Drug Eluting Beads for TACE

1. T de Baere Institut Gustave Roussy, Villejuif Drug Eluting Beads for TACE

2. • Clinical results of Drug eluting beads - Rational - HCC - NET (neuroendocrine tumors) or GEP (gastroanteropancreatic endocrine tumors) - Colrectal cancer metastases

3. 101 CL Rart = QA (1 - Er ) 81 100000 AUC (15-72 h) µg/g*min 80000 R art 61 60000 0.1 41 40000 Tumor Er 0.5 21 20000 Liver 0 1 0.9 Carboplatin IV IAH IAH+embolization 24 18 12 6 QA (L/h) Rational (Pohlen, U et al. J Surg Res 2000; 92 : 165-70) • High clearance (CL) • High extraction ratio (Er) • Er at first pass • Keep it longer in the liver • Low blood flow (Qa) • Embolization

4. Rational Doxorubicin in plasma Doxorubicin in tumor IA free doxorubicin IA free doxorubicin IA DEB doxorubicin IA DEB doxorubicin Pharmakokinetic in animal Courtesy of J Geschwind Courtesy of J Geschwind

5. Rational Doxorubicin in plasma Doxorubicin in tumor IA free doxorubicin IA free doxorubicin IA DEB doxorubicin IA DEB doxorubicin Pharmakokinetic in animal Courtesy of J Geschwind Courtesy of J Geschwind Pharmakokinetic in human

6. Preliminary clinical results

7. Difficulties in evaluating Preliminary clinical results 64% Response rate ** Varela M, Llovet J, Bruix J, J Hepatol 2007

8. Difficulties in evaluating Preliminary clinical results 20% 35-37% 44% EASL RECIST * Lo C, Hepatology 2002 & Llovet JM, Lancet 2002 ** Varela M, Llovet J, Bruix J, J Hepatol 2007

9. Difficulties in evaluating Preliminary clinical results

10. 71 patients HCC (3-10cm) Child A (27), Child B (44) EASL (intention to treat) CR : 15.5% OR : 66.2% to 85.5% across the 4 treatments (Malagari K, Abdominal imaging 2007)

11. 71 patients HCC (3-10cm) Child A (27), Child B (44) EASL (intention to treat) CR : 15.5% OR : 66.2% to 85.5% across the 4 treatments Best Overall response : 53/71 = 74% (Malagari K, Abdominal imaging 2007)

12. 71 patients HCC (3-10cm) Child A (27), Child B (44) EASL (intention to treat) CR : 15.5% OR : 66.2% to 85.5% across the 4 treatments Survival 97.5% @ 12 months 91.1% @ 18 months 88.2% @ 30 months (Malagari K, Abdominal imaging 2007)

13. 4ml of 300-500 mm DEB + 100 mg doxorubicin • Neuroendocrine liver metastases • Morphologic RECIST @ 1 months • Partial response8/20 (40%) • Minor response 2/20 (10%) • Stable disease 5/20 (25%) • Progressive disease 1/20 (5%)

14. 4ml of 300-500 mm DEB + 100 mg doxorubicin • Neuroendocrine liver metastases • Morphologic RECIST @ 1 months - 3 months • Partial response8/20 (40%) - 16/20 (80%) • Minor response 2/20 (10%) - 2/20 (10%) • Stable disease 5/20 (25%) - 1/20 (5%) • Progressive disease 1/20 (5%) - 1/20 (5%)

15. DEB preliminary results • 4ml of 300-500 mm DEB + 100 mg doxorubicin • Neuroendocrine liver metastases • Morphologic RECIST @ 1 months - 3 months • Partial response8/20 (40%) - 16/20 (80%) • Minor response 2/20 (10%) - 2/20 (10%) • Stable disease 5/20 (25%) - 1/20 (5%) • Progressive disease 1/20 (5%) - 1/20 (5%) • 20% peripheral liver necrosis associate with more post-procedural pain (In press, JVIR)

16. DEB preliminary results • 4ml of 300-500 mm DEB + 100 mg doxorubicin • Neuroendocrine liver metastases • Morphologic RECIST @ 1 months - 3 months • Partial response8/20 (40%) - 16/20 (80%) • Minor response 2/20 (10%) - 2/20 (10%) • Stable disease 5/20 (25%) - 1/20 (5%) • Progressive disease 1/20 (5%) - 1/20 (5%) Lipiodol TACE PR: 41% MR: 33% SD: 15% (A Roche & T de Baere; Europ Radiol 2003)

17. Irinotecan DEBProof-of-Concept Study: Design • Evaluation of TACE in a rat liver metastasis model • Model: Diffuse liver metastasis is induced by injecting 4x106 CC531-lac-Z rat colorectal carcinoma cells into the portal vein of male Wag/Rij rats • Objectives: • Compare embolization only to Irinotecan (low and high dose) • Doses chosen: 20 mg/kg and 30 mg/kg Irinotecan • Determine the effectiveness in terms • reduction in tumor cell load • liver weight

18. Irinotecan DEB Proof-of-Concept Study: Preliminary Data • Preliminary results presented at AACR (Washington, April 06) p=0.07 p=0.05 DC Bead Irinotecan 20mg/kg+DEB Irinotecan 30mg/kg+DEB Embolizqtion No Drug Chemoemebolization of rat colorectal liver metastases with drug eluting beads loaded with irinotecan or doxorubicin. Clin Exp Metastasi 2008. Eyol E et al

19. DC beads and colorectal metastases 62 patients with CRC metastases At least 2 previous lines of chemotherapy Tumor burden < 70% Bilirubin w X2 normal value 138 courses of TACE with Irinotecan-DEB 2ml DEB 100-300 & 2ml 300-500 / 200 mg irinotecan 1-3 courses TACE every 3/4 weeks 55 right, 47 left, 39 right+left 48 X 2ml & 90 X 4ml (Aliberti C, Fiorentini G, Cancer Research 2006) (Aliberti C, Fiorentini G, CIRSE 2008)

20. DC beads and colorectal metastases 62 patients with CRC metastases Med Follow-up = 15.4 months Response EASL = 85% RECIST = 78% @ 3 months Improvement of QOL = 90% during 3-12 months (med= 6.5) Survival Median survival not reached at 22 months Median free of symptioms 5.3 months Median to new chemo 6.3 months (Aliberti C, Fiorentini G, Cancer Research 2006) (Aliberti C, Fiorentini G, CIRSE 2008)

21. Combined treatment CT immediately post DEB injection CT at 6 weeks Angiogram Post RF of colorectal mets (R Lencioni, J Hepatology 2008)

22. DEB future • Randomization DEB / Conventional • Precision V in Europe (completed) • MRI at 3m and 6m • Efficacy (treatment response). • European Association for the Study of the Liver (EASL) • Response Evaluation Criteria in Solid Tumours(RECIST) • SURVIVAL ? • Colo-rectal cancer • Hudge population, numerous drugs in 1st to 3rd lines

23. Drug Eluting Beads • Reproducibility > Lipiodol • Low systemic level drug • Increase in efficacy • Decrease toxicity • Encouraging preliminary results • combination with so called targeted therapy ? • sorafenib, sunitinib, …