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OVARIAN CANCER COMMITTEE Phillip Harter / Christian Marth

OVARIAN CANCER COMMITTEE Phillip Harter / Christian Marth. Ovarian CancerCommittee Agenda. Summary of ongoing and recently closed trials Christian Marth AGO-OVAR OP.4/Desktop III trial Phillipp Harter ICON-8 Jonathan Lederman

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OVARIAN CANCER COMMITTEE Phillip Harter / Christian Marth

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  1. OVARIAN CANCER COMMITTEE Phillip Harter / Christian Marth

  2. Ovarian CancerCommittee Agenda • Summary of ongoing and recently closed trials Christian Marth • AGO-OVAR OP.4/Desktop III trial Phillipp Harter • ICON-8 Jonathan Lederman • MucinousEOC – GOG 241 Jonathan Lederman • NCIC CTG OV21: A Phase II/III Study of Intraperitoneal (Ip) Diane ProvencherPlus Intravenous (Iv) Chemotherapy Versus Iv Carboplatin Plus Paclitaxel In Patients With Epithelial Ovarian Cancer Optimally Debulked At Surgery Following Neoadjuvant Intravenous Chemotherapy • DDPC-PREOC: A randomised phase III trial of weekly Ros Glasspoolcarboplatin and paclitaxel versus pegylated liposomal doxorubicin in recurrent, platinum resistant, epithelial ovarian cancer

  3. Closed Trials

  4. EORTC 55971/CHORUS Upfront Surgery vs Neoadjuvant Chemotherapy Patients closed / 550 Leading EORTC Participating NCIC CTG Presentation IGCS 2008

  5. NACT + IDS versus PDS: ITT Median PFS PDS: 12 months IDS: 12 months HR for IDS:0.99 (0.87, 1.13)

  6. AGO-OVAR-9 Carbo Paclitaxel +/- Gemcitabine Patients closed 1742 Leading AGO-OVAR Participating GINECO, NSGO Presented ASCO 2009

  7. GCIG Intergroup study (AGO-OVAR/GINECO/NSGO)Protocol # AGO-OVAR 9 RANDOMISATION Gemcitabine 800 mg/m² d1+8 iv Paclitaxel 175 mg/m² 3 h iv Carboplatin AUC 5 iv * Strata: * FIGO stage * post-op residual tumor * Surgery Interval-surgery y/n * Center q 21 x 6 Paclitaxel 175 mg/m² 3 h iv Carboplatin AUC 5 iv q 21 x 6 * evaluated in preceding Phase II Study protocol # AGO-OVAR 8 AGO Ovarian Cancer Study Group (AGO-OVAR)

  8. Progression-free (RECIST & GCIG CA125) and Overall SurvivalbyTherapywithinStratum 2+3 (FIGO IIB-IV) TC793 pts. / 401 evts. median 48.9 [43.1-51.2] mos. TCG 774 pts. / 404 evts. median 45.8 [40.0-49.5] mos. TC793 pts. / 588 evts. median 16.0 [14.9-17.4] mos. TCG 774 pts. / 629 evts. median 14.7 [14.0-15.9] mos. P r o b a b i l i t y [months] HR = 1.03 [95% CI: 0.90-1.18] p = 0.6955 HR = 1.17 [95% CI: 1.05-1.31] p = 0.0065

  9. SCOTROC 4 Carbo Flat Dosing vs Intrapatient Dose Escalation Patients closed 937 Leading SGCTG Participating ANZGOG Report ASCO 2009 ... trial has been closed to recruitment, with no evidence of benefit for intra-patient dose escalation of carboplatin.

  10. Tarceva Trial EORTC 55041 Tarceva consolidation 2 years Primary Chemotherapy Control Patients closed / 835 Leading EORTC Participating AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO

  11. ICON-7 TC ± BEVACIZUMAB Patients closed / 1520 Leading MRC/NCRI Participating NCIC CTG, AGO OVAR, GINECO, GEICO EORTC, ANZGOG, NSGO

  12. GOG 218 CT vs CT + Bevacizumab Placebo vs CT + Bevacizumab concurrent and extended Patients closed / 1800 Leading GOG Participating ECOG, NCCTG, NSABP, SWOG

