R System. Lymphadenectomy pelvic para-aortic no Lymphadenectomy 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 Endpoints: OS, PFS, QoL Strata: centre, PS,age Lymphadenectomy In Ovarian Neoplasms AGO – OVAR OP.3 (LION) 80/ 640 Supported by Deutsche Forschungsgemeinschaft

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

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 AGO-OVAR12 R C T C T C T C T C T C T C T C T C T C T C T C T = Vargatef 2 x 200 mg po qd = Placebo  120 weeks C = Carboplatin AUC 5-6 d1 T = Paclitaxel 175 mg/m 2 (3h) d1 q21d / 6 courses Vargatef / Placebo : - no intake on days of chemotherapy - dose: 200 mg po bid (combi + mono) - dose adaptation in case of undue toxicity - max. duration of 120 weeks in non-progressing pts SURGERYSURGERY n=1300

Pazopanib consolidation 1 yr First Line Chemotherapy Control Patients 80 / 900 Leading AGO-OVAR Participating AGO Austria, ANZGOG, BGOG, GEICO, GINECO, ICORG, JGOG, KGOG, MANGO, MITO, NSGO, US-Sites: California Consortium, NY GOG, SWOG AGO-OVAR 16

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 Survival Follow-up (post-PD) First-line Chemotherapy (allow ip, neoadj) Placebo (12 months) Pazopanib (12 months) If not PD Treatment Period RANDOMIZERANDOMIZE Observation (to PD) Screening Baseline Post-Treatment Period Follow-up Period

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

CT vs CDDP + Irinotecan Patients 416 / 652 Leading JGOG ParticipatingGINECO, GOG, KGOG, MITO, SGCTG JGOG-3017 Clear Cell Carcinoma

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)

RANDOMIZATION TC Paclitaxel 175 mg/m 2 (d1) Carboplatin AUC 6 (d1) Every 3 wk x 6 CPT-11/CDDP CPT mg/m 2 (d1, 8, 15) Cisplatin 60 mg/m 2 (d1) Every 4 wk x 6 International Cooperative Phase III Study for Clear Cell Carcinoma -Clear Cell Ca -Stage I~IV 225 patients in each arm, 450 total for 3 years 326 patients in each arm, 652 total for 4.25 years

JGOG3017/GCIG T RIAL

Weekly CT vs 3-weekly CT (QoL) Patients 72 / 500 Leading MITO Participating MaNGO, AGO-OVAR MITO-7

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 RANDOM Carboplatin AUC 2 Paclitaxel 60 mg/mq day 1, every 21days Carboplatin AUC 6 Paclitaxel 175 mg/mq day 1 - every 21days

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

RANDOM LIPOSOMAL DOXORUBICIN 40 mg/mq day1 every 28 days CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/mq day1 every 21 days Cross-over at Progression CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/mq day1 every21gg LIPOSOMAL DOXORUBICIN 40 mg/mq day1 every 28 days Trial design The objective of this trial is the 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

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

ICON 6 Start up slides Oct 2009 ICON 6 Design schema Arm A Reference arm 6 cycles of chemotherapy plus Placebo No Progressive disease Maintenance cediranib after chemotherapy Maximum 18 months from randomisation Arm B Chemotherapy Plus cediranib during Chemotherapy Arm C Chemotherapy plus cediranib during Chemotherapy No Progressive disease Placebo Maximum 18 months from randomisation No Progressive disease Placebo Maximum 18 months from randomisation 2:3:3 RANDOMISATION

ICON6 Cediranib Dose Reduction Cediranib dose initially selected at 30mg/d in ICON6. Reduced to 20 mg Stage I re-started Stage I now completed 103 patients entered (11 UK; 6 CDN) Stage II being prepared with expansion of chemotherapy options to be discussed by ITMG Sunday 11th Oct- Belgrade ICON 6 Start up slides Oct 2009

Planned Trials

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

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

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 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 RANDOMRANDOM RANDOMRANDOM Cytoreductive surgery Cytoreductive surgery platinu m- based chemo- therapy * recom mende d platinu m- based chemo- therapy * recom mende d no surgery

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: Again limited funding - participating groups have to pay local costs (DESKTOP II model – Presentation/Publication/Co-authorship) AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

Collaborative Nursing Study MITO12 Pathway 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”

Weekly Paclitaxel vs weekly Paclitaxel and Pazopanib in patients with resistant/refractoryovarian cancer: Phase II randomized multicenter trial MITO - 11

Trial design Aim of the trial is to compare the PFS of weekly paclitaxel vs weekly paclitaxel and pazopanib RANDOM Pazopanib 800 mg/day Paclitaxel 80 mg/mq day 1, every 28days Paclitaxel 80 mg/mq day 1, 8, 15 - every 28 days

