1. GCIG Meeting 29th May 2009 The Implications of Primary Chemotherapy for Clinical Trials Iain McNeish Professor of Gynaecological Oncology Barts and the London School of Medicine LONDON

2. EORTC 55971 trial Stage IIIc/IV ovarian, Fallopian tube, peritoneal ca (n=718) RANDOMISE Primary Debulking Surgery 3 cycles platinum-based chemo Optional interval surgery ≥ 3 cycles platinum-based chemo Primary Chemotherapy 3 cycles platinum-based chemo Interval debulking if no PD ≥ 3 cycles platinum-based chemo Primary end-point: Overall survival Secondary end-points: PFS, QoL, complications

3. EORTC 55971 trial Eligibility Biopsy-proven ovarian cancer OR Suggestive FNA, with pelvic mass, met >2cm outside pelvis (or proof of stage IV disease) and CA125:CEA ratio >25 WHO PS 0 - 2 Fit for either primary surgery or primary chemotherapy Recruitment 718 patients randomised Sept 1998 - Dec 2006 498 events reached August 2008 Median follow-up 4.8 years

4. Overall survival (ITT)

5. Progression-free survival (ITT)

6. Overall survival (Per protocol)

7. Hazard ratios by stage

8. Post-operative complications PDS (n = 329) NACT - IDS (n = 339) Post-op mortality (<28/7) 2.7%0.6% Post-op sepsis8%2% G3/4 haemorrhage 7%1% G3/4 VTE2.4%0.3%

9. Multi-variate analyses for OS p value Optimal debulking 0.0001 Histological subtype 0.0003 Largest tumour at randomisation 0.0008 FIGO stage (IIIc vs IV) 0.0008 Age 0.002 WHO PS NS Grade NS Treatment arm NS

10. Primary Chemotherapy Primary chemo is a reality Up to 40% in Europe esp UK How to integrate primary chemo? Anti-VEGF therapies Dose dense/weekly schedules

11. 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 P q 1/52 ARM6: C q 1/52 P q 1/52 Bevacizumab q 3/52 Standard ~GOG218 & ICON7 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 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) 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

12. Designing phase III trials #1# 2 # 3# 4# 5# 6 Surgery Carboplatin and Taxol (+/- bevacizumab) q3/52 vs d1 d8d15d1 d8 d15 e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52 d1d8d15d1 d8 d15 d1d8d15d1 d8 d15 #1# 2 # 3# 4# 5# 6 e.g. Carboplatin and Taxol + A.N. Other q3/52 or #1# 2 # 3# 4# 5# 6 d1 BUT - trial design must incorporate IDS…

13. Designing phase III trials #1# 2 # 3# 4# 5# 6 Carboplatin and Taxol (+/- bevacizumab) q3/52 vs d1 d8d15d1 d8 d15 e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52 d1d8d15d1 d8 d15 d1d8d15d1 d8 d15 #1# 2 # 3# 4# 5# 6 SURGERY How to manage interval surgery? – ? omit bevacizumab from # 3 – ? extend time from # 3 to surgery to 4 weeks – ? omit bevacizumab from # 4 – ? extend time from surgery to # 4 to 4 weeks

14. Designing phase III trials #1# 2 # 3# 4# 5# 6 Carboplatin and Taxol (+/- bevacizumab) q3/52 vs d1 SURGERY d1d8d15d1 d8 d15 e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52 d1d8d15d1 d8 d15 d1d8d15d1 d8 d15 #1# 2 # 3# 4# 5# 6 How to manage weekly chemotherapy and surgery? - ? give # 3 as d1 only (ie same as q 3/52 regime)? - ? omit # 3 day 15 - ? when to restart post-surgery

15. 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 P q 1/52 ARM6: C q 1/52 P q 1/52 Bevacizumab q 3/52 ~GOG218 & ICON7 MITO NOVEL JGOG study NOVEL ICON8 Stage 2 trial design if ICON7 and GOG 218 are positive are ‘positive’ for PFS Option 1 2:1 randomisation* Total 2000 patients 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)

16. 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 P q 1/52 3 weeks out of 4 Standard Proposed MITO JGOG study ICON 8 If bevacizumab trials ‘negative’ for PFS 3 arm 1:1: 1 randomisation 600 patients per arm, Total 1800- 3yrs recruitment 2 years follow up 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