Abstract 527P
Background
MIV-818 is an orally administered troxacitabine-based nucleotide prodrug currently undergoing phase 1 clinical trial (NCT03781934). It is rapidly metabolized by human hepatocytes, directing high levels of the chain-terminating nucleotide tri-phosphate to the liver, while minimizing exposure to other organs.
Methods
Patients (pts), ≥18 years, ECOG performance status < 1, adequate organ function, with advanced inoperable HCC, iCCA or LM from solid tumours of gastrointestinal origin were enrolled. MIV-818 as a single agent was administered as an inter-patient dose escalation 3+3 cohort design in the phase IB part of this trial reported here. The primary objective is to assess safety and tolerability. A key secondary objective was to evaluate the overall response rate based on RECIST v1.1. As exploratory objectives, on-treatment liver biopsies were collected to assess the pharmacokinetics and the pharmacodynamic effects of MIV-818.
Results
Nine evaluable pts (6M; 3F), median age = 64 years (range: 47-74) with HCC (5), mixed HCC/iCCA (1) iCCA (1) or LM (2) from GI tract solid tumours, previously treated with median 2 (1-7) lines of therapy, were included. Starting dose was 40 mg for 5 days in 21-day cycles. The most common treatment emergent AEs were those in the haematological system; raised LFTs and pruritus were also commonly reported. Out of 9 pts, one pt experienced a DLT (Maculopapular rash grade 3) during the first cycle of treatment. The longest duration of treatment was 9 cycles, seen in 1 pt. Tumour biopsies showed evidence of selective, drug-induced, DNA damage, measured as phosphorylation of histone H2AX, in tumour tissue with minimal or no impact of MIV-818 observed in healthy liver tissue.
Conclusions
MIV-818 had an acceptable safety and tolerability profile, with haematological suppression being the most common AE. Biomarker data of liver biopsies demonstrated a selective effect of MIV-818 on cancer cells. The study will now evaluate MIV-818 in combination with other agents in HCC patients.
Clinical trial identification
NCT03781934.
Editorial acknowledgement
Legal entity responsible for the study
Medivir AB.
Funding
Medivir AB.
Disclosure
D. Sarker: Financial Interests, Personal, Advisory Board, null: Eisai; Financial Interests, Personal, Invited Speaker, null: MSD; Financial Interests, Personal, Advisory Board, null: Ipsen; Financial Interests, Personal, Advisory Board, null: Bayer; Financial Interests, Personal, Invited Speaker, null: Bayer; Financial Interests, Personal, Invited Speaker, null: AstraZeneca; Financial Interests, Personal, Invited Speaker, null: Eisai; Financial Interests, Personal, Other, Travel and conference fees: Ipsen; Financial Interests, Personal, Advisory Board, null: Surface Oncology; Financial Interests, Personal, Other, Travel and Conference Fees: MiNA Therapeutics; Financial Interests, Personal, Advisory Board, null: AAA; Financial Interests, Institutional, Invited Speaker, null: UCB; Financial Interests, Institutional, Invited Speaker, null: Eisai; Financial Interests, Institutional, Invited Speaker, null: MiNA Therapeutics; Financial Interests, Institutional, Invited Speaker, null: Medivir AB; Financial Interests, Institutional, Invited Speaker, null: MSD; Financial Interests, Institutional, Invited Speaker, null: Bayer; Financial Interests, Institutional, Invited Speaker, null: RedX; Financial Interests, Institutional, Invited Speaker, null: GSK; Financial Interests, Institutional, Invited Speaker, null: Starpharma; Financial Interests, Institutional, Invited Speaker, null: Adaptimmune; Financial Interests, Institutional, Invited Speaker, null: Blueprint; Financial Interests, Institutional, Invited Speaker, null: H3; Financial Interests, Institutional, Invited Speaker, null: Regeneron; Financial Interests, Institutional, Invited Speaker, null: Taiho; Financial Interests, Institutional, Invited Speaker, null: AstraZeneca; Financial Interests, Institutional, Invited Speaker, null: Ipsen; Financial Interests, Institutional, Funding, null: Roche; Financial Interests, Institutional, Funding, null: Inspirata; Non-Financial Interests, Advisory Role, null: Medivir; Non-Financial Interests, Advisory Role, null: UCB; Non-Financial Interests, Advisory Role, null: MiNA Therapeutics. T.R..J. Evans: Financial Interests, Institutional, Advisory Role: Karus; Financial Interests, Institutional, Advisory Board: Eisai; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Advisory Board: Ascelia; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Advisory Board: Roche/Genenetech; Financial Interests, Institutional, Speaker’s Bureau: BMS; Financial Interests, Institutional, Speaker’s Bureau: Eisai; Financial Interests, Institutional, Speaker’s Bureau: MSD; Financial Interests, Institutional, Speaker’s Bureau: Nucana; Other, Institutional, Other: Genmab; Financial Interests, Institutional, Expert Testimony: Medivir; Financial Interests, Institutional, Funding: Adaptimmune; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Athenex; Financial Interests, Institutional, Funding: Basilea; Financial Interests, Institutional, Funding: Beigene; Financial