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Novel Therapeutics in Gynecological Malignancies

Novel Therapeutics in Gynecological Malignancies. Tamar Safra, MD Tel Aviv Sourasky Medical Center, Tel Aviv. Ovarian Cancer- New Treatments Uterine Cancer – Evolving Treatment. Ovarian Cancer. The most lethal of gynecologic malignancies Future goals Early detection

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Novel Therapeutics in Gynecological Malignancies

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  1. Novel Therapeutics in Gynecological Malignancies Tamar Safra, MD Tel Aviv Sourasky Medical Center, Tel Aviv

  2. Ovarian Cancer- New TreatmentsUterine Cancer – Evolving Treatment

  3. Ovarian Cancer • The most lethal of gynecologic malignancies • Future goals • Early detection • Development of novel agents

  4. Ovarian Cancer • New drugs and analogs of old drugs • New schedules for old drugs • Methods to overcome drug resistance • Biological agents • Combination of chemotherapy with biological therapy • Hormonal therapy

  5. Mitotic Spindle Inhibitors

  6. New Taxanes • Taxanes and epothilones - under active clinical development • Overcome drug resistance • Enhance tumor delivery • Reduced neuropathy • Reduced alopecia • Xyotax, a polyglutamate conjugated to paclitaxel - activity without alopecia • Abraxane - nanoparticle paclitaxel forumulation is under investigation

  7. Paclitaxel Poliglumex (PPX) • Conjugate of paclitaxel with poly-L-glutamic acid • Enhances distribution in tumor • Prolonged release of free paclitaxel • Greater activity • Active in tumors with MDR (Multi-Drug Resistance) gene • Shorter administration

  8. GOG 212 Phase III Study : Maintenance Chemotherapy for EOC Paclitaxel 175 mg/m2 q 28 days x 12 EOC with CR after 6 cycles of chemotherapy PPX 175mg/m2 q 28 days x 12 Observation

  9. Different Schedules of old drugs

  10. Topotecan • An S-phase specific drug • Activity and toxicity are schedule dependent • Investigated methods • Daily administration – 5 days q 3 weeks • Low‑dose continuous infusion (CI) • Weekly schedule

  11. Topotecan Mechanism of Action Topoisomerase I creates DNA breaks for repair and replication Topotecan binds to topoisomerase I creating DNA breaks Damage toDNA causescell death

  12. Topotecan Daily

  13. Study Design Multicenter, prospective, randomized phase-III study Topotecan 1.5 mg/m2/d D1-5 Q21d 30-minute infusion Stratification by age, ascites and previous response to platinum-based therapy Paclitaxel 175 mg/m2 D1 Q21d over 3 hours Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

  14. 1.0 topotecan(n=112) 0.8 Paclitaxel (n=114) 0.6 P =.072 Proportion 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 Time (weeks) Time to Progression Median TTP 19.8w 14.7w Ten Bokkel Huinink. Ann Onc. 2004;15:100-3

  15. Hematological Side Effects Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

  16. Topotecan Continuous Infusion (CI)

  17. Continuous Infusion Phase-II 0.4 mg/m2/24h, D1-21 Q28d N=24 Response • RR - 35% (95% CI, 15% to 54%) • TTP - 26 weeks Grade III-IV toxicity • 31% neutropenia • 52% anemia requiring transfusion • 4% thrombocytopenia Hochster H. J Clin Oncol. 1999;17:2553-61

  18. Topotecan Weekly

  19. Weekly Topotecan in Patients with Recurrent or Persistent Epithelial Ovarian Cancer Phase-II Study Safra T, Inbar M, Levy T et al

  20. Objectives To investigate the safety and efficacy of weekly topotecan in relapsed and persistant EOC Safra T, Inbar M, Levy T et al

  21. Treatment Regimen 4 mg/m² topotecan D1,8,15 Q28d Safra T, Inbar M, Levy T et al

  22. Patients Characteristics • N=45 • Age – median 64y (range 42-87) • Stage – Ic-IIc in 4 (9%) patients III-IV in 41 (91%) patients • Platinum status – Sensitive 56% Resistant 44% • Previous chemotherapy – median 1(range 1-5) Safra T, Inbar M, Levy Taet al

  23. RESULTSResponse Rates Safra T, Inbar M, Levy T et al

  24. Time to Progression Median TTP 4.43m (95%CI, 3.64-5.23) Safra T, Inbar M, Levy T et al

  25. Overall Survival 1Y OS - 76% 2Y OS - 50% OS – median 11.6+ m (0.57-31) Safra T, Inbar M, Levy T et al

  26. Toxicity (2) Hochster H. J Clin Oncol. 1999;17:2553-61 (1) Ten Bokkel Huinink. Ann Onc. 2004;15:100-3

  27. Conclusions • Weekly topotecan is efficacious in relapsed and persistent EOC • Weekly topotecan is very feasible • Low rate of grade III-IV hematological toxicity • Mild non-hematological toxicity with no alopecia Safra T, Inbar M, Levy T et al

