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Ovarian Committee Closed Trials EORTC 55971/CHORUS Upfront Surgery vs Neoadjuvant Chemotherapy Patients closed / 550 Leading EORTC Participating NCIC CTG Presentation planned at IGCS 2008 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 (AGO DESKTOP OVAR II) Validation of a score of predictive factors for complete resection in platinum-sensitive recurrent ovarian cancer A project of the AGO Kommission OVAR AGO Study Group Ovarian Cancer (AGO-OVAR) Nordostdeutsche Gesellschaft f. Gyn. Onkologie (NOGGO) Arbeitsgemeinschaft Gyn. Onkologie Austria (AGO-Austria) Multicenter Italian Trials in Ovarian Cancer (MITO) An open-label prospective multicenter-trial © P. Harter 2008 AGO DESKTOP OVAR II - BACKGROUND • what is the surgical endpoint ? 1 0,9 survival probability 0,8 no residuals median OS 45.2 mos. 0,7 0,6 0,5 0,4 0,3 0 vs. 1-10 mm: 0,2 HR: 4.17 (CI 2,42 - 7,16); p < 0.001 0,1 0 vs. 10+ mm: HR: 3.31 (CI 1,86 - 5,88); p < 0.001 residuals > 10 mm median OS 19.7 mos. residuals 1 - 10 mm median OS 19.6 mos. 0 0 12 DESKTOP OVAR I 24 36 48 months © P. Harter 2008 AGO DESKTOP OVAR II: DESIGN • PS ECOG = 0 • no residuals after primary surgery (or, if unknown: initially FIGO I/II) • absence of ascites > 500 ml Surgery is planned ? Yes No (basic collective 1) predictive score positive (all items) ? Yes (CRR 79%) Laparotomy calculated numbers (1st endpoint): No (CRR 43%) 110 pts. with positive score and a complete resection rate (CRR) of at least 75% will show only descriptive analysis of further therapy with 95% probability that a positive score can predict CR in >2 of 3 pts. Platinum-based combination chemotherapy © P. Harter 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%) Surgery 148 pts (57%) Study collective: AGO score + 1st relapse 129 pts (87%) No surgery 113 pts (43%) 2nd relapse 19 pts (13%) Score negative 255 pts (49%) Surgery 80 pts (31%) 1st relapse 64 pts (80%) No surgery 175 pts (69%) 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%) © P. Harter 2008 AGO DESKTOP OVAR II – SURGICAL RESULTS Frequency of complete resection by applying the AGO Score 100 90 80 DESKT Hypoth 70 60 50 40 75 76 Score positive Score positive Score positive all patients 1st relapse 2nd relapse 30 68 20 10 0 complete resection in 76% of the study collective = AGO score could predict complete resection in at least 2 out of 3 patients © P. Harter 2008 AGO DESKTOP OVAR II: CONCLUSIONS • The DESKTOP II trial has shown that 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 © P. Harter 2008 AGO-OVAR OP.4 (AGO DESKTOP OVAR III) Prospectively randomized evaluation of cytoreductive surgery as adjunct preceding standard platinum-based chemotherapy in platinum-sensitive recurrent cancer of the ovary, fallopian tube, or peritoneum AGO Study Group Ovarian Cancer (AGO-OVAR) An open-label prospectively randomized phase III multicenter-trial © P. Harter 2008 AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer Platinum-sensitive recurrent cancer of the ovaries, fallopian tubes, or peritoneum PFI > 6 mos since first chemotherapy which was Platinum-based No prior chemotherapy for this 1st relapse Complete resection seems feasible and positive AGO score: • PS ECOG 0 • no ascites > 500 ml • prior complete debulking or initial FIGO I/II (if data available) R A N D O M Cytoreductive surgery n ~ 300 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 © P. Harter 2008 DESKTOP III – the next steps • • • • Protocol development GCIG discussion Ethical approval Germany First patient in 12/08 01/09 02/08 04/08 © P. Harter 2008 DESKTOP III – the next steps Interested in participation as single center or GCIG group ? E-mail: [email protected] © P. Harter 2008 Tarceva Trial EORTC 55041 Tarceva consolidation 2 years Primary Chemotherapy Control Patients closed / 835 Leading EORTC Participating AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO 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?? AGO-OVAR-9 Carbo Paclitaxel +/- Gemcitabine Patients closed 1742 Leading AGO-OVAR Participating GINECO, NSGO, Open Trials SCOTROC 4 Carbo Flat Dosing vs Intrapatient Dose Escalation Patients 930 / 1300 Leading SGCTG Participating ANZGOG ICON-7 TC ± BEVACIZUMAB Patients 1200 / 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 1350 / 1800 Leading GOG Participating ECOG, NCCTG, NSABP, SWOG JGOG-3017 Clear Cell Carcinoma CT vs CDDP + Irinotecan Patients 271/600 Leading JGOG Participating GINECO, GOG, KGOG, MITO, SGCTG 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 Study Co-Chair Toru Sugiyama, MD (Iwate Medical University) Seiji Isonishi, MD (Jikei University School of Medicine) Fumitoshi Terauchi, MD (Toho University) GCIG Study -Clear Cell Ca -Stage I~IV RANDOMIZATION International Cooperative Phase III Study for Clear Cell Carcinoma TC Paclitaxel 175 mg/m2 (d1) Carboplatin AUC 6 (d1) Every 3 wk x 6 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 JGOG 259 KGOG 13 As of 11/13/2008 JGOG3017/GCIG Trial • Progress – May 2008 International DMC – August 2008 • International Web based Central Pathology Review HECTOR Carbo Topo vs Chemo (CT or CG) in recurrent Platinum-sensitive ovarian cancer Patients 304/ 550 Leading NOGGO/AGO-OVAR Participating AGO-AUSTRIA, GEICO AGO – OVAR OP.3 (LION) Lymphadenectomy In Ovarian Neoplasms epithelial invasive ovarian cancer System. Lymphadenectomy pelvic FIGO IIB - IV para-aortic ethical approval 8/2008 ECOG 0/1 and R no CI against LNE First patient in December no visible extraand intra-abdominal tumor residuals n = 640 no Lymphadenectomy no bulky lymph nodes Endpoints: OS, PFS, QoL, toxicity/complications Strata: centre, PS ,age LION –the next steps 1st patient in: 11/08 LION receives public funding limited to national trials (and sites), therefore, international participation Should be planned as cooperative studies. We could offer every study group or centre that wants to conduct a „similar-to-LION – protocol“ - Complete protocol - Complete CRF - joint analysis Eligible consenting patient relapsing > 6 months after completion of first treatment RANDOMISE 2:3:3 Arm A (Reference Arm) 6 cycles of chemotherapy* plus Placebo during chemotherapy Placebo for a maximum of 18 months from randomisation, or until progressive disease Arm B 6 cycles of chemotherapy * plus cediranib during chemotherapy Placebo for a maximum of 18 months from randomisation, or until progressive disease Follow up visits: Every 3 months until protocol defined disease progression, then 6 monthly for up to 5 years after randomisation, then annually Arm C 6 cycles of chemotherapy * plus cediranib during chemotherapy Cediranib for a maximum of 18 months from randomisation, or until progressive disease First Stage: Primary outcome measure: Second Stage: Primary outcome measure: Secondary outcome measures: Toxicity Third Stage: Primary outcome measure: Secondary outcome measures: Ancilliary Studies: Health Economics (HE) Translational Research (TR) Safety Progression-Free Survival (PFS) Overall Survival (OS) and Overall Survival (OS) Progression Free Survival(PFS) Quality of Life (QoL)Toxicity 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 – 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 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 5 2008 Revised Stage I Analysis Sept 2009 Request statements of interest from Stage 2 groups April 2009 Draft contracts prepared for interested GCIG groups Trial Status 9 Centres Open 6 UK 3 Canada 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 2014 - Dec 2014 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 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 OPEN 5 sites in UK & 5 in Canada 1/08 PlannedTrials 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) Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 21-day cycles Oxaliplatin 130 mg/m2 Capecitabine 850mg/m2 bd 6 21-day cycles Clinical assessment every 6 weeks for 36 weeks Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 21-day cycles 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 Bevacizumab 7.5mg/kg given every 3 weeks for 5 or 6** cycles 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. Prospective International Sites UK ( NCRI/ SGCTG) GOG Group Country GINECO France AGO Germany MaNGO Italy MITO Italy NSGO KGOG Denmark Sweden Finland Norway Korea New MITO Projects 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 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: 