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 MucinousEOC – GOG 241 Jonathan Lederman NCIC CTG OV21: A Phase II/III Study of Intraperitoneal (Ip) Diane Provencher Plus 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 Glasspool carboplatin and paclitaxel versus pegylated liposomal doxorubicin in recurrent, platinum resistant, epithelial ovarian cancer

Closed Trials

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

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

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

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 (RECIST & GCIG CA125) and Overall Survival by Therapy within Stratum 2+3 (FIGO IIB-IV) TC 793 pts. / 588 evts. median 16.0 [14.9-17.4] mos. TCG 774 pts. / 629 evts. median 14.7 [14.0-15.9] mos. [months] HR = 1.03 [95% CI: 0.90-1.18] p = 0.6955 TC 793 pts. / 401 evts. median 48.9 [43.1-51.2] mos. TCG 774 pts. / 404 evts. median 45.8 [40.0-49.5] mos. P r o b a b i l i t y 1217 pat. mit CA125 Progresse / RECIST Progresse bei S2+S3 HR = 1.17 [95% CI: 1.05-1.31] p = 0.0065

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.

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

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

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

Progression-Free Survival (ITT) CD CP Median PFS, mo 11.3 9.4 HR (95% CI) 0.82 (0.72, 0.94) Log-rank p-value (superiority) 0.005 P-value (non-inferiority) <0.001

Open Trials

AGO – OVAR OP.3 (LION) Lymphadenectomy In Ovarian Neoplasms R 80/ 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 80/ 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

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

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

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

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

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)

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)

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)

Carbo Paclitaxel +/- BIBF 1120 (Vargatef) 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

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 paclitaxel patients with advanced ovarian cancer C T C T C T C T C T C T = Vargatef 2 x 200 mg po qd 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 5-6 d1 T = Paclitaxel 175 mg/m2 (3h) d1 q21d / 6 courses C T C T C T C T C T C T = Placebo n=1300  120 weeks

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

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

JGOG-3017 Clear Cell Carcinoma CT vs CDDP + Irinotecan Patients 396 / 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-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 326 patients in each arm, 652 total for 4.25 years

JGOG3017/GCIG Trial

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

Phase III multicenter trial First line weekly carboplatin and paclitaxel vs every 3 weeks carboplatin/paclitaxel in patients with ovarian cancer: Phase III multicenter trial 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 Carboplatin AUC 6 Paclitaxel 175 mg/mq RANDOM day 1 - every 21days Carboplatin AUC 2 Paclitaxel 60 mg/mq day 1,8 15 - every 21days

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

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)

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

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”

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

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)

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

Gynaecologic Cancer Intergroup Trial 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 Results of ICON 4 study demonstrated a survival advantage for combination chemotherapy in relapsed ovarian cancer for the first time. Following this a new trial was planned in second line treatment of ovarian cancer that would aim to improve survival, answer a number of key questions with a multi-arm multi-stage design and provide information to select agents for future first line therapy studies. Astra-zeneca were interested in evaluating cediranib in ovarian cancer and this was therefore selected.

cediranib after chemotherapy ICON 6 Design schema 2:3:3 RANDOMISATION 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 Maximum 18 months from randomisation ICON 6 Start up slides Oct 2009

Outcome measures Stage I- Safety Safety analysis after ~ 33 patients entered into Arms B & C at 20mg dose Stage II – Activity ~ 50 deaths, 90 events, ~ 450 patients Progression free survival (PFS) Overall survival (OS) Stage III- Confirmation of Efficacy Progression-free survival (PFS) Toxicity Quality of life, Health Economics, Translational substudies ICON 6 Start up slides Oct 2009

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 BR 24 – cediranib 30mg/d. Excess of toxicty in cediranib arm . PFS endpoint met for continuation into phase 3 in BR 24. Horizon 2 + 3 – planned end of phase 2 efficacy and tolerability analysis of patients in all 3 Horizon trials, undertaken by IDMC. IDMC stated that having observed tolerability and efficacy , it would have been appropriate to contine with 20mg or 30mg. Trial decided to contine with 20mg and idmc endorsed this. ICON 6 Start up slides Oct 2009

Recruitment Prediction Based on recruitment to date 450 new patients by Oct 2010 (550 patients in total) Stage 2 data maturity Expected 90 PFS events and 50 deaths in control arm would be observed by April 2011 CLINICAL TRIAL TR QoL HE Other groups

