UPDATE ON GCIG TRIALS FOR EPITHELIAL OVARIAN CANCER

UPDATE ON GCIG TRIALS FOR EPITHELIAL OVARIAN CANCER
Christian Marth

Ovarian Cancer Diagnosis Surgery First-line Chemotherapy Consolidation
Platinum-sensitive Recurrence Chemotherapy Platinum-resistant Recurrence

Ovarian Cancer Diagnosis Surgery Closed Trials Open Trials EORTC 55971
CHORUS Surgery

Closed Trials

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

Randomised trial comparing primary debulking surgery (PDS) with neoadjuvant chemotherapy (NACT) followed by interval debulking (IDS) in stage IIIC-IV ovarian,fallopian tube and peritoneal cancer.

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical characteristics (PP1)
Postoperative mortality (< 28 days) 2,7% 0,6% Postoperative sepsis 8% 2% Fistula (bowel/GU) 1,2% / 0,3% 0,3% / 0,6% Operative time (minutes) 180 Red blood cell transfusion 51% 53% Hemorhage Grade 3/4 7% 1% Venous Gr 3/4 2,4% 0,3% Range operation time to te voegen. Hospitalisatieduur? Tijd van randomisatie tot PDS of NACT. Omit red blood cell transfusion in slide?

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

Ovarian Cancer First-line Chemotherapy Consolidation Closed Trials
Open Trials First-line Chemotherapy AGO-OVAR-9 CT ± GEM SCOTROC-4 ICON-7 GOG-218 EORTC 55041 Tarceva Consolidation

AGO-OVAR-9 Carbo Paclitaxel +/- Gemcitabine Patients closed 1742
Leading AGO-OVAR Participating GINECO, NSGO,

GCIG Intergroup study (AGO-OVAR/GINECO/NSGO) Protocol # AGO-OVAR 9
R A N D O M I S A T I O N 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) 71 71 72 72

Progression-free Survival (RECIST & GCIG CA125) by Therapy
within Stratum 2+3 (FIGO IIB-IV) – Kaplan-Meier TC 793 pts. / 588 evts. median 16.0 [ ] mos. TCG 774 pts. / 629 evts. median 14.7 [ ] mos. HR = 1.17 [95% CI: ] Logrank test: p = 1217 pat. mit CA125 Progresse / RECIST Progresse bei S2+S3 [months] Patients at risk

Overall Survival by Therapy within Stratum 2+3 (FIGO IIB-IV)
TC 793 pts. / 401 evts. median 48.9 [ ] mos. TCG 774 pts. / 404 evts. median 45.8 [ ] mos. P r o b a b i l i t y HR = 1.03 [95% CI: ] p = [months] Patients at risk AGO Ovarian Cancer Study Group (AGO-OVAR)

SCOTROC 4 Carbo Flat Dosing vs Intrapatient Dose Escalation
Patients closed 932 Leading SGCTG Participating ANZGOG

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

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

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

Platinum-sensitive Recurrence
Ovarian Cancer Closed Trials Open Trials Platinum-sensitive Recurrence Surgery Chemotherapy AGO-OVAR OP-2 Desktop II CALYPSO Platinum-resistant Recurrence

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

AGO DESKTOP OVAR II – FLOW CHART
08/06 – 03/08: Screening of 516 pts with platinum-sensitive relapse in 46 centres Score positive 261 pts (51%) Score negative 255 pts (49%) Surgery 148 pts (57%) No surgery 113 pts (43%) Surgery 80 pts (31%) No surgery 175 pts (69%) Study collective: AGO score + 1st relapse 129 pts (87%) 2nd relapse 19 pts (13%) 1st relapse 64 pts (80%) 2nd relapse 16 pts (20%) Selection process: 228 pts (44.2%) had cytoreductive surgery for recurrent OC -> Primary study collective (AGO score +, 1st relapse) : 129 pts (25%)

