Transcript Document

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
EORTC 55971 trial
Stage IIIc/IV ovarian, Fallopian tube, peritoneal ca
(n=718)
RANDOMISE
Primary Debulking Surgery
Primary Chemotherapy
3 cycles platinum-based chemo
3 cycles platinum-based chemo
Optional interval surgery
Interval debulking if no PD
≥ 3 cycles platinum-based chemo
≥ 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 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
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
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
Standard
ARM1: C q 3/52
P q 3/52
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)
~GOG218 & ICON7
Primary surgery
Randomised after
surgery
NAC
Randomised before
neoadjuvant chemo
to 3 cycles chemo,
surgery, then 3 cycles
chemo)
ARM2: C q 3/52
P q 3/52
Bevacizumab q 3/52
JGOG study
ARM3: C q 3/52
P q 1/52
Novel
ARM4: C q 3/52
P q 1/52
Bevacizumab q 3/52
MITO
ARM5: C q 1/52
P q 1/52
NOVEL
ARM6: C q 1/52
P q 1/52
Bevacizumab q 3/52
Aim of stage 1 is to establish which
arms should be taken into stage 2
based.
Primary outcome measures:
Toxicity
Feasibility
Designing phase III trials
Carboplatin and Taxol (+/- bevacizumab) q3/52
#1
d1
#2
#3
d1
d1
#4
d1
#5
#6
d1
d1
vs
Surgery
e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52
#1
d1
#2
d8
d15 d1
#3
d8
d15 d1
#4
d8
d15 d1
#5
d8 d15
d1
#6
d8
d15 d1
d1
#2
#3
d1
d1
#4
d1
d15
or
e.g. Carboplatin and Taxol + A.N. Other q3/52
#1
d8
#5
#6
d1
d1
BUT - trial design must incorporate IDS…
Designing phase III trials
Carboplatin and Taxol (+/- bevacizumab) q3/52
#1
d1
#2
#3
d1
d1
#4
d1
#5
#6
d1
d1
vs
SURGERY
e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52
#1
d1
#2
d8
d15 d1
#3
d8
d15
d1
#4
d8 d15
d1
#5
d8 d15
d1
#6
d8
d15 d1
d8
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
d15
Designing phase III trials
Carboplatin and Taxol (+/- bevacizumab) q3/52
#1
d1
#2
#3
d1
d1
#4
d1
#5
#6
d1
d1
vs
SURGERY
e.g. Carboplatin and Taxol (+/- bevacizumab) q1/52
#1
d1
#2
d8
d15 d1
#3
d8
d15
d1
#4
d8 d15
d1
#5
d8 d15
d1
#6
d8
d15 d1
d8
d15
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
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 & ICON7
ARM2: C q 3/52
P q 3/52
Bevacizumab q 3/52
JGOG study
ARM3: C q 3/52
P q 1/52
Primary surgery
Randomised after
surgery
NAC
Randomised before
chemo to 3 cycles
chemo, surgery, then 3
cycles chemo)
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
NOVEL
ARM4: C q 3/52
P q 1/52
Bevacizumab q 3/52
MITO
ARM5: C q 1/52
P q 1/52
NOVEL
ARM6: C q 1/52
P q 1/52
Bevacizumab q 3/52
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)
PRIMARY OUTCOME MEASURE:
OS
SECONDARY OUTCOME MEASURES:
PFS
TOXICITY
HE
QOL
TR
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
Standard
ARM1: C q 3/52
P q 3/52
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
Primary surgery
Randomised after
surgery
Neoadjuvant
chemotherapy
randomised before
chemo to 3 cycles
chemo, surgery, then
3 cycles chemo)
JGOG study
ARM3: C q 3/52
P q 1/52
Proposed MITO
ARM5: C q 1/52
P q 1/52
3 weeks out of 4
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