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Transcript of Ovarian Committee. Closed Trials Upfront Surgery vs Neoadjuvant Chemotherapy Patients closed / 550...
Ovarian Committee
Closed TrialsClosed Trials
Upfront Surgery vs Neoadjuvant Chemotherapy
Patients closed / 550
Leading EORTC
Participating NCIC CTG
Presentation planned at IGCS 2008
EORTC 55971/CHORUS
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 DESKTOP II
© P. Harter 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
An open-label prospective multicenter-trial
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)
© P. Harter 2008
AGO DESKTOP OVAR II - BACKGROUNDAGO DESKTOP OVAR II - BACKGROUND• what is the surgical endpoint ?what is the surgical endpoint ?
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 12 24 36 48
months
surv
ival
pro
babi
lity
0 vs. 1-10 mm:HR: 4.17 (CI 2,42 - 7,16); p < 0.0010 vs. 10+ mm:HR: 3.31 (CI 1,86 - 5,88); p < 0.001
no residualsmedian OS 45.2 mos.
residuals > 10 mmmedian OS 19.7 mos.residuals 1 - 10 mmmedian OS 19.6 mos.
DESKTOP OVAR I
Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006
© 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%) No (CRR 43%)
Laparotomy only descriptive analysis of further therapy
Platinum-based combination chemotherapy
* CRR: Results from DESKTOP-OVAR I
calculated numbers (1st endpoint):
110 pts. with positive score and a complete
resection rate (CRR) of at least 75% will show
with 95% probability that a positive score can
predict CR in >2 of 3 pts.
© P. Harter 2008
08/06 – 03/08: Screening of 516 pts with platinum-sensitive relapse in 46 centres
Score positive261 pts (51%)
Score negative255 pts (49%)
Surgery148 pts (57%)
No surgery113 pts (43%)
Surgery80 pts (31%)
No surgery175 pts (69%)
1st relapse64 pts(80%)
2nd relapse19 pts(13%)
2nd relapse16 pts(20%)
Selection process:
228 pts (44.2%) had cytoreductive surgery for recurrent OC
-> Primary study collective (AGO score +, 1st relapse) : 129 pts (25%)
AGO DESKTOP OVAR II – FLOW CHART
Study collective:AGO score +1st relapse
129 pts (87%)
© P. Harter 2008
Frequency of complete resection by applying the AGO Score
AGO DESKTOP OVAR II – SURGICAL RESULTS
complete resection in 76% of the study collective =
AGO score could predict complete resection in at least 2 out of 3 patients
75 7668
0
10
20
30
40
50
60
70
80
90
100
Score positive Score positive Score positive
all patients 1st relapse 2nd relapse
DESKTOPHypothesis
© 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 standardplatinum-based chemotherapy in platinum-sensitive
recurrent cancer of the ovary, fallopian tube, or peritoneum
An open-label prospectively randomized phase III multicenter-trial
AGO Study Group Ovarian Cancer (AGO-OVAR)
© 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-sensitiverecurrent cancer of theovaries, fallopian tubes, orperitoneum
PFI > 6 mos since firstchemotherapy which wasPlatinum-based
No prior chemotherapyfor this 1st relapse
Complete resectionseems feasible and positive AGO score:• PS ECOG 0• no ascites > 500 ml• prior complete debulking or initial FIGO I/II (if data available)
RANDOM
Cytoreductivesurgery platinum-based
chemotherapy*recommended
* 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
no surgery
n ~ 300
© P. Harter 2008
DESKTOP III – the next steps
• Protocol development 12/08
• GCIG discussion 01/09
• Ethical approval Germany 02/08
• First patient in 04/08
© P. Harter 2008
Interested in participation as single center or GCIG group ?
E-mail: [email protected]
DESKTOP III – the next steps
Tarceva consolidation 2 yearsPrimary Chemotherapy
Control
Patients closed / 835
Leading EORTC
Participating AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO
Tarceva Trial EORTC 55041
TC vs C + Caelyx
Patients closed / 976
Leading GINECO
Participating AGO-AUSTRIA, AGO-OVAR, ANZGOG, EORTC, MANGO, MITO, NCIC/CTG, NSGO
Presentation ASCO 2009??
