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Ovarian Committee
Closed Trials
EORTC 55971/CHORUS
Upfront Surgery
vs
Neoadjuvant Chemotherapy
Patients
closed / 550
Leading
EORTC
Participating
NCIC CTG
Presentation planned at IGCS 2008
AGO-OVAR-OP.2 DESKTOP II
Evaluation of predictive factors for complete
resection in platinum-sensitive recurrent
ovarian cancer
Patients
closed/412
Leading
AGO-OVAR
Participating
AGO-AUSTRIA, MITO,
selected Canadian+Australian
centers
Report
IGCS 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
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)
An open-label prospective multicenter-trial
© P. Harter 2008
AGO DESKTOP OVAR II - BACKGROUND
• what is the surgical endpoint ?
1
0,9
survival probability
0,8
no residuals
median OS 45.2 mos.
0,7
0,6
0,5
0,4
0,3
0 vs. 1-10 mm:
0,2 HR: 4.17 (CI 2,42 - 7,16); p < 0.001
0,1 0 vs. 10+ mm:
HR: 3.31 (CI 1,86 - 5,88); p < 0.001
residuals > 10 mm
median OS 19.7 mos.
residuals 1 - 10 mm
median OS 19.6 mos.
0
0
12
DESKTOP OVAR I
24
36
48
months
© 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%)
Laparotomy
calculated numbers (1st endpoint):
No (CRR 43%)
110 pts. with positive score and a complete
resection rate (CRR) of at least 75% will show
only descriptive analysis of further therapy
with 95% probability that a positive score can
predict CR in >2 of 3 pts.
Platinum-based combination chemotherapy
© P. Harter 2008
AGO DESKTOP OVAR II – FLOW CHART
08/06 – 03/08: Screening of 516 pts with platinum-sensitive relapse in 46 centres
Score positive
261 pts (51%)
Surgery
148 pts
(57%)
Study collective:
AGO score +
1st relapse
129 pts (87%)
No surgery
113 pts
(43%)
2nd relapse
19 pts
(13%)
Score negative
255 pts (49%)
Surgery
80 pts
(31%)
1st relapse
64 pts
(80%)
No surgery
175 pts
(69%)
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%)
© P. Harter 2008
AGO DESKTOP OVAR II – SURGICAL RESULTS
Frequency of complete resection by applying the AGO Score
100
90
80
DESKT
Hypoth
70
60
50
40
75
76
Score positive
Score positive
Score positive
all patients
1st relapse
2nd relapse
30
68
20
10
0
complete resection in 76% of the study collective =
AGO score could predict complete resection in at least 2 out of 3 patients
© 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
© 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
AGO Study Group Ovarian Cancer (AGO-OVAR)
An open-label prospectively randomized phase III multicenter-trial
© 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)
R
A
N
D
O
M
Cytoreductive
surgery
n ~ 300
platinum-based
chemotherapy*
recommended
no surgery
* 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
© P. Harter 2008
DESKTOP III – the next steps
•
•
•
•
Protocol development
GCIG discussion
Ethical approval Germany
First patient in
12/08
01/09
02/08
04/08
© P. Harter 2008
DESKTOP III – the next steps
Interested in participation
as single center or GCIG group ?
E-mail: [email protected]
© P. Harter 2008
Tarceva Trial EORTC 55041
Tarceva consolidation 2 years
Primary Chemotherapy
Control
Patients
closed / 835
Leading
EORTC
Participating
AGO-AUSTRIA, ANZGOG, GINECO,
MRC/NCIC, MANGO
CALYPSO
TC
vs
C + Caelyx
Patients
closed / 976
Leading
GINECO
Participating
AGO-AUSTRIA, AGO-OVAR,
ANZGOG, EORTC, MANGO,
MITO, NCIC/CTG, NSGO
Presentation ASCO 2009??
