcinoma and Solid Tumor Liver Metastases

Ruth Plummer et al. J Hepatocell Carcinoma. .

Abstract

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.

Keywords: fostrox; hepatocellular carcinoma; nucleotide prodrug; pharmacodynamics; pharmacokinetics; phase 1.

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Conflict of interest statement

Professor Ruth Plummer reports personal fees from Pierre Faber, Bayer, Novartis, BMS, Ellipses, Immunocore, Genmab, Astex Therapeutics, MSD, Nerviano, AmLo, Incyte, Cybrexa, Benevolent AI, and Sanofi Aventis, outside the submitted work. Dr Debashis Sarker reports personal fees from MSD, Eisai, AstraZeneca, Ipsen, Bayer; SIRTEX, AAA, ROCHE, SERVIER, AbbVie, Incyte; non-financial support from Medivir; grants from UCB, during the conduct of the study. Dr Eric Van Cutsem reports participation to advisory boards for AbbVie, Agenus, ALX, Amgen, Arcus Biosciences, Astellas, AstraZeneca, Bayer, Beigene, Bexon Clinical, Biontech, Boehringer Ingelheim, Bristol-Myers Squibb, Canfour, Daiichi, Debiopharma, Elmedix, Eisai, Galapagos, GSK, Hookipa Biotech, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Simcere, Takeda, Taiho, Terumo, outside the submitted work. Dr Beate Haugk reports royalties from Springer publication, outside the submitted work. Dr Malene Jensen is an employee and stockholder of Medivir AB. Dr Tom Morris reports personal fees from Medivir, during the conduct of the study; personal fees from AstraZeneca, Calliditas Therapeutics AB, Ascelia Pharma AB, Oxford Vacmedix Ltd, outside the submitted work. Dr Pia Baumann and Dr Karin Tunblad are employees at Medivir. Professor Fredrik Öberg is an employee and shareholder of Medivir AB. In addition, Professor Fredrik Öberg has a patent WO 2016/030335 issued to Medivir AB. Professor Thomas Evans reports grants, personal fees from Medivir, during the conduct of the study; grants, personal fees, and/or non-financial support from Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, Celgene, Eisai, MSD, Nucana, Nurix, Seagen, Pfizer, Adaptimmune, Astellas, Amgen, Avacta, Beigene, Basilea, BioNTech, Boehringer Ingelheim, Codiak, Exelixis, CytomX, Immunocore, iOnctura, Johnson & Johnson, Lilly, MiNa Therapeutics, Moderna, Novartis, Sapience, Starpharma, T3P, UCB, Verastem, Sanofi, Ascelia, Immodulon, Roche, Genmab, and Springer Nature, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Study overview.
Figure 2
Figure 2
Observed concentrations of fostrox in Cycle 1 Day 1 (A), the alanine metabolite (AM) Cycle 1 Day 1 (B), troxacitabine in Cycle 1 Day 1 (C) and troxacitabine in Cycle 1 (D) in phase 1b. The arrows indicate fostrox dose administrations. Each curve presents individual patient data (eg, 1B, 2B etc.). The lower limit of quantification (LLOQ) was 0.2 nM, 1.0 nM, and 3.0 nM for fostrox, TRX, and AM, respectively.
Figure 3
Figure 3
Concentrations of fostrox and its metabolites in plasma and liver biopsies in cycle 2 in two patients diagnosed with metastatic liver disease. For a sample amount of 10 mg, the LLOQ was 100 nM for AM, 40 nM for TRX and 50 nM for TRX-MP, TRX-DP and TRX-TP.
Figure 4
Figure 4
Liver tumor biopsies. (A) DNA damage (pH2AX %) in normal liver tissue compared to tumor tissue; (B) DNA damage before fostrox and in cycle 2 of fostrox treatment in tumor biopsies from 3 patients; (C) Proliferation (Ki67%) in normal liver tissue compared to tumor; (D) Correlation between proliferation (Ki67%) and DNA-damage (pH2AX %); (E) Comparison of the level of DNA-damage (pH2AX %) in normoxic (GLUTneg) and hypoxic (GLUT1pos) tumor regions; (F) Level of TP53 positive cells in normal liver tissue compared with tumor.
See this image and copyright information in PMC

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