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GCIG Meeting 29th May 2009
The Implications of PrimaryChemotherapy for Clinical Trials
Iain McNeishProfessor of Gynaecological Oncology
Barts and the London School of MedicineLONDON
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
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
Overall survival (ITT)
Progression-free survival (ITT)
Overall survival (Per protocol)
Hazard ratios by stage
Post-operative complications
PDS
(n = 329)
NACT - IDS
(n = 339)Post-op mortality (<28/7)
2.7% 0.6%
Post-op sepsis 8% 2%
G3/4 haemorrhage
7% 1%
G3/4 VTE 2.4% 0.3%
Multi-variate analyses for OS
p valueOptimal debulking 0.0001Histological subtype 0.0003Largest tumour at randomisation 0.0008FIGO stage (IIIc vs IV) 0.0008Age 0.002WHO PS NSGrade NSTreatment arm NS
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
Primary surgery Randomised after
surgeryNAC
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:
ToxicityFeasibility
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 designRandomisation 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
Designing phase III trials
#1 # 2 # 3 # 4 # 5 # 6
Surgery
Carboplatin and Taxol (+/- bevacizumab) q3/52
vs
d1 d1 d1 d1 d1 d1
d1 d8 d15 d1 d8 d15
e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52
d1 d8 d15 d1 d8 d15 d1 d8 d15 d1 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 d1 d1 d1 d1 d1
BUT - trial design must incorporate IDS…
Designing phase III trials
#1 # 2 # 3 # 4 # 5 # 6
Carboplatin and Taxol (+/- bevacizumab) q3/52
vs
d1 d1 d1 d1 d1 d1
d1 d8 d15 d1 d8 d15
e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52
d1 d8 d15 d1 d8 d15 d1 d8 d15 d1 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
Designing phase III trials
#1 # 2 # 3 # 4 # 5 # 6
Carboplatin and Taxol (+/- bevacizumab) q3/52
vs
d1 d1 d1 d1 d1 d1
SURGERY
d1 d8 d15 d1 d8 d15
e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52
d1 d8 d15 d1 d8 d15 d1 d8 d15 d1 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
Primary surgery Randomised after
surgeryNAC
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 PFSOption 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:PFSTOXICITYHEQOLTR2:1 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)
Primary surgery Randomised after
surgeryNeoadjuvant
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 PFS3 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:PFSToxicityHEQoLTR