  28. Multiple Drug Resistance (MDR)

  29. Using Erlotinib To Overcome ABCG2-Mediated Chemoresistance To Topotecan Rebecca Kosloff, MD

  30. ABCG2 is one of the MDR genes Half-transporter structure causing efflux of the drug to the extracellular material Higher affinity for TKIs then other MDR1 Examples of TKI’s: Erlotinib Gefitinib Imatinib ABCG2

  31. Hypothesis Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer Topotecan Topotecan Intracellular extracellular ABCG2 Erlotinib

  32. Phase I and II and pharmacokinetics are on the way

  33. Biologics/targeted drug therapy

  34. Epidermal Growth Factor Receptor (EGFR)

  35. Extracellular Intracellular Transactivation P P Src PLCg GAP Grb2 Shc Nck Vav Grb7 Crk PKC Ras Abl JNK PI3KAkt MAPK Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis Effects of HER1/EGFR Activation

  36. EGFR targeted therapy P P P TKIs Ligand– toxin conjugates Anti-ligand- blocking antibodies P Antibody– toxin conjugates Anti-HER1/EGFR-blocking antibodies 3 4 2 1 5 Noonberg SB, Benz CC. Drugs 2000;59:753–67

  37. Erbitux Herceptin Cell membrane Erlotinib Tyrosine-kinase domain HER1/EGFR HER2 Anti-HER monoclonal antibodies • Inhibit cell-cycle progression; potentiate apoptosis • Decrease production of angiogenic factors • Recruit natural killer cells to tumours • Enhance receptor internalisation Agus D, et al. Cancer Cell 2002;2:127–37Baselga J. Cancer Cell 2002;2:93–95

  38. Anti-EGFR studies have been initiated – most are not yet published • Anecdotal responses noted in phase I studies, encouraging phase II studies • Cetuximab (Erbitux) • Trastuzumab (Herceptin) - RR only 7.3%* • EMD72000 • GOG - a phase II study of cetuximab • EMD72000 - a phase II trial , completed but not yet reported • Combinations with chemotherapy are being studied in small scale * Bookman et al. J Clin Oncol. 21(2):283-90, 2003

  39. Small Molecules – TKI’s (Tyrosine Kinase Inhibitors)

  40. Erlotinib (Tarceva) • TKI –EGFR indicated in metastatic disease of pancreas and NSCLC • Inhibitor of ABCG2 • Preclinical data with topotecan • Some response as a single agent in ovarian cancer * • N=34 pts , heavily pretreated • RR 6% • SD 44% • Median OS 8 m • Erlotinib in combination with docetaxel and carboplatin as first line treatment for ovarian cancer shown some response ** * Gordon et al, Int J Gynecol Cancer 2005;15:785–792 **Finkler et al., ASCO Ann Meeting Proc 2001; 20:208a (abstr 831)

  41. Anti-angiogenic therapies

  42. The angiogenic switch in tumor development • Larger tumor • Vascular • Metastatic potential • Small tumor (1–2mm) • Avascular • Dormant Angiogenic switch Results in over-expressionof pro-angiogenic signals,such as VEGF Adapted from Bergers G, et al. Nature 2002;3:401–10

  43. Bevacizumab (Avastin) - a monoclonal antibody Prevents interaction VEGF with its receptors Prevents activation of downstream signalling pathways Vascular regression VEGF Bevacizumab X – P P– – P P– X Growth Proliferation Migration Survival Anti-VEGF antibody

  44. Blocking VEGF may cause existing tumour blood vessels to regress and lead to tumour shrinkage Shrinking tumour Regressing vasculature Jain RK. Nat Med 2001;7:987–9

  45. Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial or Primary Peritoneal Cancer

  46. GOG 218: Bevacizumab Plus Standard Chemotherapy Randomization Placebo q 21 d x 15 mo Carboplatin plus Paclitaxel q 21 d x 6 Patients with previously untreated suboptimal advanced stage epithelial ovarian cancer or primary peritoneal cancer (N =2000) Placebo q 21 d x 15 mo Carboplatin plus Paclitaxel q 21 d x 6 plus Bevacizumab 15 mg/kg cycles 2-6 Bevacizumab q 21 d x 15 mo Carboplatin plus Paclitaxel q 21 d x 6 plus Bevacizumab 15 mg/kg cycles 2-6

  47. Endocrine Therapy

  48. Tamoxifen • Several positive phase II studies using tamoxifen • RR=17%* • 2 patients having greater than a 5 year response* • GOG-0198 - Phase III trial of tamoxifen compared with thalidomide in EOC * Ahlgren, et al. Journal of Clinical Oncology 1993, 11:1957-68.

  49. Aromatase inhibitors • A phase II study of Letrozole (Femara) 2.5 mg/d in 50 patients showed: • Ten patients with SD on CT for at least 12 weeks* • Response correlated with - higher estrogen receptors, lower erbB2, and higher EGFR* • Another phase II study ** of letrozole 2.5 mg/d with 27 patients showed: • RR of 15% • No correlation was found between response and estrogen/progesterone receptor expression • Aromatase inhibitors - need to be examined in Phase III studies and in combination with cytotoxic agents. * Bowman, et al. Clinical Cancer Research 2002, 8:2233-9. ** Papadimitriou, et al. Oncology 2004, 66(2):112-7.

  50. Locally Advanced Endometrial cancerChemotherapy Radiotherapy or Combination

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