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 NCI of Naples is the coordinating centre Study started November 10 2008 The expected duration of the study: 20 months 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 CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/mq day1 every 28 days 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 informations NCI of Naples is the coordinating centre Started November 10 2008 The expected duration of study: 4 years Thank you for your attention http://www.mito-group.it Multicenter, randomised, double-blind, Phase III trial to investigate the efficacy and safety of BIBF 1120 (Vargatef) in combination with standard treatment of carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in patients with advanced ovarian cancer AGO - OVAR12 / 1199.15 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 AGO - OVAR16 / VEG110655 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, Diane Provencher, Mark Heywood, Chris Gallagher, Jonathan Ledermann, Ana Oaknin, ?Maurie Markman Dongsheng Tu, Ding Chen 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-led GCIG 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? Trial PFS IV SWOG 8501/ GOG 104 GOG114 SWOG 9227 GOG 172 IP OS Median (months) P HR Median (months) P HR .02 .76 .05 .81 .03 .75 Cyclo 600 mg/m2 IV q 21 days x 6 Cisplatin 100 mg/m2 IP q 21 days x 6 NS NS NS 49 Cyclo 600 mg/m2 IV + cis 100 mg/m2 IV q 21 days x 6 None NS NS NS 41 CarboAUC 9 IV x 2 cycles; paclitaxel 135 mg/m2 IV 24 hrs day 1 q 21 days x6 Cis 100 mg/m2 IP day 2 q 21 days x 6 cycles 27.9 .01 .78 63.2 Paclitaxel 135 mg/m2 IV 24 hrs day 1; cis 75 mg/m2 IV day 2 q 21 days x 6 None 22.2 Paclitaxel 135 mg/m2 IV 24 hrs day 1 Cis 100 mg/m2 IP day 2 q 21 days x 6 ; paclitaxel 60 mg/m2 IP day 8 23.8 Paclitaxel 135 mg/m2 IV 24 hrs day 1; cisplatin 75 mg/m2 IV day 2 None 18.3 52.2 .05 .80 65.6 49.7 EORTC-led GCIG Trial Overall Survival: NACT + delayed debulking vs. Primary debulking (Standard) NACT approach associated with significantly LESS Post-op sepsis Post-op (1-28 d) mortality Gr 3/4 Bleeding Gr 3/4 Thromboembolism Vergote IGCS 2008 Basic Design Patients with EOC 3-4 cycles neoadjuvant chemo Initial surgery: < 1 cm residual 3 cycles 3 cycles IP/IV IV Carbo/Taxol platinum and taxol Endpoints: PFS and OS Design Issues Questions Which IP platinum? • some interested in carboplatin based • some prefer cisplatin based Day 8 Taxol? (JGOG data suggest this may be important and part of impact of Armstrong regimen) Dose IP cisplatin (75 or 100?) Design Issues Questions Solutions Which IP platinum? • some interested in carboplatin based • some prefer cisplatin based Use phase II III design and evaluate carboplatin vs. cisplatin in phase II portion so decision evidence based Day 8 Taxol? (JGOG data suggest this may be important and part of impact of Armstrong regimen) Add day 8 Taxol to ALL study arms Dose IP cisplatin (75 or 100?) Select 75 as dose since exposure still enhanced, toxicity less and this is in keeping with practice R Phase II IV Carbo IP Carbo (Taxol) IP Cisplatin (Taxol) IV Taxol IV Taxol IV Taxol Then….. This or….. Phase II R IV Carbo IP Carbo (Taxol) IP Cisplatin (Taxol) IV Taxol IV Taxol IV Taxol Phase III IV Carbo IP Carbo (Taxol) IV Taxol IV Taxol This….. Phase II R IV Carbo IP Carbo (Taxol) IP Cisplatin (Taxol) IV Taxol IV Taxol IV Taxol Phase III IV Carbo IV Taxol IP Cisplatin (Taxol) IV Taxol Details: Phase II Arms/Doses Arm 1 (control) Paclitaxel 135 mg/m2 (3 hr) IV day 1 Carboplatin AUC 5(6) IV day 1 Paclitaxel 60 mg/m2 IV day 8 Arm 2: IP cisplatin based: Paclitaxel 135 mg/m2 (3 hr) IV day 1 Cisplatin 75 mg/m2 IP day 1 Paclitaxel 60 mg/m2 IP day 8 Arm 3: IP carboplatin based: Paclitaxel 135 mg/m2 (3 hr) IV d1 Carboplatin AUC 5(6) IP day 1 Paclitaxel 60 mg/m2 IP day 8 Repeat q 3 wk x 3 cycles Phase II: Endpoints for selecting IP arm • 9-month progression rate post randomization • Completion rate of treatment (feasibility): to assess toxic effects and technical issues Standard Therapy Patients with EOC 3-4 cycles neoadjuvant chemo Initial surgery: < 1 cm residual 3 cycles IV Carbo/Taxol 9 mo at 9 mo post debulking, normally expect ~40% pts to have progressed (based on NCIC CTG and NCRI data) Phase III endpoints Primary Endpoint: • Progression free survival Secondary Endpoints: • Overall survival • Toxic effects • Quality of life • Translational research • Health Economic evaluation Key Eligibility Criteria • Histologically confirmed initial FIGO stage IIB-III (?