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

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Presentation on theme: "Novel Therapeutics in Gynecological Malignancies Tamar Safra, MD Tel Aviv Sourasky Medical Center, Tel Aviv Tamar Safra, MD Tel Aviv Sourasky Medical Center,"— Presentation transcript:

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

2 Ovarian Cancer- New Treatments Uterine Cancer – Evolving Treatment

3 Ovarian Cancer The most lethal of gynecologic malignancies Future goals –Early detection –Development of novel agents 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 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 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 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/m 2 q 28 days x 12 Paclitaxel 175 mg/m 2 q 28 days x 12 PPX 175mg/ m 2 q 28 days x 12 PPX 175mg/ m 2 q 28 days x 12 Observation EOC with CR after 6 cycles of chemotherapy EOC with CR after 6 cycles of chemotherapy

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 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 to DNA causes cell death

12 Topotecan Daily

13 Study Design Topotecan 1.5 mg/m 2 /d D1-5 Q21d 30-minute infusion Topotecan 1.5 mg/m 2 /d D1-5 Q21d 30-minute infusion Ten Bokkel Huinink. J Clin Oncol 1997;15: Multicenter, prospective, randomized phase-III study Stratification by age, ascites and previous response to platinum-based therapy Paclitaxel 175 mg/m 2 D1 Q21d over 3 hours Paclitaxel 175 mg/m 2 D1 Q21d over 3 hours

14 Time to Progression Time (weeks) topotecan(n=112) Paclitaxel (n=114) Proportion P =.072 Ten Bokkel Huinink. Ann Onc. 2004;15:100-3 Median TTP 19.8w 14.7w Median TTP 19.8w 14.7w

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

16 Topotecan Continuous Infusion (CI)

17 Continuous Infusion Phase-II Response RR - 35% (95% CI, 15% to 54%) TTP - 26 weeks Response RR - 35% (95% CI, 15% to 54%) TTP - 26 weeks Hochster H. J Clin Oncol. 1999;17: mg/m 2 /24h, D1-21 Q28d N= mg/m 2 /24h, D1-21 Q28d N=24 Grade III-IV toxicity 31% neutropenia 52% anemia requiring transfusion 4% thrombocytopenia Grade III-IV toxicity 31% neutropenia 52% anemia requiring transfusion 4% thrombocytopenia

18 Topotecan Weekly

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

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

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

26 Toxicity (2) Hochster H. J Clin Oncol. 1999;17: (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 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 –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 –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 –Examples of TKI’s: Erlotinib Gefitinib Imatinib

31 Hypothesis Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer Topotecan Intracellularextracellular Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer Topotecan Intracellularextracellular 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 Effects of HER1/EGFR Activation Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis SrcPLC  GAPGrb2ShcNckVavGrb7Crk PKC Ras JNK Abl PI3KAkt Extracellular IntracellularTransactivation MAPK PP

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

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

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 EMD a phase II trial, completed but not yet reported Combinations with chemotherapy are being studied in small scale 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 EMD 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 ** 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 Adapted from Bergers G, et al. Nature 2002;3:401–10 Angiogenic switch Results in over-expression of pro-angiogenic signals, such as VEGF Small tumor (1–2mm) Avascular Dormant Small tumor (1–2mm) Avascular Dormant Larger tumor Vascular Metastatic potential Larger tumor Vascular Metastatic potential

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

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

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

47 Endocrine Therapy

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

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. 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: ** Papadimitriou, et al. Oncology 2004, 66(2): * Bowman, et al. Clinical Cancer Research 2002, 8: ** Papadimitriou, et al. Oncology 2004, 66(2):112-7.

50 Locally Advanced Endometrial cancer Chemotherapy Radiotherapy or Combination

51 GOG # patients 208 patients whole abdomen RT 208 patients whole abdomen RT 194 patients adriamicin and cisplatin 194 patients adriamicin and cisplatin Randomized

52 Disease Free Survival P=0.007

53 Overall Survival P=0.004

54 GOG#122 Sites of Relapse (%) GOG#122 Sites of Relapse (%) WAIAP Overall5450 Pelvic1318 Abdominal1614 Extra-abdomianl2218

55 WAIAPP Un-adjusted38%42%? Stage-adjusted*38%50%0.007 GOG#122 5-year Diseases-free Survival GOG#122 5-year Diseases-free Survival * More unfavorable stages in AP arm Randall M JCO, 2006

56 Grade 3-4WAI (%)AP (%) WBC462 ANC<185 GI1320 Hepatic31 Cardiac015 Neurologic<17 Tx-related deathsN=4N=8 Feasibility of GOG#122 Adverse Treatment Effects Feasibility of GOG#122 Adverse Treatment Effects

57 How to Improve Treatment in Uterine Adenocarcinoma Adjuvant Chemotherapy (CT) is at least as good as radiotherapy (RT) Should we omit pelvic RT? How best to combine RT and CT? What is the best CT? Adjuvant Chemotherapy (CT) is at least as good as radiotherapy (RT) Should we omit pelvic RT? How best to combine RT and CT? What is the best CT?

58 What is the best chemotherapy Regimen ? Adriamycin Cisplatin Carboplatin Paclitaxel Adriamycin Cisplatin Carboplatin Paclitaxel Combination improves RR with limited improvements in PFS and OS in patients with advanced/recurrent disease. The GOG has conducted several phase III trials comparing Adria to Adria/Cis (GOG 107), AC to AT (GOG 163), AC to TAP (GOG 177) Combination improves RR with limited improvements in PFS and OS in patients with advanced/recurrent disease. The GOG has conducted several phase III trials comparing Adria to Adria/Cis (GOG 107), AC to AT (GOG 163), AC to TAP (GOG 177) Phase II studies have identified several active agents:

59 Endometrial Cancer Front-line Randomized Trials Advanced/Recurrent RRMedian OS (mos) GOG 163 Doxorubicin/Cisplatin40%12.4 Doxorubicin/Paclitaxel44%13.6 GOG 163 Doxorubicin/Cisplatin34%12.1 Doxorubicin/Paclitaxel/Cisplatin/G-CSF57%15.3

60 Conclusion Adjuvant CT should be used in most pts with advanced endometrial cancer That shouldn’t be done at the expense of adjuvant RT New strategies to combine CT and RT are needed IMRT may provide a venue to combine CT and RT concurrently Adjuvant CT should be used in most pts with advanced endometrial cancer That shouldn’t be done at the expense of adjuvant RT New strategies to combine CT and RT are needed IMRT may provide a venue to combine CT and RT concurrently

61 Tel-Aviv Medical Center, Tel-Aviv, ISRAEL

62 Thank You


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