1. Ovarian Committee

2. Closed Trials

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

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

5. © P. Harter 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 An open-label prospective multicenter-trial 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)

6. © P. Harter 2008 AGO DESKTOP OVAR II - BACKGROUND what is the surgical endpoint ? 0 vs. 1-10 mm: HR: 4.17 (CI 2,42 - 7,16); p < 0.001 0 vs. 10+ mm: HR: 3.31 (CI 1,86 - 5,88); p < 0.001 no residuals median OS 45.2 mos. residuals > 10 mm median OS 19.7 mos. residuals 1 - 10 mm median OS 19.6 mos. DESKTOP OVAR I Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006

7. © 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%) No (CRR 43%) Laparotomyonly descriptive analysis of further therapy Platinum-based combination chemotherapy * CRR: Results from DESKTOP-OVAR I calculated numbers (1st endpoint): 110 pts. with positive score and a complete resection rate (CRR) of at least 75% will show with 95% probability that a positive score can predict CR in >2 of 3 pts.

8. © P. Harter 2008 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%) 1st relapse 64 pts (80%) 2nd relapse 19 pts (13%) 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 – FLOW CHART Study collective: AGO score + 1st relapse 129 pts (87%)

9. © P. Harter 2008 Frequency of complete resection by applying the AGO Score AGO DESKTOP OVAR II – SURGICAL RESULTS complete resection in 76% of the study collective = AGO score could predict complete resection in at least 2 out of 3 patients DESKTOP Hypothesis

10. © 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

11. © 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 An open-label prospectively randomized phase III multicenter-trial AGO Study Group Ovarian Cancer (AGO-OVAR)

12. © 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) RANDOMRANDOM Cytoreductive surgery platinum-based chemotherapy* recommended * 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 no surgery n ~ 300

13. © P. Harter 2008 DESKTOP III – the next steps Protocol development 12/08 GCIG discussion01/09 Ethical approval Germany02/08 First patient in04/08

14. © P. Harter 2008 Interested in participation as single center or GCIG group ? E-mail: philipp.harter@hsk-wiesbaden.de DESKTOP III – the next steps

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

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

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

18. Open Trials

19. Carbo Flat Dosing vs Intrapatient Dose Escalation Patients 930 / 1300 Leading SGCTG Participating ANZGOG SCOTROC 4

20. TC ± BEVACIZUMAB Patients 1200 / 1520 Leading MRC/NCRI Participating NCIC CTG, AGO OVAR, GINECO, GEICO EORTC(?), ANZGOG, NSGO ICON-7

21. CT vs CT + Bevacizumab Placebo vs CT + Bevacizumab concurrent and extended Patients 1350 / 1800 Leading GOG Participating ECOG, NCCTG, NSABP, SWOG GOG 218

22. CT vs CDDP + Irinotecan Patients 271/600 Leading JGOG ParticipatingGINECO, GOG, KGOG, MITO, SGCTG JGOG-3017 Clear Cell Carcinoma

23. 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)

24. GCIG Study RANDOMIZATION TC Paclitaxel 175 mg/m 2 (d1) Carboplatin AUC 6 (d1) Every 3 wk x 6 CPT-11/CDDP CPT-11 60 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

25. JGOG3017/GCIG Trial As of 11/13/2008 JGOG 259 KGOG 13

26. JGOG3017/GCIG Trial Progress – May 2008 International DMC – August 2008 International Web based Central Pathology Review

27. Carbo Topo vs Chemo (CT or CG) in recurrent Platinum-sensitive ovarian cancer Patients 304/ 550 Leading NOGGO/AGO-OVAR Participating AGO-AUSTRIA, GEICO HECTOR

28. 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, toxicity/complications Strata: centre, PS,age Lymphadenectomy In Ovarian Neoplasms AGO – OVAR OP.3 (LION) n = 640 ethical approval 8/2008 First patient in December

29. 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

31. 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.