AGO DESKTOP OVAR II – SURGICAL RESULTS
Frequency of complete resection by applying the AGO Score DESKTOP Hypothesis complete resection in 76% of the study collective = AGO score could predict complete resection in at least 2 out of 3 patients

AGO DESKTOP OVAR II: CONCLUSIONS
A surgical multicentre study within the GCIG is feasible and could answer complex questions in an appropriate interval The AGO-Score is a useful and reliable tool to predict complete resection in at least 2 out of 3 patients First score succesfully validated in surgery for ovarian cancer The comorbidity is comparable to surgery in primary ovarian cancer Outcome in the score negative subgroup will be further analysed

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

Ovarian Cancer Diagnosis Surgery Closed Trials Open Trials EORTC 55971
CHORUS AGO-OVAR OP-3 LION Surgery

AGO – OVAR OP.3 (LION) Lymphadenectomy In Ovarian Neoplasms R n = 640
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 n = 640 no Lymphadenectomy Endpoints: OS, PFS, QoL Strata: centre, PS ,age Supported by Deutsche Forschungsgemeinschaft

Participating groups/sites:
AGO Study Group (24 centres initiated) MITO (11 centres planned – ethical approval 06/09) KGOG AGO Austria Single sites: Leuven Recruitment: 26 / 640 pts

Ovarian Cancer First-line Chemotherapy Consolidation Closed Trials
Open Trials First-line Chemotherapy AGO-OVAR-9 CT ± GEM JGOG-3017 Clear cell carcinoma mEOC SCOTROC-4 MITO-7 ICON-7 JGOG IP Trial GOG-218 AGO-OVAR-12 EORTC 55041 Tarceva AGO-OVAR-16 VEG Consolidation

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

Ovarian Trial Protocols Randomized Phase III Trial of Paclitaxel plus
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)

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 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 326 patients in each arm, 652 total for 4.25 years

JGOG3017/GCIG Trial JGOG 345 KGOG 15 As of 5/27/2009

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

Cancer Research UK & UCL Cancer Trials Centre
mEOC A multicentre randomised GCIG Intergroup factorial trial comparing oxaliplatin + capecitabine, bevacizumab and carboplatin + paclitaxel in patients with previously untreated mucinous Epithelial Ovarian Cancer (mEOC) Cancer Research UK & UCL Cancer Trials Centre

2x2 Factorial Trial Design
mEOC FIGO stages II–IV OR recurrent stage I; No previous chemotherapy; >18yrs; PS=0-2 Randomise (332 patients – 83 patients in each arm) Oxaliplatin 130 mg/m2 Capecitabine 850mg/m2 bd 6 21-day cycles Bevacizumab 7.5mg/kg given every 3 weeks for 5 or 6** cycles Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 21-day cycles Oxaliplatin 130 mg/m2 Capecitabine 850mg/m2 bd 6 21-day cycles Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 21-day cycles Bevacizumab 7.5mg/kg given every 3 weeks for 5 or 6** cycles Clinical assessment every 6 weeks for 36 weeks Bevacizumab 7.5mg/kg given every 3 weeks for 12 cycles Clinical assessment every 6 weeks for 36 weeks Response assessment: CT scans are carried out post cycle 3 of chemo, and 1 month after completion of cycle 6 Follow up: 3 monthly years 1-2, 6 monthly years 3-5 *The carboplatin dose depends on the method used to obtain GFR. If GFR has been estimated, AUC=6, if GFR has been measured, AUC=5 **Bevacizumab can be omitted from the first cycle of if chemotherapy must be started within 4 weeks of surgery.