AGO-OVAR-9
Carbo Paclitaxel +/- Gemcitabine
Patients
closed 1742
Leading
AGO-OVAR
Participating
GINECO, NSGO,
Open Trials
SCOTROC 4
Carbo Flat Dosing vs Intrapatient Dose Escalation
Patients
930 / 1300
Leading
SGCTG
Participating
ANZGOG
ICON-7
TC
±
BEVACIZUMAB
Patients
1200 / 1520
Leading
MRC/NCRI
Participating
NCIC CTG, AGO OVAR, GINECO, GEICO
EORTC(?), ANZGOG, NSGO
GOG 218
CT vs CT + Bevacizumab
Placebo vs
CT + Bevacizumab concurrent and extended
Patients
1350 / 1800
Leading
GOG
Participating
ECOG, NCCTG, NSABP, SWOG
JGOG-3017 Clear Cell Carcinoma
CT
vs
CDDP + Irinotecan
Patients
271/600
Leading
JGOG
Participating
GINECO, GOG, KGOG,
MITO, SGCTG
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
Study Co-Chair
Toru Sugiyama, MD (Iwate Medical University)
Seiji Isonishi, MD (Jikei University School of Medicine)
Fumitoshi Terauchi, MD (Toho University)
GCIG Study
-Clear Cell Ca
-Stage I~IV
RANDOMIZATION
International Cooperative Phase III
Study for Clear Cell Carcinoma
TC
Paclitaxel 175 mg/m2 (d1)
Carboplatin AUC 6 (d1)
Every 3 wk x 6
CPT-11/CDDP
CPT-11 60 mg/m2 (d1, 8, 15)
Cisplatin 60 mg/m2 (d1)
Every 4 wk x 6
225 patients in each arm, 450 total for 3 years
326 patients in each arm, 652 total for 4.25 years
JGOG3017/GCIG Trial
JGOG 259
KGOG 13
As of 11/13/2008
JGOG3017/GCIG Trial
• Progress
– May 2008 International DMC
– August 2008
• International Web based Central Pathology Review
HECTOR
Carbo Topo vs Chemo (CT or CG) in recurrent
Platinum-sensitive ovarian cancer
Patients
304/ 550
Leading
NOGGO/AGO-OVAR
Participating
AGO-AUSTRIA, GEICO
AGO – OVAR OP.3 (LION)
Lymphadenectomy In Ovarian Neoplasms
epithelial invasive
ovarian cancer
System. Lymphadenectomy
 pelvic
FIGO IIB - IV
 para-aortic
ethical
approval
8/2008
ECOG 0/1 and
R
no
CI against
LNE
First
patient
in December
no visible extraand intra-abdominal
tumor residuals
n = 640
no Lymphadenectomy
no bulky lymph nodes
Endpoints: OS, PFS, QoL, toxicity/complications
Strata: centre, PS ,age
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
Eligible consenting patient
relapsing > 6 months after
completion of first treatment
RANDOMISE
2:3:3
Arm A
(Reference Arm)
6 cycles of chemotherapy*
plus Placebo during
chemotherapy
Placebo for a maximum of
18 months from
randomisation, or until
progressive disease
Arm B
6 cycles of chemotherapy *
plus cediranib during
chemotherapy
Placebo for a maximum of 18
months from randomisation, or
until progressive disease
Follow up visits:
Every 3 months until protocol
defined disease progression,
then 6 monthly for up to 5
years after randomisation,
then annually
Arm C
6 cycles of chemotherapy *
plus cediranib during
chemotherapy
Cediranib for a maximum of
18 months from
randomisation, or until
progressive disease
First Stage:
Primary outcome measure:
Second Stage:
Primary outcome measure:
Secondary outcome measures:
Toxicity
Third Stage:
Primary outcome measure:
Secondary outcome measures:
Ancilliary Studies:
Health Economics (HE)
Translational Research (TR)
Safety
Progression-Free Survival (PFS)
Overall Survival (OS) and
Overall Survival (OS)
Progression Free Survival(PFS)
Quality of Life (QoL)Toxicity
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.
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
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
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
Item
Timelines – Updated November 2008
First patient in UK
December 2007
First patient in Canada
July 2008
TMG recommendation to
reduce dose
October 2008
IDMC Review
November 5 2008
Revised Stage I Analysis
Sept 2009
Request statements of interest
from Stage 2 groups
April 2009
Draft contracts prepared for
interested GCIG groups
Trial Status
9 Centres
Open 6 UK
3 Canada
May - August 2009
Meetings with individual groups
May – September 2009
Activation of stage 2 groups
November 2009
Second stage analysis
Was planned for Dec-10
Last patient randomised
Was planned for Dec-12
Last patient completed
treatment
Was planned for Jun-13
Data mature for final analysis
Was planned for Dec-13
Results available
May 2014 - Dec 2014
31 patients
recruited.