32. 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

33. 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

34. 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

35. Trial Status 9 Centres Open 6 UK 3 Canada 31 patients recruited. ItemTimelines – Updated November 2008 First patient in UKDecember 2007 First patient in CanadaJuly 2008 TMG recommendation to reduce doseOctober 2008 IDMC ReviewNovember 5 2008 Revised Stage I AnalysisSept 2009 Request statements of interest from Stage 2 groupsApril 2009 Draft contracts prepared for interested GCIG groups May - August 2009 Meetings with individual groupsMay – September 2009 Activation of stage 2 groupsNovember 2009 Second stage analysisWas planned for Dec-10 Last patient randomisedWas planned for Dec-12 Last patient completed treatmentWas planned for Jun-13 Data mature for final analysisWas planned for Dec-13 Results availableMay 2014 - Dec 2014

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

37. PlannedTrials

38. 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

39. 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/m 2 6 21-day cycles Oxaliplatin 130 mg/m 2 Capecitabine 850mg/m 2 bd 6 21-day cycles Carboplatin AUC 5/6* Paclitaxel 175mg/m 2 6 21-day cycles Bevacizumab 7.5mg/kg given every 3 weeks for 5 or 6** cycles Oxaliplatin 130 mg/m 2 Capecitabine 850mg/m 2 bd 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.

40. Prospective International Sites GroupCountry GINECOFrance AGOGermany MaNGOItaly MITOItaly NSGO Denmark Sweden Finland Norway KGOGKorea UK ( NCRI/ SGCTG) GOG

41. New MITO Projects

42.  Aim of the trial is to compare the two schedules in terms of quality of life RANDOM Carboplatin AUC 2 Paclitaxel 60 mg/mq day 1,8 15 - every 21days Carboplatin AUC 6 Paclitaxel 175 mg/mq day 1 - every 21days First line weekly carboplatin and paclitaxel vs every 3 weeks carboplatin/paclitaxel in patients with ovarian cancer: the MITO – 7 trial

43. 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

44. 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)

45. Administrative information  NCI of Naples is the coordinating centre  Study started November 10 2008  The expected duration of the study: 20 months

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

47. 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

48. 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) Statistics

49. Administrative informations  NCI of Naples is the coordinating centre  Started November 10 2008  The expected duration of study: 4 years

50. Thank you for your attention http://www.mito-group.it

51. 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

52. 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

53. 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

54. Rationale 21.6% overall decrease in risk of death after primary surgery with IP cisplatin-based treatment21.6% 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.Many EOC patients receive neoadjuvant systemic treatment before debulking is attempted. EORTC-led GCIG trial: neoadjuvant=upfront with lower morbidity!!!EORTC-led GCIG trial: neoadjuvant=upfront with lower morbidity!!! Patients undergoing neoadjuvant chemotherapy not included in IP studiesPatients undergoing neoadjuvant chemotherapy not included in IP studies

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

56. TrialPFSOS IVIP Median (months) PHR PHR SWOG 8501/ GOG 104 Cyclo 600 mg/m 2 IV q 21 days x 6 Cisplatin 100 mg/m 2 IP q 21 days x 6 NSNSNS49.02.76 Cyclo 600 mg/m 2 IV + cis 100 mg/m 2 IV q 21 days x 6 NoneNSNSNS41 GOG114 SWOG 9227 CarboAUC 9 IV x 2 cycles; paclitaxel 135 mg/m 2 IV 24 hrs day 1 q 21 days x 6 Cis 100 mg/m 2 IP day 2 q 21 days x 6 cycles 27.9.01.7863.2.05.81 Paclitaxel 135 mg/m 2 IV 24 hrs day 1; cis 75 mg/m 2 IV day 2 q 21 days x 6 None22.252.2 GOG 172 Paclitaxel 135 mg/m 2 IV 24 hrs day 1 Cis 100 mg/m 2 IP day 2 q 21 days x 6 ; paclitaxel 60 mg/m 2 IP day 8 23.8.05.8065.6.03.75 Paclitaxel 135 mg/m 2 IV 24 hrs day 1; cisplatin 75 mg/m 2 IV day 2 None18.349.7

57. EORTC-led GCIG Trial Overall Survival: NACT + delayed debulking vs. Primary debulking (Standard) Vergote IGCS 2008 NACT approach associated with significantly LESS Post-op sepsis Post-op (1-28 d) mortality Gr 3/4 Bleeding Gr 3/4 Thromboembolism

58. 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

59. Design Issues Questions Which IP platinum? some interested in carboplatin basedsome interested in carboplatin based some prefer cisplatin basedsome 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?)