Summary Academic GCIG Trial with MRC/NCRI Group as lead group Coordinated by MRC CTU Sponsored by MRC (UK) UK CTAAC funding for MRC CTU Administrative support from AZ for international coordination Grant from AZ to cover coordination by GCIG groups and some per patient support After publication data may be used by AZ to support license extension AZ support for TR sample collection at Stage 2 - under discussion ICON 6 Start up slides Oct 2009

Planned Trials

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”

MITO 12 – Groups involved MaNGo (8 centers) Others? 58 patients enrolled

Phase II randomized multicenter trial 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 Paclitaxel 80 mg/mq day 1, 8, 15 - every 28 days RANDOM Pazopanib 800 mg/day Paclitaxel 80 mg/mq day 1,8 15 - every 28days

Statistics Phase 2 open-label multicentre trial Assuming a median PFS in the control arm equal to 3 months (Kristensen ASCO 2008) and a median PFS in the experimental arm equal to 4.6 months (corresponding to a Hazard ratio of 0.65) 61 events are required (East 5 software). With a possible accrual rate of 4 patients/month, 72 patients (36 for each arm) will be enrolled in about 1.5 year Planned to start December 2009

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

Intraperitoneal Trial Under Planning at JGOG

IP Trial under Planning in JGOG IntraPeritoneal therapy for Ovarian Cancer with Carboplatin (iPocc) Phase II/III Design Eligibility Ovarian, Peritoneal and Fallopian Tube Stage II, III, and IV Optimal and Suboptimal Targeting Accrual 754 during 3 years 120 patients for Phase II component First enrollment January 2010

iPocc Trial Design Primary Endpoint: PFS Epithelial Ovarian, Peritoneal, Fallopian Tube Cancer Stages II-IV Optimal, Suboptimal 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

AGO-OVAR-OP DESKTOP IV recurrent ovarian cancer Patients 0/? Leading AGO-OVAR Participating ?

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 GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/- bevacizumab compared with oxaliplatin and capecitabine +/- bevacizumab as first line chemotherapy in patients with mucinous Epithelial Ovarian Cancer (mEOC) Cancer Research UK & UCL Cancer Trials Centre

mEOC Trial Objectives Cancer Research UK & UCL Cancer Trials Centre The mEOC study is a multi-national collaboration with the Gynecologic Oncology Group, USA (GOG -0241) Primary Aims: Does chemotherapy with oxaliplatin + capecitabine improve the survival of patients with mucinous ovarian cancer, compared to standard chemotherapy with carboplatin + paclitaxel. In addition whether bevacizumab improves overall survival of patients with mucinous epithelial ovarian cancer. Secondary Objectives: Progression free survival, response rates, toxicity, quality of life (QoL) QoL: All patients will be assessed using FACT-O TOI, FACT/GOG-NTX Subscale and EQ-5D QoL questionnaires. Translational research: Patients may opt to donate a sample of their tumour taken at time of surgery, for future research. 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 x 21-day cycles Bevacizumab 15mg/kg given every 3 weeks for 5 or 6** cycles Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 x 21-day cycles Oxaliplatin 130 mg/m2 Capecitabine 850mg/m2 bd 6 x 21-day cycles Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 x 21-day cycles Bevacizumab 15mg/kg given every 3 weeks for 5 or 6** cycles Clinical assessment every 6 weeks for 36 weeks Telephone call at week 3 between every 6-week visit Bevacizumab 15mg/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, 1 month after completion of cycle 6, then 3 monthly for Year 1 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.

mEOC Trial Criteria Inclusion Criteria: Exclusion Criteria: Histological diagnosis of mucinous ovarian carcinoma FIGO stage II-IV Aged 18 or above Life expectancy >3 months No previous chemotherapy or radiotherapy Recurrent stage I ECOG performance status 0, 1 and 2 Fit for protocol treatments Urine dipstick for proteinuria <2+ Adequate coagulation parameters Exclusion Criteria: Histological diagnosis of non-mucinous ovarian carcinoma Previous history of malignancy except cervical carcinoma in situ, and basal cell carcinoma of the skin Concurrent uncontrolled medical condition Previous chemotherapy, radiotherapy or any investigational treatment for ovarian or rectal cancer. Symptoms or history of peripheral neuropathy Previous history of malabsorption or other conditions preventing oral treatment Clinically significant cardiac disease, including M.I. in last 12 months Criteria excluding bevacizumab therapy Cancer Research UK & UCL Cancer Trials Centre