MITO-7 Weekly CT vs 3-weekly CT (QoL) Patients 25 / 500 Leading MITO
Participating MaNGO, AGO-OVAR

First line weekly carboplatin and paclitaxel vs every 3 weeks carboplatin/paclitaxel in patients with ovarian cancer: the MITO – 7 trial Aim of the trial is to compare the two schedules in terms of quality of life Risk of progression at 18 months as primary end-point Carboplatin AUC 6 Paclitaxel 175 mg/mq RANDOM day 1 - every 21days Carboplatin AUC 2 Paclitaxel 60 mg/mq day 1, every 21days

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

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)

Administrative information and status of the trial
NCI of Naples is the sponsor Study started November The expected duration of the study: 20 months 49 centers (43 MITO; 6 MANGO), 5 open 25 patients enrolled

Pathway to diagnosis of ovarian cancer: an observational retrospective multicentered study MITO Nursing

Study objectives Describe frequency and duration of symptoms in the 12 months preceding ovarian cancer diagnosis Describe time intervals (weeks) of sentinel events onset of first persistent symptoms first physician visit Cyto-histological diagnosis of ovarian cancer Classify diagnostic delays according to the expanded Andersen’s model of total patient delay.

Patient compilation of ovarian cancer symptom survey
Methods Patient compilation of ovarian cancer symptom survey Review of clinical documentation Directed patient interview1 Corner J, Hopkinson J, Fitzsimmons D, Barcaly s, Muers M (2005). Is late diagnosis of lung cancer inevitable? Interview study of patients’ recollections of symptoms before diagnosis. Thorax 60:

Time Intervals in weeks
Pathway to diagnosis of ovarian cancer: an exploratory study Time Intervals in weeks

Coordinating centre: Clinical Trials Unit National Cancer Institute Naples
Web-based procedures Register to be authorized user Identify study of interest (MITO nursing) Download documents and submit for Ethics Committee evaluation Study data entry Research nurse coordinator:

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

Planned Japanese IP Trial
Epithelial Ovarian Cancer Stages II-IV Excluding Clear Cell Carcinoma Randomization 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 Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL, Cost

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

NCIC CTG OV21 Helen Mackay
Phase II/III Study of IP/IV Chemotherapy versus IV Chemotherapy in Patients with Epithelial Ovarian Cancer Optimally Debulked Following Neoadjuvant Chemotherapy NCIC CTG OV21 Helen Mackay

Participating Centres
Lead group – NCIC CTG Collaborators – NCRI (UK), GEICO (Spain) Canada UK USA? Spain

Rationale 21.6% overall decrease in risk of death after primary surgery with IP cisplatin-based treatment Many EOC patients receive neoadjuvant systemic treatment before debulking is attempted. EORTC trial: neoadjuvant=upfront with lower morbidity!!! Patients undergoing neoadjuvant chemotherapy not included in IP studies

Do EOC patients who have received neoadjuvant chemotherapy benefit from IP therapy?

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

Then….. R IV Carbo IV Taxol IP Carbo (Taxol) IV Taxol
IP Cisplatin (Taxol) IV Taxol Phase II Then…..

This or….. R IV Carbo IV Taxol IP Carbo (Taxol) IV Taxol
IP Cisplatin (Taxol) IV Taxol Phase II Phase III IV Carbo IV Taxol IP Carbo (Taxol) IV Taxol

This….. R IV Carbo IV Taxol IP Carbo (Taxol) IV Taxol
IP Cisplatin (Taxol) IV Taxol Phase II Phase III IP Cisplatin (Taxol) IV Taxol IV Carbo IV Taxol

Phase II: Endpoints for selecting IP arm.
9-month progression rate post randomization Completion rate of treatment Toxic effects Feasibility

Phase III endpoints Primary Endpoint: Progression free survival
Secondary Endpoints: Overall survival Toxic effects Quality of life

Key Eligibility Criteria
Histologically confirmed initial FIGO stage IIB-IV EOC, peritoneal or fallopian tube cancer 3-4 cycles neoadjuvant platinum based chemotherapy TAH,BSO and cytoreductive surgery with residual disease 1 cm or less. Adequate organ function ECOG 2 or less 7 days prior to randomisation