  13. AGO-OVAR-OP.2 DESKTOP II Evaluation of predictive factors for complete resection in platinum-sensitive recurrent ovarian cancer Patients closed/412 Leading AGO-OVAR Participating AGO-AUSTRIA, MITO, selected Canadian+Australian centers Report IGCS 2008

  14. AGO-OVAR-OP.2 DESKTOP II 08/06 – 03/08: Screening of 516 ptswith platinum-sensitive relapse in 46 centres Study collective: AGO score + 1st relapse 129 pts (87%) Score positive + First relapse 76% Complete resection Frequency of complete resection by applying the AGO Score

  15. Calypso TC vs C + Caelyx Patients closed / 976 Leading GINECO Participating AGO-AUSTRIA, AGO-OVAR, ANZGOG, EORTC, MANGO, MITO, NCIC/CTG, NSGO Presentation ASCO 2009

  16. Progression-Free Survival (ITT)

  17. Open Trials

  18. AGO – OVAR OP.3 (LION) Lymphadenectomy In Ovarian Neoplasms epithelial invasive ovarian cancer FIGO IIB - IV ECOG 0/1 and no CI against LNE no visible extra- and intra-abdominal tumor residuals no bulky lymph nodes System. Lymphadenectomy • pelvic • para-aortic R 80/ 640 no Lymphadenectomy Endpoints: OS, PFS, QoL Strata: centre, PS ,age Supported by Deutsche Forschungsgemeinschaft

  19. AGO-OVAR-OP.4 DESKTOP III Cytoreductive surgery vs NO surgery in platinum-sensitive recurrent EOC Patients 0 / 385 Leading AGO-OVAR Participating ?

  20. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer • Complete resection seems feasible and a positive AGO-score • Strata: • Platinum-free-interval • 6-12 vs > 12 months • 1st line platinum • based chx: yes vs no Cytoreductive surgery R A N D O M platinum-based chemotherapy* recommended no surgery • * Recommended platinum-based chemotherapy regimens: • - carboplatin/paclitaxel • carboplatin/gemcitabine • carboplatin/pegliposomal doxorubicin • (if calypso-trial shows equivalence to carboplatin-paclitaxel) • or other platinum combinations in prospective trials

  21. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) • Primary objective: • - Overall survival • Secondary objectives: • - Progression-free survival • - Quality of Life: EORTC QLQ 30 and NCCN FOSI • - Rate of complete resection as prognostic factor • - Complication rates of surgery • Exploratory analysis of surgical characteristics • and chemotherapy, prognostic factors

  22. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) • Inclusion criteria (1): • Patients with 1st recurrence of platinum sensitive, invasive epithelial ovarian-, fallopian tube- or primary peritoneal cancer of any inital stage • Progression-free interval of at least 6 months after end of last platinum based chemotherapy OR recurrence within 6 months or later after primary surgery if the patient has not received prior chemotherapy in patients with FIGO I. Non cytostatic maintenance therapy not containing platinum will not be considered for this calculation

  23. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) • Inclusion criteria (2): • A positive AGO-score: Obligatory requirements for a positive AGO recurrence score in platinum-sensitive disease: • (1) Performance status ECOG 0 • (2) Complete resection at 1st surgery (if unknown FIGO I/II). If report from 1st surgery is not available contact study chairman • (3) Absence of ascites (cut off 500 ml: radiological or ultrasound estimation) • Complete resection of the tumor by median laparotomy seems possible (estimated by an experienced surgeon). Intra-abdominal disease has to be excluded by MRI/CT, if other surgical approaches for extra-abdominal recurrences only are planned • Age > 18 years, signed and written informed consent

  24. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) • Exclusion criteria (1): • Patients with non-epithelial tumors or borderline tumors • Patients without recurrence, but are scheduled for diagnostic/second-look surgery or debulking surgery after completion of chemotherapy • Patients with second, third or later recurrence • Patients with secondary malignancies who have been treated by laparotomy, as well as other neoplasms, if the treatment might interfere with the treatment of relapsed ovarian cancer or if major impact on prognosis is expected

  25. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) • Exclusion criteria (2): • Patients with so-called platinum-refractory tumor, i.e. progression during chemotherapy or recurrence within 6 months atfe end of former first platinum-containing chemotherapy • Only palliative surgery planned • Metastases not accessible to surgical removal • Any concomitant disease not allowing surgery and/or chemotherapy • Any medical history indicating excessive peri-operative risk • Any current medication inducing considerable surgical risk (e.g. anticoagulant agents, bevacizumab)

