København, Danmark – 13. september 2011 – Topotarget A/S (NASDAQ OMX: TOPO.CO) har i dag meddelt, at kliniske data (videnskablige resuméer) vil blive præsenteret på The European Multidisciplinary Cancer Congress i Stockholm den 23.-27. september 2011.
Nedenfor er en liste over de videnskabelige resuméer der nu er tilgængelige på http://stockholm2011.ecco-org.eu/Programme;
Abstract 6597, Monday 26 September, time: 8.00-10.00, Hall C
A phase II study of epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter study of the Mayo Phase 2 Consortium (P2C) and the Cancer Therapeutics Research Group (CTRG)
W. Yeo1, H.C. Chung2, S.L. Chan1, L.Z. Wang,3 R. Lim3, J. Picus4, M. Boyer5, C. Erlichman6, A.T.C. Chan1, B.C. Goh3. Department of Clinical Oncology1, Chinese University of Hong Kong, Hong Kong. Division of Haematology-Onology, Yonsei Cancer Center, Yonsei University College of Medicine, Korea2. Department of Haematology-Oncology, National University Hospital, Singapore3. Washington University, School of Medicine, St. Louis, MO, USA4. Sydney Cancer Centre, Royal Prince Alfred Hospital, Australia5. Mayo Phase 2 Consortium6.
Background: Patients with unresectable hepatocellular carcinoma (HCC) carry a dismal prognosis. Epigenetic aberrations have been reported in HCC. Belinostat is a novel, low molecular weight, histone deacetylase inhibitor. The purpose of this study was to assess the efficacy of epigenetic therapy with belinostat in patients with unresectable HCC.
Patients and methods: Major eligibility criteria included histologically confirmed HCC that is not amenable to curative treatment; ECOG£2; adequate organs functions. The belinostat dose used was 1400 mg/m2/day i.v. on day 1-5 every 3 weeks, as defined in a prior phase I study. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were response rate (RR) according to RECIST and overall survival (OS). Adverse events were reported using CTCAE v3.
Results: 42 patients were accrued. Prior therapies included surgery (36%), radiofrequency ablation (7%), transarterial therapy (50%); prior systemic therapies (38%). Median follow-up was 20.0 months. Median cycle no. was 2 (range: 1-12). The PR and SD rate was 2.4% (1/42) and 45.2% (19/42) respectively. Median PFS was 2.64 months (95%C.I. 1.55-3.17) and OS was 6.60 months (95%C.I. 4.53-11.60). Grade >3 toxicities that occurred in >5% included: 4 (9.5%) abdominal pain, 4 (9.5%) hyperbilirubinemia, 4 (9.5%) raised alanine transaminase, 3 (7.1%) anemia, 3 (7.1%) vomiting, 2 (4.8%) distension, 2 (4.8%) hemorrhage, 2 (4.8%) prolonged QTc and 2 (4.8%) dehydration. One patient developed sudden death but it was determined not likely due to study medication.
Conclusions: With the majority of patients having failed prior therapy, epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. Further studies including combinational study with other agents is warranted.
Acknowledgement: The study was sponsored by the Division of Cancer Treatment and Diagnosis, National Cancer Institute, U.S.A, and its collaborator TopoTarget.
Abstract 7105, Sunday 25 September, time: 11-12, Hall A8
Belinostat in Combination With Carboplatin and Paclitaxel (BelCaP) for Treatment of Bladder Cancer - a Pharmacokinetic Study of Exposure to Belinostat and Its Metabolites
Co-authors: R.J. Jones1, J. Tjørnelund2, K.D. Erichsen3, L. Sengeløv4, J. De Bono5
1Cancer Research UK Beatson Laboratories, Centre for Oncology and Applied Pharmacology, Glasgow, United Kingdom ; 2Topotarget, Clinical Pharmacology, Copenhagen, Denmark ; 3Topotarget, Medical Affairs, Copenhagen, Denmark ; 4Herlev Hospital, Department Oncology, Copenhagen, Denmark ; 5Royal Marsden Hospital, Institute for Cancer Research, Sutton, United Kingdom
Background: Belinostat (Bel, PXD101) is a class I and II Histone DeACetylase (HDAC) inhibitor. A single arm Ph II study was conducted to evaluate the safety and activity of Belinostat, Carboplatin and Paclitaxel (BelCaP) in patients (pts) with Transitional Cell Carcinoma of the Bladder (TCCB) (n=15). A part of the study was a pharmacokinetic study of plasma exposure to Bel and its metabolites. The in vitro efficacy of belinostat and its metabolites were compared and related to plasma exposure in pts.