Study Arms: Phase II Arm 1
Day 1:Paclitaxel 135 mg/m2 IV day 1 plus carboplatin AUC 5 (measured)/ AUC 6 (calculated) IV Day 8:Paclitaxel 60 mg/m2 IV day 8 Q 21 days x 3 cycles

Study Arms: Phase II Arm 2 Day 1: Paclitaxel 135 mg/m2 IV plus Cisplatin 75 mg/m2 IP Day 8: Paclitaxel 60 mg/m2 IP Q 21 days x 3 cycles

Study Arms: Phase II Arm 3
Day 1: Paclitaxel 135 mg/m2 IV plus carboplatin AUC 5 (measured)/ AUC (calculated) IV IP Day 8: Paclitaxel 60 mg/m2 IP Q 21 days x 3 cycles

Statistics Phase III Portion
Progression free survival: Seek improvement of IP over control with hazard ratio of 0.8 (Median increase PFS 4.3 mo, mo) 80% power, 2-sided alpha 0.05 Need 631 progression events To detect need additional 630 patients randomized after phase II completed Overall Survival: Same numbers will detect hazard ratio of 0.80 once 631 deaths seen (10 month increase in median survival) Total no of patients =780

Other points!! Correlative studies Quality of Life Economic analysis
Nursing studies

OV.21 – Nursing Study Objectives: Correlate nursing practices associated with IP therapy with treatment efficacy, toxic effects and quality of life. Rationale To date there are no trial based evidence that defines best nursing practice related to administration of IP chemotherapy Design Questionaire Patient positioning during and after administration of IP therapy The pre-warming of IP fluid The use of home hydration practices after administration of IP therapy.

Plan Protocol: at final stage of development
Planned Health Canada submission: May 2009 Anticipated central activation: July/August 2009 IP guidelines developed to accompany study

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

AGO-OVAR12 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 paclitaxelin patients with advanced ovarian cancer C T C T C T C T C T C T = Vargatef 2 x 200 mg po qd 2 SURGERY 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 R C = Carboplatin AUC d1 T = Paclitaxel 175 mg/m2 (3h) d1 q21d / 6 courses 1 C T C T C T C T C T C T = Placebo n=1300  120 weeks

Participating groups:
AGO Study Group AGO Austria BGOG GINECO MANGO MITO NSGO US Oncology First patient in: September 2009 Recruitment: 0/1300

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

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

Participating groups:
AGO Study Group AGO Austria ANZGOG BGOG GEICO GINECO ICORG JGOG KGOG MANGO MITO NSGO US-Sites: California Consortium, NY GOG, SWOG First patient in: June 2009 Recruitment: 0/900

ICON8 Stage 1 trial design
Randomisation weighted in favour of research arms 1:2:2:2:2:2 Number of patients requires further discussion on what is needed to demonstrate feasibility GOG218 15m bevacizumab 15mg/kg (concurrent and extended) or bevacizuamb 15mg/kg 6 cycles (concurrent only) ICON7 12 months treatment with bevacizumab 7.5mg/kg ICON8: bevacizumab 7.5mg/kg for 6 cycles (concurrent only) Primary surgery Randomised after surgery NAC Randomised before neoadjuvant chemo to 3 cycles chemo, surgery, then 3 cycles chemo) ARM1: C q 3/52 P q 3/52 ARM2: C q 3/52 P q 3/52 Bevacizumab q 3/52 ARM3: C q 3/52 P q 1/52 ARM4: C q 3/52 P q 1/52 Bevacizumab q 3/52 ARM5: C q 1/52 ARM6: C q 1/52 Bevacizumab q 3/52 Standard ~GOG218 & ICON7 Proposed MITO Novel JGOG study NOVEL Aim of stage 1 is to establish which arms should be taken into stage 2 based. Primary outcome measures: Toxicity Feasibility