  26. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) Datamanagemt: e-CRF (MACRO) Randomisation: Fax Central Monitoring/Queries: AGO Statistics: HR 0.7 favouring surgery Sample size: 408 patients/244 events Recruitment: 36 months IDMSC: R. Coleman (chair), J. Berek, D Chi, J. Paul (statistics)

  27. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) The next steps: Protocol finalized (-> review participating groups) Ethical approval for Germany:12/09 -> FPI 01/2010 Identifikation of interested GCIG-groups/single centres -> representatives contact: p.harter@gmx.de office-wiesbaden@ago-ovar.de Again limited funding - participating groups have to pay local costs (DESKTOP II model – Presentation/Publication/Co-authorship)

  28. AGO-OVAR-12 Carbo Paclitaxel +/- BIBF 1120 (Vargatef) Patients 0 / 1300 (2:1 random) Leading AGO-OVAR Participating AGO Austria, BGOG, GINECO, MANGO, MITO, NSGO, US Oncology

  29. AGO-OVAR12 C C C C C C C C C C C C = Vargatef 2 x 200 mg po qd T T T T T T T T T T T T R C = Carboplatin AUC 5-6 d1 T = Paclitaxel 175 mg/m2 (3h) d1 = Placebo  120 weeks Multicenter, randomised, double-blind, Phase III trial to investigate the efficacy and safety of Vargatef (BIBF 1120) in combination with standard treatment of carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel patients with advanced ovarian cancer SURGERY Vargatef / Placebo : - nointake on daysofchemotherapy - dose: 200 mg pobid (combi + mono) - dose adaptation in caseofunduetoxicity - max. durationof 120 weeks in non-progressingpts q21d / 6 courses n=1300

  30. AGO-OVAR 16 Pazopanib consolidation 1 yr First Line Chemotherapy Control Patients 0 / 900 Leading AGO-OVAR Participating AGO Austria, ANZGOG, BGOG, GEICO, GINECO, ICORG, JGOG, KGOG, MANGO, MITO, NSGO, US-Sites: California Consortium, NY GOG, SWOG

  31. AGO-OVAR16 A Phase III Study to Evaluate the Efficacy and Safety of Pazopanib Monotherapy Versus Placebo in Women Who Have not Progressed after First Line Chemotherapy for Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Follow-up Period Treatment Period Post-Treatment Period Screening Baseline RANDOM I ZE Pazopanib (12 months) Observation (to PD) First-line Chemotherapy (allow ip, neoadj) Survival Follow-up (post-PD) If not PD Placebo (12 months)

  32. HECTOR Carbo Topo vs Chemo (CT or CG) in recurrent Platinum-sensitive ovarian cancer Patients 508 / 550 Leading NOGGO/AGO-OVAR Participating AGO-AUSTRIA, GEICO

  33. JGOG-3017 Clear Cell Carcinoma CT vs CDDP + Irinotecan Patients 396 / 652 Leading JGOG Participating GINECO, GOG, KGOG, MITO, SGCTG

  34. JGOG3017/GCIG Ovarian Trial Protocols Randomized Phase III Trial of Paclitaxel plus Carboplatin (TC) Therapy versus Irinotecan plus Cisplatin (CPT-P) Therapy as a First Line Chemotherapy for Clear Cell Carcinoma of the Ovary Study Chair Toru Sugiyama, MD (Iwate Medical University) Study Co-Chair Seiji Isonishi, MD (Jikei University School of Medicine) Fumitoshi Terauchi, MD (Toho University)

  35. International Cooperative Phase III Study for Clear Cell Carcinoma TC Paclitaxel 175 mg/m2 (d1) Carboplatin AUC 6 (d1) Every 3 wk x 6 -Clear Cell Ca -Stage I~IV RANDOMIZATION CPT-11/CDDP CPT-11 60 mg/m2 (d1, 8, 15) Cisplatin 60 mg/m2 (d1) Every 4 wk x 6 225 patients in each arm, 450 total for 3 years 326patients in each arm, 652total for4.25 years