Interests, Institutional, Funding: Berg Pharma; Financial Interests, Institutional, Funding: Bicycle; Financial Interests, Institutional, Funding: BiolineRx; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Celgene; Financial Interests, Institutional, Funding: Clovis; Financial Interests, Institutional, Funding: CytomX; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: Halozyme; Financial Interests, Institutional, Funding: Immunocore; Financial Interests, Institutional, Funding: iOncologi; Financial Interests, Institutional, Funding: Iovance; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: J&J; Financial Interests, Institutional, Funding: Lilly; Financial Interests, Institutional, Funding: Medivir; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: MiNA Therapeutics; Financial Interests, Institutional, Funding: Modulate; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Nucana; Financial Interests, Institutional, Funding: Plexxikon; Financial Interests, Institutional, Funding: Roche/Genentech; Financial Interests, Institutional, Funding: Sanofi/Aventis; Financial Interests, Institutional, Funding: Sierra; Financial Interests, Institutional, Funding: UCB; Financial Interests, Institutional, Funding: Verastem; Financial Interests, Institutional, Funding: Vertex. E. Van Cutsem: Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Halozyme; Financial Interests, Personal, Advisory Role: Array; Financial Interests, Personal, Advisory Role: Biocartis; Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Personal, Advisory Role: Daiichi; Financial Interests, Personal, Advisory Role: PierreFabre; Financial Interests, Personal, Advisory Role: Sirtex; Financial Interests, Personal, Advisory Role: Taiho; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal and Institutional, Funding: Amgen; Financial Interests, Personal and Institutional, Funding: Bayer; Financial Interests, Personal and Institutional, Funding: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Funding: Lilly; Financial Interests, Personal and Institutional, Funding: Novartis; Financial Interests, Personal and Institutional, Funding: Roche; Financial Interests, Personal and Institutional, Funding: Celgene; Financial Interests, Personal and Institutional, Funding: Ipsen; Financial Interests, Personal and Institutional, Funding: Merck; Financial Interests, Personal and Institutional, Funding: Servier; Financial Interests, Personal and Institutional, Funding: BMS. H. Prenen: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Vfor; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: Bayer; Financial Interests, Personal, Other: Roche. M.R. Middleton: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Immunocore; Financial Interests, Personal, Advisory Board: BiolineRx; Financial Interests, Personal, Advisory Board: J&J; Financial Interests, Personal, Advisory Board: Vista; Financial Interests, Personal, Advisory Board: Vaccitech; Financial Interests, Personal and Institutional, Funding: Immunocore; Financial Interests, Personal and Institutional, Funding: Novartis; Financial Interests, Personal and Institutional, Funding: AstraZeneca; Financial Interests, Personal and Institutional, Funding: Roche; Financial Interests, Personal and Institutional, Funding: Amgen; Financial Interests, Personal and Institutional, Funding: Millenium; Financial Interests, Personal and Institutional, Funding: BMS; Financial Interests, Personal and Institutional, Funding: Vertex; Financial Interests, Personal and Institutional, Funding: Merck; Financial Interests, Personal and Institutional, Funding: Array BioPharma; Financial Interests, Personal and Institutional, Funding: Regeneron; Financial Interests, Personal and Institutional, Funding: Pfizer; Financial Interests, Personal and Institutional, Funding: Replimmunen; Non-Financial Interests, Personal, Other: Genesis Care. S. Bhoi: Financial Interests, Personal and Institutional, Full or part-time Employment: Medivir AB; Financial Interests, Personal and Institutional, Stocks/Shares: Medivir AB. K. Tunblad: Financial Interests, Personal and Institutional, Full or part-time Employment: Medivir AB; Financial Interests, Personal and Institutional, Stocks/Shares: Medivir AB. F. Oberg: Financial Interests, Personal and Institutional, Leadership Role: Medivir AB; Financial Interests, Personal and Institutional, Member of the Board of Directors: Medivir AB; Financial Interests, Personal and Institutional, Full or part-time Employment: Medivir AB; Financial Interests, Personal and Institutional, Stocks/Shares: Medivir AB; Financial Interests, Personal and Institutional, Royalties: Medivir AB. T. Morris: Financial Interests, Personal, Leadership Role: Medivir AB; Financial Interests, Personal, Advisory Board: Medivir AB. R. Plummer: Financial Interests, Personal, Advisory Board: Astex; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Biosceptre; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: CV6 Therapeutics; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Institutional, Royalties: Clovis Oncology; Financial Interests, Personal, Other: Beigene; Financial Interests, Personal, Other: SOTIO.