ICON6:Multistage design
Gynaecologic Cancer Intergroup Trial:
MRC/NCRI, NCIC, ANZ-GOG, IMN, EORTC, GINECO,
GEICO, MANGO, NSGO, ICMB
Stage I
 Safety analysis after ~33 patients entered into B &C
Stage II ( ~50 deaths - 90 events)
 Progression-free survival (PFS)
 Overall survival (OS)
Stage III (~ 2000 patients)
 Overall survival (OS)
 Progression-free survival (PFS)
 Toxicity
 Quality of life
 Health economics
 Molecular genetics
OPEN 5 sites in UK
& 5 in Canada 1/08
PlannedTrials
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
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/m2
6 21-day cycles
Oxaliplatin 130
mg/m2
Capecitabine
850mg/m2 bd
6 21-day cycles
Clinical assessment every 6
weeks for 36 weeks
Carboplatin AUC
5/6*
Paclitaxel 175mg/m2
6 21-day cycles
Oxaliplatin 130 mg/m2
Capecitabine
850mg/m2 bd
6 21-day cycles
Bevacizumab
7.5mg/kg given
every 3 weeks for 5
or 6** cycles
Bevacizumab
7.5mg/kg given every
3 weeks for 5 or 6**
cycles
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.
Prospective International Sites
UK ( NCRI/ SGCTG) GOG
Group
Country
GINECO
France
AGO
Germany
MaNGO
Italy
MITO
Italy
NSGO
KGOG
Denmark
Sweden
Finland
Norway
Korea
New MITO Projects
First line weekly carboplatin and paclitaxel vs
every 3 weeks carboplatin/paclitaxel in
patients with ovarian cancer:
the MITO – 7 trial
 Aim of the trial is to compare the two schedules in terms of quality
of life
Carboplatin AUC 6
Paclitaxel 175 mg/mq
RANDOM
day 1 - every 21days
Carboplatin AUC 2
Paclitaxel 60 mg/mq
day 1,8 15 - every 21days
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
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)
Administrative information
NCI of Naples is the coordinating centre
Study started November 10 2008
The expected duration of the study: 20 months
Liposomal doxorubicin stealth vs
carboplatin/taxol in recurrent ovarian
cancer patients with platinum-free
interval between 6-12 months
MITO - 8
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
RANDOM
LIPOSOMAL
DOXORUBICIN 40 mg/mq
CARBOPLATIN AUC 5 +
PACLITAXEL 175 mg/mq
day1 every 28 days
day1 every21gg
Cross-over at
Progression
LIPOSOMAL
DOXORUBICIN
40 mg/mq
day1 every 28 days
CARBOPLATIN AUC 5 +
PACLITAXEL 175 mg/mq
day1 every 21 days
Statistics
• 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)
Administrative informations
NCI of Naples is the coordinating centre
Started November 10 2008
The expected duration of study: 4 years
Thank you for your attention
http://www.mito-group.it
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
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
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
Rationale
• 21.6% 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.
• EORTC-led GCIG trial: neoadjuvant=upfront
with lower morbidity!!!
• Patients undergoing neoadjuvant chemotherapy
not included in IP studies
Do EOC patients who have received
neoadjuvant chemotherapy
benefit from IP therapy?
Trial
PFS
IV
SWOG
8501/
GOG
104
GOG114
SWOG
9227
GOG
172
IP
OS
Median
(months)
P
HR
Median
(months)
P
HR
.02
.76
.05
.81
.03
.75
Cyclo 600 mg/m2
IV q 21 days x 6
Cisplatin 100
mg/m2 IP q 21
days x 6
NS
NS
NS
49
Cyclo 600 mg/m2
IV + cis 100 mg/m2
IV q 21 days x 6
None
NS
NS
NS
41
CarboAUC 9 IV x 2
cycles; paclitaxel
135 mg/m2 IV 24
hrs day 1 q 21 days
x6
Cis 100 mg/m2 IP
day 2 q 21 days x
6 cycles
27.9
.01
.78
63.2
Paclitaxel 135
mg/m2 IV 24 hrs
day 1; cis 75
mg/m2 IV day 2 q
21 days x 6
None
22.2
Paclitaxel 135
mg/m2 IV 24 hrs
day 1
Cis 100 mg/m2 IP
day 2 q 21 days x
6 ; paclitaxel 60
mg/m2 IP day 8
23.8
Paclitaxel 135
mg/m2 IV 24 hrs
day 1; cisplatin 75
mg/m2 IV day 2
None
18.3
52.2
.05
.80
65.6
49.7
EORTC-led GCIG Trial Overall Survival:
NACT + delayed debulking vs.