CALYPSO
Carbo Paclitaxel +/- Gemcitabine
Patients closed 1742
Leading AGO-OVAR
Participating GINECO, NSGO,
AGO-OVAR-9
Open TrialsOpen Trials
Carbo Flat Dosing vs Intrapatient Dose Escalation
Patients 930 / 1300
Leading SGCTG
Participating ANZGOG
SCOTROC 4
TC ± BEVACIZUMAB
Patients 1200 / 1520
Leading MRC/NCRI
Participating NCIC CTG, AGO OVAR, GINECO, GEICO EORTC(?), ANZGOG, NSGO
ICON-7
CT vs CT + Bevacizumab Placebo vs CT + Bevacizumab concurrent and extended
Patients 1350 / 1800
Leading GOG
Participating ECOG, NCCTG, NSABP, SWOG
GOG 218
CT vs CDDP + Irinotecan
Patients 271/600
Leading JGOG
Participating GINECO, GOG, KGOG, MITO, SGCTG
JGOG-3017 Clear Cell Carcinoma
JGOG3017/GCIGOvarian 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 Toru Sugiyama, MD (Iwate Medical University)Study Co-Chair Seiji Isonishi, MD (Jikei University School of Medicine)
Fumitoshi Terauchi, MD (Toho University)
GCIG Study
RA
ND
OM
IZA
TIO
N 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
International Cooperative Phase III Study for Clear Cell Carcinoma
-Clear Cell Ca
-Stage I~IV
225 patients in each arm, 450 total for 3 years
326 patients in each arm, 652 total for 4.25 years
JGOG3017/GCIG Trial
As of 11/13/2008JGOG 259KGOG 13
JGOG3017/GCIG Trial
• Progress– May 2008 International DMC– August 2008
• International Web based Central Pathology Review
Carbo Topo vs Chemo (CT or CG) in recurrent Platinum-sensitive ovarian cancer
Patients 304/ 550
Leading NOGGO/AGO-OVAR
Participating AGO-AUSTRIA, GEICO
HECTOR
R
System. Lymphadenectomy
pelvic
para-aortic
no Lymphadenectomy
epithelial invasive ovarian cancer
FIGO IIB - IV
ECOG 0/1 and no CI against LNE
no visible extra- and intra-abdominal
tumor residuals
no bulky lymph nodes
Endpoints: OS, PFS, QoL, toxicity/complications Strata: centre, PS ,age
Lymphadenectomy In Ovarian Neoplasms
AGO – OVAR OP.3 (LION)
n = 640
ethical approval 8/2008 First patient in December
LION –the next steps
1st patient in: 11/08
LION receives public funding limited to nationaltrials (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
RANDOMISE2 : 3 : 3
Arm A (Reference Arm)
Arm B Arm C
6 cycles of chemotherapy* plus Placebo during
chemotherapy
6 cycles of chemotherapy *
plus cediranib during chemotherapy
6 cycles of chemotherapy *
plus cediranib during chemotherapy
Placebo for a maximum of 18 months from
randomisation, or until progressive disease
Placebo for a maximum of 18 months from randomisation, or
until progressive disease
Cediranib 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
First Stage: Primary outcome measure: Safety
Second Stage: Primary outcome measure: Progression-Free Survival (PFS) Secondary outcome measures: Overall Survival (OS) and Toxicity
Third Stage: Primary outcome measure: Overall Survival (OS) Secondary outcome measures: Progression Free Survival(PFS)
Quality of Life (QoL)Toxicity
Ancilliary Studies:Health Economics (HE)Translational Research (TR)
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
Trial Status
9 Centres Open 6 UK 3 Canada
31 patients recruited.