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. Must be completed ≤ 4 weeks prior prior to randomization • Adequate organ function • Imaging after surgery prior to first cycle • ECOG 2 or less 7 days prior to randomization • QoL questionaire • Note: if randomized in OR, must satisfy safety related eligibility before IP treatment starts Key Ineligibility Criteria • Prior chemotherapy for ovarian cancer (other than neoadjuvant) • Borderline histology • CCF/ventricular arrhythmias • Bowel obstruction • At surgery Left sided bowel resection Extensive intra/post operative adhesions • Experience with prior chemotherapy > grade 1 peripheral neuropathy prior allergic reaction Status • Study approved by: – – – – – NCIC CTG NCRI (Nov 12/08) GEICO SWOG committee (but no CTEP submission yet) Interest in other groups??? (NB: no external funding) • Protocol drafted and in mature form • IP guideline first draft • Need: – – – – CTEP review/approval CTA submissions etc IP workshop? EDC training Discussion 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 based on efficacy and tolerability • Efficacy: – The primary endpoint is the rate of PD at 9 months post randomization – 50 patients per arm: we have 90% power to detect the “winner” the arm with true PD rate 12% lower than the other – Also with this number, we have 80% power to test null hypothesis that true PD rate is 52.5% or more (and thus non-interesting--reject) versus alternative that PD rate is 35% or lower (interesting). • Feasibility: not feasible if fewer than 50% patients can complete planned IP therapy Statistics Phase III Portion • Progression free survival: – Seek improvement of IP over control with hazard ratio of 0.8 (Median 1721.3 mo) – 80% power, 2-sided alpha 0.05 – Need 631 progression events (if one sided alpha: need 497 progression events) – To detect need an additional 630 patients randomized (490 additional if one-sided alpha) (assuming 200 patients per year recruited) after phase II completed – Overall Survival: Same numbers will detect hazard ratio of 0.80 once 631 (or 497) deaths seen The p-value of one-sided test for null hypothesis that 9 month PD rate of patients on this arm is 52.5% or higher will be first reviewed for each arm: 1. If it is significant for both IP study arms, completion rate of IP treatment for both will be examined: a. If stopping rule specified above is not met for any of them, the arm with lower PD rate will be declared as the winner and the experimental arm for phase III part of this study; b. If only one arm meets the stopping rule, the other arm will be declared as the winner and the experimental arm for phase III part of this study, regardless of its 9 month PD rate; c. If both arms meet the stopping rule, neither of the IP arms will be picked and trial will not proceed to phase III. 2. If it is significant for one of the IP study arms and this arm does not meet the stopping rule based on completion rate of IP treatment, it will be declared as the winner and the experimental arm for phase III part of this study. Otherwise, the trial will not proceed to phase III. 3. If it is not significant for any of the IP study arms, the 9-month PD rate for IV arm will be examined to see whether patients recruited are of very bad prognosis. An IP treatment may be picked up as a winner based on above guideline regardless of the p-values of the tests. Statistics: Phase II Portion • 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 Study Question • To determine if 3 cycles of IV/IP chemotherapy improves progression free (PFS) and overall survival (OS) compared to 3 cycles of standard IV carboplatin/paclitaxel following optimal debulking at initial surgery performed after 3-4 cycles neoadjuvant chemotherapy in patients with EOC. • If positive, this trial would also offer evidence to support the use of only 3 IP cycles of treatment SGCTG/NCRI GCIG 29th May 2008 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