ICON8 Stage 2 trial design
if ICON7 and GOG 218 are positive are ‘positive’ for PFS Option 1 2:1 randomisation* Total patients Primary surgery Randomised after surgery NAC Randomised before chemo to 3 cycles chemo, surgery, then 3 cycles chemo) ARM2: C q 3/52 P q 3/52 Bevacizumab q 3/52 ARM3: C q 3/52 P q 1/52 ARM4: C q 3/52 P q 1/52 Bevacizumab q 3/52 ARM5: C q 1/52 ARM6: C q 1/52 Bevacizumab q 3/52 ~GOG218 & ICON7 Proposed MITO NOVEL JGOG study GOG218 concurrent arm not worse than control will provide support for 6 cycles of bevacizumab Subgroup analyses to explore effect of effect of treatments in subgroups defined by primary surgery or NAC PRIMARY OUTCOME MEASURE: OS SECONDARY OUTCOME MEASURES: PFS TOXICITY HE QOL TR 2:1 randomisation in favour of standard arm ( 800 patients) and 400 in each research arm gives 1,200 patients in each pairwise comparison loses a little power but will save patients (total 2000)

ICON 8 If bevacizumab trials ‘negative’ for PFS
3 arm 1:1: 1 randomisation 600 patients per arm, Total yrs recruitment 2 years follow up Primary surgery Randomised after surgery Neoadjuvant chemotherapy randomised before chemo to 3 cycles chemo, surgery, then 3 cycles chemo) ARM1: C q 3/52 P q 3/52 ARM3: C q 3/52 P q 1/52 ARM5: C q 1/52 3 weeks out of 4 Standard Proposed MITO JGOG study Aim of trial is to compare efficacy of dose dense chemotherapy against standard 3 weekly regimens (Arm 1 vs Arm 2 and Arm 1 vs Arm 3 If dose dense regimens both better than standard, compare dose dense paclitaxel with dose dense carboplatin and paclitaxel (Arm 2 vs Arm 3) Subgroup analyses to explore effect of effect of treatments in subgroups defined by primary surgery or NAC Primary outcome measure: OS Secondary outcome measures: PFS Toxicity HE QoL TR

Platinum-sensitive Recurrence
Ovarian Cancer Closed Trials Open Trials Platinum-sensitive Recurrence Surgery Chemotherapy AGO-OVAR OP-2 Desktop II AGO-OVAR OP-7 Desktop III CALYPSO HECTOR C-Topo vs CT or CG ICON-6 MITO-8 SGCTG / NCRI Platinum-resistant Recurrence

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

AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) Platinum-free-interval
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 R A N D O M Cytoreductive surgery 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

AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) Secondary objectives:
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

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, 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

Inclusion criteria (2): Complete resection seems feasible and a positive AGO-score: (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 feasible. Intra-abdominal disease has to be excluded by MRI/CT, if other surgical approaches for extra-abdominal recurrences only are planned Patient is willing to accept result of randomisation Age > 18 years, signed and written informed consent

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

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)

Datamanagemt and Randomisation: e-CRF (MACRO) Central Monitoring Statistics: HR 0.7 favouring surgery Sample size: 385 patients/244 events Recruitment: 36 months Participating groups from GCIG: - protocol will be sent out soon to everybody Again no full funding - participating groups have to pay local costs

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

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

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

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 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

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)

Administrative information and status of the trial
NCI of Naples is the sponsor Study started November The expected duration of the study: 20 months 56 centers (43 MITO; 7 MANGO, 6 Belgium), 12 open 3 patients enrolled AGO grant application ongoing

Thank you for your attention

Dose reductions and Drug stoppages
9/24 patients continue on 30mg trial drug 8/24 patients had a dose reduction 6 continue on 20mg. 7/24 patients stopped trial drug permanently 5 not dose reduced prior to stopping. Of those patients who stopped: 1 progressed 1 had an allergic reaction to the trial drug 1 patient refused to restart trial drug 4 stopped on account of toxicity.