Cancer Research UK & UCL Cancer Trials Centre mEOC 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 http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=4667 Contact Email: mEOC@ctc.ucl.ac.uk Cancer Research UK & UCL Cancer Trials Centre

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

A proposal by the NCRI and SGCTG ICON8 Outline Proposal for the next international, first-line ovarian cancer trial A proposal by the NCRI and SGCTG 74

Initial Outline Proposal To answer questions around Weekly paclitaxel (JOG, ASCO 2008 abs) Bevacizumab (ICON7/GOG218 abs 2010) Immediate & delayed primary surgery (EORTC 55971, IGCS 2008 abs, CHORUS – ongoing) Aim to maximise eligible population and questions answered Initial application for 6 arm adaptive multi-arm multi-stage design investigating dose-fractionated chemotherapy and bevcizumab declined Suggestion from CTAAC to reapply with simpler three arm trial without bevacizumab 75

(A) Immediate Primary Surgery (IPS) (B) Delayed Primary Surgery (DPS) Current Proposal ARM1: C q 3/52 P q 3/52 (current std) (A) Immediate Primary Surgery (IPS) (B) Delayed Primary Surgery (DPS) Surgery (IPS) Surgery (DPS) Chemotherapy (ARM 1-3 x 6) (Arm 1-3 x 3) One trial with pre-specified stratification for IPD v DPS ARM2: C q 3/52 P q 1/52 Randomisation ARM3: C q 1/52 P q 1/52 Plan to use lower dose of paclitaxel than JOG for arm 2: Carboplatin AUC6 d1Paclitaxel 60mg/m2 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/m2 76

Outcome Measures Primary Stage I Stage II: PFS and OS Feasibility of using dose-fractionated arms with both IPS and DPS >80% receive 6 cycles (lower limit of 90% CI not < 60%) >80% receive >90% planned dose intensity (lower limit of 90% CI not <60%) Toxicity (guide only at present) If G2 neuropathy and G3/4 other toxicities >15% then need to consider continuation Special consideration in DPS arm for surgical 30d mortality and morbidity Stage II: PFS and OS 77

Statistics Most current/planned trials (inc. ICON7, GOG218, MITO, JGOG trials) target HR of 0.75-0.80 Assumption median OS 36m for IPS and 30m DPS (poorer PS group) = 34m overall For HR of 0.75, p=0.025 (2 main comparisons) and 90% power 1590 patients are required Aim 2yr recruitment, 3yr follow up Open to option of prospective meta-analysis with other studies but ICON8 powered as single study 78

Current Situation Even if ICON7/GOG trials positive Outline application for funding pending Novelty of this trial is: weekly carboplatin and weekly paclitaxel arm Inclusion of IPS and DPS patients Even if ICON7/GOG trials positive Still many questions re dose, duration, cost-effectiveness etc and bevacizumab not suitable for all Large eligible population for this study therefore hopefully fast recruitment

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 0 / 780 Leading NCIC CTG Participating GEICO, NCRI, SWOG

A Gynecologic Cancer Intergroup (GCIG) Trial led by the NCIC CTG A PHASE II/III STUDY OF INTRAPERITONEAL (IP) PLUS INTRAVENOUS (IV) CHEMOTHERAPY VERSUS IV CARBOPLATIN PLUS PACLITAXEL IN PATIENTS WITH EPITHELIAL OVARIAN CANCER OPTIMALLY DEBULKED AT SURGERY FOLLOWING NEOADJUVANT INTRAVENOUS CHEMOTHERAPY: A Gynecologic Cancer Intergroup (GCIG) Trial led by the NCIC CTG NCIC CTG Protocol Number: OV.21 NCRI: UCL08/0379 GEICO: 0902

Central activation

NCIC CTG STUDY CO-CHAIRS: HELEN MACKAY DIANE PROVENCHER NCRI CO-CHAIR: CHRISTOPHER GALLAGHER GEICO CO-CHAIR: ANA OAKNIN TRIAL COMMITTEE: MARK HEYWOOD PHYSICIAN COORDINATOR: RALPH MEYER BIOSTATISTICIAN: DONGSHENG TU QUALITY OF LIFE COORDINATOR: LORI BROTTO COORDINATOR OF NURSING STUDY: LISA TINKER TRANSLATIONAL RESEARCH COORDINATOR: JEREMY SQUIRE STUDY COORDINATOR: CHAD WINCH SPONSOR: NCIC CTG

Rationale Although 21.6% overall decrease in risk of death after primary surgery with IP cisplatin-based treatment Cogent arguments against IP therapy Many EOC patients receive neoadjuvant systemic treatment before debulking is attempted. EORTC trial: neoadjuvant=upfront with lower morbidity!!! (abstract)

Our question Do EOC patients who have received neoadjuvant chemotherapy/optimal cytoreduction benefit from shorter course of IP therapy?