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
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
ICON6:Multistage design
Stage III (~ 2000 patients) Overall survival (OS) Progression-free survival (PFS) Toxicity Quality of life Health economics Molecular genetics
Stage I Safety analysis after ~33 patients entered into B &C
Stage II ( ~50 deaths - 90 events) Progression-free survival (PFS) Overall survival (OS)
Gynaecologic Cancer Intergroup Trial:MRC/NCRI, NCIC, ANZ-GOG, IMN, EORTC, GINECO, GEICO, MANGO, NSGO, ICMB
OPEN 5 sites in UK& 5 in Canada 1/08
PlannedTrialsPlannedTrials
mEOCA 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 DesignmEOC 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
Carboplatin AUC 5/6*
Paclitaxel 175mg/m2
6 21-day cycles
Bevacizumab 7.5mg/kg given
every 3 weeks for 5 or 6** 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**
cyclesClinical assessment every 6
weeks for 36 weeks
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
Group Country
GINECO France
AGO Germany
MaNGO Italy
MITO Italy
NSGODenmarkSwedenFinlandNorway
KGOG Korea
UK ( NCRI/ SGCTG) GOG
New MITO Projects
Aim of the trial is to compare the two schedules in terms of quality of life
RANDOM
Carboplatin AUC 2Paclitaxel 60 mg/mq
day 1,8 15 - every 21days
Carboplatin AUC 6Paclitaxel 175 mg/mq
day 1 - every 21days
First line weekly carboplatin and paclitaxel vs every 3 weeks carboplatin/paclitaxel in
patients with ovarian cancer:
the MITO – 7 trial
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
RANDOM
LIPOSOMALDOXORUBICIN
40 mg/mqday1 every 28 days
CARBOPLATIN AUC 5 +PACLITAXEL 175 mg/mq
day1 every 21 days
Cross-over atProgression
CARBOPLATIN AUC 5 +PACLITAXEL 175 mg/mq
day1 every21gg
LIPOSOMALDOXORUBICIN 40 mg/mq
day1 every 28 days
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
• 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)
Statistics
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 toinvestigate the efficacy and safety of BIBF 1120 (Vargatef)in combination with standard treatment of carboplatin and
paclitaxel compared to placebo plus carboplatin and paclitaxelin patients with advanced ovarian cancer
AGO - OVAR12 / 1199.15
a
A Phase III Study to Evaluate the Efficacy and Safety of PazopanibMonotherapy Versus Placebo in Women Who Have not
Progressed after First Line Chemotherapy for Epithelial Ovarian,Fallopian Tube, or Primary Peritoneal Cancer
AGO - OVAR16 / VEG110655
a
Phase II/III Study of IP/IV Phase II/III Study of IP/IV Chemotherapy Chemotherapy versusversus IV IV
Chemotherapy in Patients with Chemotherapy in Patients with Epithelial Ovarian Cancer Epithelial Ovarian Cancer
Optimally Debulked Following Optimally Debulked Following Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy
NCIC CTG OV21NCIC CTG OV21
Helen Mackay, Diane Provencher, Mark Helen Mackay, Diane Provencher, Mark Heywood, Chris Gallagher, Jonathan Heywood, Chris Gallagher, Jonathan
Ledermann, Ana Oaknin, ?Maurie Ledermann, Ana Oaknin, ?Maurie Markman Markman
Dongsheng Tu, Ding ChenDongsheng Tu, Ding Chen
RationaleRationale• 21.6% overall decrease in risk of death 21.6% overall decrease in risk of death
after primary surgery with IP cisplatin-after primary surgery with IP cisplatin-based treatmentbased treatment
• Many EOC patients receive Many EOC patients receive neoadjuvant neoadjuvant systemic treatmentsystemic treatment before debulking is before debulking is attempted. attempted.
• EORTC-led GCIG trial: EORTC-led GCIG trial: neoadjuvant=upfront with lower neoadjuvant=upfront with lower morbidity!!! morbidity!!!
• Patients undergoing neoadjuvant Patients undergoing neoadjuvant chemotherapy not included in IP studies chemotherapy not included in IP studies
Do EOC patients who have Do EOC patients who have received neoadjuvant received neoadjuvant
chemotherapy benefit from IP chemotherapy benefit from IP therapy?therapy?