  36. JGOG3017/GCIG Trial

  37. MITO-7 Weekly CT vs 3-weekly CT (QoL) Patients 65 / 500 Leading MITO Participating MaNGO, AGO-OVAR

  38. MITO - 7 First line weekly carboplatin and paclitaxel vs every 3 weeks carboplatin/paclitaxel in patients with ovarian cancer: Phase III multicenter trial

  39. Trial design • Aim of the trial is to compare the quality of life of weekly somministration of carboplatin plus carboplatin (experimental arm) versus every 3 weeks administration of the same drugs (standard arm) in 1°-line advanced ovarian, tubal and peritoneal cancer Carboplatin AUC 6 Paclitaxel 175 mg/mq day 1 - every 21days RANDOM Carboplatin AUC 2 Paclitaxel 60 mg/mq day 1,8 15 - every 21days

  40. Statistics • Phase 3 open-label multicentre trial • Quality of life as primary end-point • Difference in FACT-O after 9 weeks: 30% • Overall survival, PFS, activity and toxicity are the secondary end-points. • Alpha error: 0.05, bilateral • Power: 80% • # patients to enroll: 400

  41. New Statistics under discussion after JGOG • Phase 3 open-label multicentre trial • Risk of progression at 18 months as primary end-point • Expected risk at 18 months in the control arm • 50% • Estimated risk at 18 months in the experimental arm • 37.5% • Overall survival, Quality of life, activity and toxicity are the secondary end-points. • Alpha error: 0.05, bilateral • Power: 80% • # patients to enroll: 500 (25 pts/month)

  42. MITO7 – Groups involved • MaNGo (8 centers) • Others? • 65 patients enrolled (12 in September)

  43. Collaborative Nursing Study MITO12Pathway to diagnosis of ovarian cancer in Italian women: an exploratory study Primary Objectives • Describe the frequency and duration of symptoms in the 12 months preceding the diagnosis of ovarian cancer (Goff symptoms survey) • Describe time intervals of sentinel events • Onset of persistent symptoms • First physician visit • Diagnosis of ovarian cancer • Describe the pathway to diagnosis according to Andersen’s model of “total patient delay”

  44. MITO-8 PLD vs CT cross-over in 6-12 m platinum-free interval Patients 18 / 253 Leading MITO Participating MaNGO, AGO-OVAR, Belgium

  45. Liposomal doxorubicin stealth vs carboplatin/taxol in recurrent ovarian cancer patients with platinum-free interval between 6-12 months MITO - 8

  46. Trial design • The objective of this trial isthe efficacy determined through analysis of overall survival (OS) of the different sequence (CP→PLD vs PLD→CP) in recurrent ovarian cancer patients with platinum-free interval 6-12 months RANDOM LIPOSOMAL DOXORUBICIN 40 mg/mq day1 every 28 days CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/mq day1 every21gg Cross-over at Progression LIPOSOMAL DOXORUBICIN 40 mg/mq day1 every 28 days CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/mq day1 every 21 days

  47. Statistics • Median Overall Survival: • expected (control arm): 18 months • auspicated (experimental arm): 27 months • Alpha error: 0.05, bilateral • Power: 80% • 193 events (progression) are needed • 253 patients are to be enrolled (planned in 4 yr)

  48. MITO8 – Groups involved • MaNGo (8 centers) • Belgium (15 centers) • AGO (funding application approved; soon ready to go) • Others? • 18 patients enrolled (5 in September)

  49. ICON6: A randomised trial of concurrent (with platinum based chemotherapy) and maintenance cediranib (AZD2171, Recentin) in women with platinum-sensitive relapsed ovarian cancer. Gynaecologic Cancer Intergroup Trial Stage 1 MRC/NCRI, NCIC Stage 2 ANZ-GOG, IMN, EORTC, GINECO, GEICO, MANGO, NSGO, ICMB and others

  50. Arm B Chemotherapy Plus cediranib during Chemotherapy Arm C Chemotherapy plus cediranib during Chemotherapy Arm A Reference arm 6 cycles of chemotherapy plus Placebo No Progressive disease Placebo Maximum 18 months from randomisation No Progressive disease Placebo Maximum 18 months from randomisation No Progressive disease Maintenance cediranib after chemotherapy Maximum 18 months from randomisation ICON 6 Design schema 2:3:3 RANDOMISATION

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