GCIG Meeting 29th May 2009 The Implications of Primary Chemotherapy for Clinical Trials Iain McNeish...

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