Primary debulking (Standard)
NACT approach associated with significantly LESS
Post-op sepsis
Post-op (1-28 d) mortality
Gr 3/4 Bleeding
Gr 3/4 Thromboembolism
Vergote IGCS 2008
Basic Design
Patients with EOC
3-4 cycles neoadjuvant chemo
Initial surgery: < 1 cm residual
3 cycles
3 cycles IP/IV
IV Carbo/Taxol platinum and taxol
Endpoints: PFS and OS
Design Issues
Questions
Which IP platinum?
• some interested in carboplatin
based
• some 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?)
Design Issues
Questions
Solutions
Which IP platinum?
• some interested in carboplatin
based
• some 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
R
Phase II
IV Carbo IP Carbo (Taxol) IP Cisplatin (Taxol)
IV Taxol
IV Taxol
IV Taxol
Then…..
This or…..
Phase II
R
IV Carbo IP Carbo (Taxol) IP Cisplatin (Taxol)
IV Taxol
IV Taxol
IV Taxol
Phase III
IV Carbo IP Carbo (Taxol)
IV Taxol
IV Taxol
This…..
Phase II
R
IV Carbo IP Carbo (Taxol) IP Cisplatin (Taxol)
IV Taxol
IV Taxol
IV Taxol
Phase III
IV Carbo
IV Taxol
IP Cisplatin (Taxol)
IV Taxol
Details: Phase II Arms/Doses
Arm 1 (control)
Paclitaxel 135 mg/m2 (3 hr) IV day 1
Carboplatin AUC 5(6) IV day 1
Paclitaxel 60 mg/m2 IV day 8
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
Paclitaxel 60 mg/m2 IP day 8
Repeat q 3 wk
x 3 cycles
Phase II:
Endpoints for selecting IP arm
• 9-month progression rate post
randomization
• Completion rate of treatment
(feasibility): to assess toxic effects and
technical issues
Standard Therapy
Patients with EOC
3-4 cycles neoadjuvant chemo
Initial surgery: < 1 cm residual
3 cycles
IV Carbo/Taxol
9 mo
at 9 mo post debulking,
normally expect ~40%
pts to have progressed
(based on NCIC CTG and
NCRI data)
Phase III endpoints
Primary Endpoint:
• Progression free survival
Secondary Endpoints:
• Overall survival
• Toxic effects
• Quality of life
• Translational research
• Health Economic evaluation
Key Eligibility Criteria
• Histologically confirmed initial FIGO stage IIB-III (?IV)
EOC, peritoneal or fallopian tube cancer
• 3-4 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 randomization
• Adequate organ function
• Imaging after surgery prior to first cycle
• ECOG 2 or less 7 days prior to randomization
• QoL questionaire
• Note: if randomized in OR, must satisfy safety related
eligibility before IP treatment starts
Key Ineligibility Criteria
• Prior chemotherapy for ovarian cancer (other than neoadjuvant)
• Borderline histology
• CCF/ventricular arrhythmias
• Bowel obstruction
• At surgery
Left sided bowel resection
Extensive intra/post operative adhesions
• Experience with prior chemotherapy
> grade 1 peripheral neuropathy
prior allergic reaction
Status
• 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 form
• IP guideline first draft
• Need:
–
–
–
–
CTEP review/approval
CTA submissions etc
IP workshop?
EDC training
Discussion
Statistics: Phase II Portion
• 50 patients in each of the 3 arms
• Assesses ONLY the IP arms at time of analysis: Select the
IP regimen based on efficacy and tolerability
• 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 therapy
Statistics Phase III Portion
• 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
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.
Statistics: Phase II Portion
• Tolerability criteria:
– Assess completion rate of IP treatment.
Assume regimen would be interesting if
>70% can complete 3 cycles and
uninteresting if < 50% complete 3 cycles.
Using these figures, arm(s) selected will be
abandoned if >= 29/50 patients cannot
complete IP therapy
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.
• If positive, this trial would also offer evidence to
support the use of only 3 IP cycles of treatment
SGCTG/NCRI
GCIG 29th 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