Materials and Methods: Pts with TCCB were treated with BelCaP every third week; Bel was given as a 1000mg/m2 30-min i.v. inf. on days 1–5 with P (175mg/m2) and subsequently Ca (AUC5) administered 2–3hrs after Bel on day 3. The plasma exposure (AUC) of Bel and its metabolites were determined. The in vitro pharmacological effect of Bel and its five major metabolites: belinostat glucuronide (BelGlcU), 3-(Anilinosulfonyl)benzene carboxylic acid (3-ASBA), methylated belinostat (Metbel), belinostat amide (Belam) and belinostat acid (Belac) were examined in a HeLa HDAC enzyme inhibition assay (HDAC-i), in WST proliferation assays and in clonogenic assays (CA). Fold differences in exposure of metabolites and belinostat (10 pts on day 3) and fold differences in in vitro efficacy of belinostat and metabolites were compared.
Results: The exposure of each metabolite relative to Bel was evaluated. The increases (molar AUC0–∞) relative to Bel were 16- (BelGlcU), 3- (3-ASBA), 1- (Metbel), 1- (Belam) and 0.5-fold (Belac).
Bel metabolites did not inhibit HDAC-i activity or cell WST proliferation in vitro. In the CAs the IC50 for Bel were 0.4 to 1.3µM. Three metabolites had weak effect relative to Bel. The fold increase in IC50 relative to Bel was: >65 (BelGlcU), >42 (Metbel) and >114 (Belam).
Conclusions: Five major human Bel metabolites (BelGlcU, 3-ASBA, Metbel, Belam and Belac) were identified in a Ph II study of BelCaP in pts with TCCB. Bel metabolites were inactive in HDAC-i assays and in WST assays and had weak activity in CA. The metabolite with highest fold exposure compared to Bel was BelGlcU (16-fold), which was 65 fold less effective in vitro than Bel. The present study finds that Bel metabolites do not have significant biological effect at therapeutic relevant plasma exposure in cancer pts.
Dagens meddelelse ændrer ikke Topotargets finansielle forventninger for helåret 2011.
Topotarget A/S
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Baggrundsoplysninger
Om belinostat
Belinostat er en lovende molekyle HDAC-hæmmer, som undersøges for sin rolle i behandlingen af en lang række solide tumorer og blodkræftsygdomme, enten alene eller i kombination med andre aktive antikræft-midler, herunder carboplatin, paclitaxel, doxorubicin, idarubicin, cis-retinoidsyre, azacitidin, 5-FU, etoposid og Velcade® (bortezomib) til injektion. HDAC-hæmmere udgør en ny mekanistisk klasse antikræftmidler, som er rettet mod HDAC-enzymerne, og de har vist sig at: stoppe kræftcellernes vækst (herunder undertyper, der er resistente over for lægemidler), inducere apoptose (programmeret celledød), fremme differentiering, hæmme angiogenese (dannelse af blodkar), og sensibilisere kræftcellerne til ikke længere at være resistente, når de anvendes i kombination med andre antikræftmidler.
Intravenøst indgivet belinostat undersøges i øjeblikket i et pivotalstudie til behandling af perifert T-celle lymfekræft (PTCL) og undersøges i en række kliniske undersøgelser som en potentiel behandling af kræft med ukendt primærtumor (CUP), kræft i æggestokkene, småcellet lungekræft, tymom, leverkræft, bløddelssarkom, lymfekræft, AML samt myelodysplastisk syndrom (MDS), enten alene eller i kombination med andre antikræftbehandlinger. Konstant intravenøs infusion (CIV) evalueres i kliniske undersøgelser til behandling af både solide tumorer og AML. Topotarget har indgået en Clinical Trial Agreement (CTA) med NCI omkring kliniske studier med belinostat for bedre at kunne forstå stoffets antitumoraktivitet.
Om Topotarget
Topotarget (NASDAQ OMX: TOPO.CO) er en skandinavisk-baseret international biotekvirksomhed med hovedkontor i Danmark dedikeret til at forbedre behandlinger mod kræft. I samarbejde med Spectrum Pharmaceuticals, Inc. fokuserer Topotarget i øjeblikket på udviklingen i de pivotale studier af dets førende lægemiddelkandidat, belinostat, som har vist en tydelig antineoplastisk effekt i behandlingen af såvel blodkræftsygdomme som solide kræftsvulster. Belinostat kan anvendes i kombination med fulde doser kemoterapi og er i registreringsfase i PTCL (perifert T-celle lymfekræft) samt i fase II i kræft med ukendt primærtumor (CUP). Topotargets primære kræftbehandlings-target er HDAC. Totect® er et markedsført produkt, som er udviklet fra Topotargets forskningsteknologi. Totect® markedsføres af selskabets egne salgsspecialister i USA. De europæiske rettigheder til Savene® blev frasolgt i marts 2010 som resultat af selskabets fokus på at udvikle og kommercialisere belinostat. For yderligere oplysninger henvises til www.topotarget.com.
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