IP vs IV carboplatin + weekly Paclitaxel Patients Leading JGOG Participating JGOG IP Trial

iPocc Trial Design Epithelial Ovarian, Peritoneal, Fallopian Tube Cancer Stages II-IV Optimal, Suboptimal Excluding Clear Cell Carcinoma Paclitaxel 80 mg/m2 IV Weekly Carboplatin AUC 6 IV Q21, 6-8 Cycles Paclitaxel 80 mg/m2 IV Weekly Carboplatin AUC 6 IP Q21, 6-8 Cycles Randomization Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL, Cost

oxaliplatin + capecitabine ± bevacizumab vs carboplatin + paclitaxel ± bevacizumab Patients 0/332 Leading NCRI/SGCTG GOG Participating AGO OVAR, GINECO, MaNGO, NSGO, KGOG MucinousEOC

Cancer Research UK & UCL Cancer Trials Centre Targets: Planned start date – November 2009; Planned end date – May 2014 European Sites: Interest from sites in UK, Denmark, Finland, Sweden, Norway, France, Italy & Germany. Approximately 40 UK sites interested. Trial is in set-up, no centres are open. Chief Investigator: Prof. Martin Gore Sponsor: University College London Contact

TC dose dense / 3weekly ± BEVACIZUMAB Patients 0 / 2000 Leading MRC/NCRI Participating ? ICON-8

Randomisation ARM1: C q 3/52 P q 3/52 (current std) ARM2: C q 3/52 P q 1/52 ARM3: C q 1/52 P q 1/52 Current Proposal (A) Immediate Primary Surgery (IPS) (B) Delayed Primary Surgery (DPS) Surgery (IPS) Surgery (DPS) Chemotherapy (ARM 1-3 x 6) Chemotherapy (Arm 1-3 x 3) Chemotherapy (Arm 1-3 x 3) One trial with pre-specified stratification for IPD v DPS Plan to use lower dose of paclitaxel than JOG for arm 2: Carboplatin AUC6 d1Paclitaxel 60mg/m 2 d 1,8,15 q3w JOG study 60% received 6 cycles, 48% required at least one dose reduction and 76% had at least one delay, doses used carboplatin AUC6 and paclitaxel 80 mg/m 2

IP/IV Platinum/T vs IV CT optimally debulked following NACT Patients 0 / 780 Leading NCIC CTG ParticipatingGEICO, NCRI, SWOG NCIC CTG OV.21

Basic Design Patients with EOC 3-4 cycles neoadjuvant chemo Initial surgery: < 1 cm residual 3 cycles IV Carbo/Taxol 3 cycles IP/IV platinum and taxol Endpoints: PFS and OS R Day 8th Optimal Surgery Shorter course

Phase II Patients will be randomized to one of the following three arms: ArmAgent(s)DoseRouteDuration Schedule DaysRepeat 1 Paclitaxel 135 mg/m 2 IV 3 hours Day 1 Every 21 days 60 mg/m 2 1 hour Day 8 Carboplatin AUC 5 if measured GFR (use AUC 6 if calculated GFR) 30 minutes* Day 1 2 Paclitaxel 135 mg/m 2 IV3 hours Day 1 60 mg/m 2 IP By gravity as rapidly as possible Day 8 Cisplatin75 mg/m 2 IP By gravity as rapidly as possible Day 1 3 Paclitaxel 135 mg/m 2 IV3 hours Day 1 60 mg/m 2 IP By gravity as rapidly as possible Day 8 Carboplatin AUC 5 if measured GFR (use AUC 6 if calculated GFR) IP By gravity as rapidly as possible Day 1 * or according to local practice

Phase III Patients will be randomized to one of the following two arms: ArmAgent(s)DoseRouteDuration Schedule DaysRepeat 1 Paclitaxel 135 mg/m 2 IV 3 hoursDay 1 Every 21 days 60 mg/m 2 1 hourDay 8 Carboplat in AUC 5 if measured GFR (use AUC 6 if calculated GFR) 30 minutes*Day 1 2The selected IP arm from Phase II (regimen as in above table) Every 21 days * or according to local practice

A randomised phase III trial of weekly carboplatin and paclitaxel versus pegylated liposomal doxorubicin in recurrent, platinum resistant, epithelial ovarian cancer Patients 0 / 250 Leading SGCTG Participating? DDPC-PREOC

Trial Design Carboplatin (AUC 3) and paclitaxel (80 mg/m2) for 3 weeks out of 4 for 6 cycles Pegylated Liposomal Doxorubicin (40 mg/m2) every 4 weeks for 6 cycles RANDOMISERANDOMISE 250 patients with platinum resistant disease Primary Endpoint: PFS Secondary Endpoints:Overall Survival Quality of Life Health Economic Analysis Response Rate Toxicity/Hypersensitivity Dose Intensity Post progression therapy

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