60. Design Issues QuestionsSolutions Which IP platinum? some interested in carboplatin basedsome interested in carboplatin based some prefer cisplatin basedsome 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

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

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

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

64. Details: Phase II Arms/Doses Arm 1 (control) Paclitaxel 135 mg/m2 (3 hr) IV day 1 Carboplatin AUC 5(6) IV day 1 Carboplatin AUC 5(6) IV day 1 Paclitaxel 60 mg/m2 IV day 8 Arm 2: IP cisplatin based: 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 Carboplatin AUC 5(6) IP day 1 Paclitaxel 60 mg/m2 IP day 8 Repeat q 3 wk x 3 cycles

65. Phase II: Endpoints for selecting IP arm 9-month progression rate post randomization9-month progression rate post randomization Completion rate of treatment (feasibility): to assess toxic effects and technical issuesCompletion rate of treatment (feasibility): to assess toxic effects and technical issues

66. Standard Therapy Patients with EOC 3-4 cycles neoadjuvant chemo Initial surgery: < 1 cm residual 3 cycles IV Carbo/Taxol at 9 mo post debulking, normally expect ~40% pts to have progressed (based on NCIC CTG and NCRI data) 9 mo

67. Phase III endpoints Primary Endpoint: Progression free survivalProgression free survival Secondary Endpoints: Overall survivalOverall survival Toxic effectsToxic effects Quality of lifeQuality of life Translational researchTranslational research Health Economic evaluationHealth Economic evaluation

68. Key Eligibility Criteria Histologically confirmed initial FIGO stage IIB-III (?IV) EOC, peritoneal or fallopian tube cancerHistologically confirmed initial FIGO stage IIB-III (?IV) EOC, peritoneal or fallopian tube cancer 3-4 cycles neoadjuvant platinum based chemotherapy3-4 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 randomizationTAH,BSO and cytoreductive surgery with residual disease 1 cm or less. Must be completed ≤ 4 weeks prior prior to randomization Adequate organ functionAdequate organ function Imaging after surgery prior to first cycleImaging after surgery prior to first cycle ECOG 2 or less 7 days prior to randomizationECOG 2 or less 7 days prior to randomization QoL questionaireQoL questionaire Note: if randomized in OR, must satisfy safety related eligibility before IP treatment startsNote: if randomized in OR, must satisfy safety related eligibility before IP treatment starts

69. Key Ineligibility Criteria Key Ineligibility Criteria Prior chemotherapy for ovarian cancer (other than neoadjuvant)Prior chemotherapy for ovarian cancer (other than neoadjuvant) Borderline histologyBorderline histology CCF/ventricular arrhythmiasCCF/ventricular arrhythmias Bowel obstructionBowel obstruction At surgeryAt surgery Left sided bowel resection Extensive intra/post operative adhesions Experience with prior chemotherapyExperience with prior chemotherapy > grade 1 peripheral neuropathy prior allergic reaction

70. Status Study approved by: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 formProtocol drafted and in mature form IP guideline first draftIP guideline first draft Need:Need: –CTEP review/approval –CTA submissions etc –IP workshop? –EDC training

71. Discussion

72. Statistics: Phase II Portion 50 patients in each of the 3 arms50 patients in each of the 3 arms Assesses ONLY the IP arms at time of analysis: Select the IP regimen based on efficacy and tolerabilityAssesses ONLY the IP arms at time of analysis: Select the IP regimen based on efficacy and tolerability Efficacy: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 therapyFeasibility: not feasible if fewer than 50% patients can complete planned IP therapy

73. Statistics Phase III Portion Progression free survival:Progression free survival: –Seek improvement of IP over control with hazard ratio of 0.8 (Median 17  21.3 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

74. 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.

75. Statistics: Phase II Portion Tolerability criteria:Tolerability criteria: –Assess completion rate of IP treatment. Assume regimen would be interesting if >70% can complete 3 cycles and uninteresting if = 29/50 patients cannot complete IP therapy

76. 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.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 treatmentIf positive, this trial would also offer evidence to support the use of only 3 IP cycles of treatment

77. SGCTG/NCRI GCIG 29 th 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