Toxicities The most common toxicities have been fatigue and diarrhoea.
Other G3 toxicities include: Alopecia Nausea Neutropaenia Mucositis Leukocytes Headache Dehydration Hypokalemia ALT/AST Elevation Pain Anorexia Dyspnoea

Dose decision AZ strategic decision to use 20mg cediranib in ongoing CRC trial program NCIC will use 20mg in combination with carboplatin and paclitaxel for new NSCLC trial Review of blinded data from ICON6 suggested that many patients were requiring dose modifications but 20mg dose appeared well tolerated Protocol amendment to reduce starting dose to 20mg/day

IDMC and TSC IDMC meeting 5 November TSC Protocol amendment submitted
Formal feedback to TSC awaited- informally IDMC supported TMG recommendation Dose reduction to 20mg for all randomised patients as soon as practical Patients not at risk of immediate toxicity if managed according to protocol guidelines Data on 50 patients randomised at 20mg dose required for extended stage 1 analysis More sites in UK and Canada can be recruited to speed accrual TSC Discussions with TSC Chair no objection to proposals Formal approval at TSC meeting 18 November Protocol amendment submitted

Trial Status 9 Centres Open 6 UK 3 Canada 31 patients recruited. Item
Timelines – Updated November 2008 First patient in UK December 2007 First patient in Canada July 2008 TMG recommendation to reduce dose October 2008 IDMC Review November Revised Stage I Analysis Sept 2009 Request statements of interest from Stage 2 groups April 2009 Draft contracts prepared for interested GCIG groups May - August 2009 Meetings with individual groups May – September 2009 Activation of stage 2 groups November 2009 Second stage analysis Was planned for Dec-10 Last patient randomised Was planned for Dec-12 Last patient completed treatment Was planned for Jun-13 Data mature for final analysis Was planned for Dec-13 Results available May Dec 2014 Trial Status 9 Centres Open 6 UK 3 Canada 31 patients recruited.

ICON6:Multistage design
Gynaecologic Cancer Intergroup Trial: MRC/NCRI, NCIC, ANZ-GOG, IMN, EORTC, GINECO, GEICO, MANGO, NSGO, ICMB Stage I Safety analysis after ~33 patients entered into B &C OPEN 5 sites in UK & 5 in Canada 1/08 Stage II ( ~50 deaths - 90 events) Progression-free survival (PFS) Overall survival (OS) Stage III (~ 2000 patients) Overall survival (OS) Progression-free survival (PFS) Toxicity Quality of life Health economics Molecular genetics

SGCTG/NCRI GCIG 29th May A Randomised Phase III Trial of Weekly Carboplatin and Paclitaxel versus Pegylated Liposomal Doxorubicin In Recurrent, Platinum Resistant, Ovarian Cancer Ros Glasspool SGCTG Andrew Clamp NCRI Hani Gabra SGCTG

Ovarian Cancer Diagnosis Surgery First-line Chemotherapy Consolidation
Closed Trials Open Trials Diagnosis Surgery First-line Chemotherapy Consolidation Platinum-sensitive Recurrence Surgery Chemotherapy Platinum-resistant Recurrence AGO-OVAR-9 CT ± GEM EORTC 55041 Tarceva SCOTROC-4 GOG-218 ICON-7 JGOG-3017 Clear cell carcinoma mEOC MITO-7 AGO-OVAR-12 AGO-OVAR-16 VEG JGOG IP Trial AGO-OVAR OP-7 Desktop III SGCTG / NCRI HECTOR C-Topo vs CT or CG ICON-6 MITO-8 AGO-OVAR OP-2 Desktop II CALYPSO

UPDATE ON GCIG TRIALS FOR EPITHELIAL OVARIAN CANCER
GCIG has demonstrated to perform very efficient important clinical trials which have changed the standard of care in the treatment of ovarian cancer Main focus has been first-line chemotherapy Surgical questions have been raised recently Treatment options in platinum-resistant recurrent disease should be further develloped

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UPDATE ON GCIG TRIALS FOR EPITHELIAL OVARIAN CANCER

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