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

Phase II/II Study of IP/IV Chemotherapy, # 256 Belgrade, 11 octobre 2009 Basic Design Patients with EOC Optimal Surgery 3-4 cycles neoadjuvant chemo Shorter course R Initial surgery: < 1 cm residual 3 cycles IV Carbo/Taxol 3 cycles IP/IV platinum and taxol Day 8th Day 8th Endpoints: PFS and OS Drs Provencher et McKay

150 patients Transition: 150 pts Total : 830 pts

(use AUC 6 if calculated GFR) By gravity as rapidly as possible Phase II Patients will be randomized to one of the following three arms: Arm Agent(s) Dose Route Duration Schedule Days Repeat 1 Paclitaxel 135 mg/m2 IV 3 hours Day 1 Every 21 days 60 mg/m2 1 hour Day 8 Carboplatin AUC 5 if measured GFR (use AUC 6 if calculated GFR) 30 minutes* 2 IP By gravity as rapidly as possible Cisplatin 75 mg/m2 3 * or according to local practice

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

Statistics: Phase II Portion 50 patients in each of the 3 arms: Assesses ONLY the IP arms at time of analysis. Select the IP regimen for phase III based Efficacy: Assuming the highest 9 month PD rate in the two IP arms is 40%, using the “pick-the-winner” design we should have 90% chance to pick the true winner which has a 6 month PD rate at least 12% lower than the other. For the two IP arms, we will first test the null hypothesis that the true PD rate at 9 months is 52.5% or higher using a one-sided test at 0.05 level and then pick up the arm for phase III study by comparing their observed 9 month PD rates

Statistics: Phase II Portion Toxicity Tolerability criteria: Assess completion rate of IP treatment. Assume regimen would be interesting if >70% can complete 3 cycles and uninteresting if < 50% complete 3 cycles. Using these figures, arm(s) selected will be abandoned if >= 29/50 patients cannot complete IP therapy Accrual

How it will work! DSMC to review efficacy then completion rate, toxicity and accrual. Guideline for DSMC Both IP arms significant, examine completion rate for both: stopping rule not met in both arms WINNER = lowest PD rate one arm meets the stopping rule WINNER = Other arm If both arms meet the stopping rule NO WINNER study closes

Phase III Patients will be randomized to one of the following two arms: Arm Agent(s) Dose Route Duration Schedule Days Repeat 1 Paclitaxel 135 mg/m2 IV 3 hours Day 1 Every 21 days 60 mg/m2 1 hour Day 8 Carboplatin AUC 5 if measured GFR (use AUC 6 if calculated GFR) 30 minutes* 2 The selected IP arm from Phase II (regimen as in above table) * or according to local practice

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

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, 17 21.3 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

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.

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

PLEASE GET INVOLVED!!!!!!!!!!!

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

GCIG Belgrade Oct 2009 Ros Glasspool A Randomised Phase III Trial of Weekly Carboplatin and Paclitaxel versus Pegylated Liposomal Doxorubicin In Recurrent, Platinum Resistant, Ovarian Cancer DDPC- PREOC GCIG Belgrade Oct 2009 Ros Glasspool

Rationale for Trial High RR and long PFS in phase II studies and retrospective series of dose dense/ fractionated Paclitaxel/Carboplatin schedules Well tolerated No randomised trials Regimen RR % PFS months OS months Ref P90, C AUC4 day 1 and 8 q21 43 6.75 8 Cadron 2007 P90, C AUC4 Day 1, 8, 15 q28 x2 53 10 13 Van der Burg 2004 P80, C AUC 2 Day 1, 8, 15 q28 37.5 3.2   Havrilesky 2003 P70, C AUC 3 Day 1, 8, 15 q 28 60 7.9 13.3 Sharma 2009 PLDH 12.3 2.1 13.3 Gordon 2001 TFI <12 m 16 3.7 12.9 Ferrandina 2008 8.3 3.1 13.5 Mutch 2007

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 R A N D O M I S E 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

Trial Status Outline proposal submitted to the NIHR Health Technology Assessment (HTA) programme in July and decision expected Oct 2009.