TrialTrial PFSPFS OSOSIVIV IPIP Median Median
(months)(months)PP HRHR Median Median
(months)(months)PP HRHR
SWOG SWOG 8501/8501/GOG GOG 104104
Cyclo 600 mg/mCyclo 600 mg/m22 IV q 21 days x 6 IV q 21 days x 6
Cisplatin 100 Cisplatin 100 mg/mmg/m22 IP q 21 IP q 21 days x 6 days x 6
NSNS NSNS NSNS 4949 .02.02 .76.76
Cyclo 600 mg/mCyclo 600 mg/m22 IV + cis 100 IV + cis 100 mg/mmg/m22 IV q 21 IV q 21 days x 6 days x 6
NoneNone NSNS NSNS NSNS 4141
GOG11GOG1144SWOG SWOG 92279227
CarboAUC 9 IV x CarboAUC 9 IV x 2 cycles; 2 cycles; paclitaxel 135 paclitaxel 135 mg/mmg/m22 IV 24 hrs IV 24 hrs day 1 q 21 days day 1 q 21 days x 6 x 6
Cis 100 mg/mCis 100 mg/m22 IP day 2 q 21 IP day 2 q 21 days x 6 cyclesdays x 6 cycles
27.927.9 .01.01 .78.78 63.263.2 .05.05 .81.81
Paclitaxel 135 Paclitaxel 135 mg/mmg/m22 IV 24 hrs IV 24 hrs day 1; cis 75 day 1; cis 75 mg/mmg/m22 IV day 2 q IV day 2 q 21 days x 6 21 days x 6
NoneNone 22.222.2 52.252.2
GOG GOG 172172
Paclitaxel 135 Paclitaxel 135 mg/mmg/m22 IV 24 hrs IV 24 hrs day 1day 1
Cis 100 mg/mCis 100 mg/m22 IP day 2 q 21 IP day 2 q 21 days x 6 ; days x 6 ; paclitaxel 60 paclitaxel 60 mg/mmg/m22 IP day 8 IP day 8
23.823.8 .05.05 .80.80 65.665.6 .03.03 .75.75
Paclitaxel 135 Paclitaxel 135 mg/mmg/m22 IV 24 hrs IV 24 hrs day 1; cisplatin day 1; cisplatin 75 mg/m75 mg/m22 IV day IV day 22
NoneNone 18.318.3 49.749.7
EORTC-led GCIG Trial Overall Survival: EORTC-led GCIG Trial Overall Survival: NACT + delayed debulking vs. NACT + delayed debulking vs. Primary debulking (Standard)Primary debulking (Standard)
Vergote IGCS 2008
NACT approach associated with significantly LESSPost-op sepsis
Post-op (1-28 d) mortality Gr 3/4 Bleeding
Gr 3/4 Thromboembolism
Basic DesignBasic Design
Patients with EOC
3-4 cycles neoadjuvant chemo
Initial surgery: < 1 cm residual
3 cycles IV Carbo/Taxol
3 cycles IP/IV platinum and taxol
Endpoints: PFS and OS
Design IssuesDesign Issues
QuestionsQuestionsWhich IP platinumWhich IP platinum??• some interested in some interested in
carboplatin basedcarboplatin based• some prefer cisplatin some prefer cisplatin
basedbased
Day 8 Taxol? Day 8 Taxol? (JGOG data suggest this may (JGOG data suggest this may be important and part of be important and part of impact of Armstrong impact of Armstrong regimen)regimen)
Dose IP cisplatin (75 or Dose IP cisplatin (75 or 100?)100?)
Design IssuesDesign Issues
QuestionsQuestions SolutionsSolutionsWhich IP platinumWhich IP platinum??• some interested in some interested in
carboplatin basedcarboplatin based• some prefer cisplatin some prefer cisplatin
basedbased
Use phase IIUse phase II III design and III design and evaluate carboplatin vs. evaluate carboplatin vs. cisplatin in phase II portion cisplatin in phase II portion so decision evidence basedso decision evidence based
Day 8 Taxol? Day 8 Taxol? (JGOG data suggest this may (JGOG data suggest this may be important and part of be important and part of impact of Armstrong impact of Armstrong regimen)regimen)
Add day 8 Taxol to ALL Add day 8 Taxol to ALL study armsstudy arms
Dose IP cisplatin (75 or Dose IP cisplatin (75 or 100?)100?)
Select 75 as dose since Select 75 as dose since exposure still enhanced, exposure still enhanced, toxicity less and this is in toxicity less and this is in keeping with practice keeping with practice
IV CarboIV Taxol
IP Carbo (Taxol)IV Taxol
IP Cisplatin (Taxol)IV TaxolPhase II
R
Then…..
IV CarboIV Taxol
IP Carbo (Taxol)IV Taxol
IP Cisplatin (Taxol)IV TaxolPhase II
IV CarboIV Taxol
IP Carbo (Taxol)IV Taxol
R
Phase III
This or…..
IV CarboIV Taxol
IP Carbo (Taxol)IV Taxol
IP Cisplatin (Taxol)IV TaxolPhase II
IV CarboIV Taxol
R
Phase III
IP Cisplatin (Taxol)IV Taxol
This…..
Details: Details: Phase IIPhase II Arms/DosesArms/Doses
Arm 1 (control)Arm 1 (control)Paclitaxel 135 mg/m2 (3 hr) IV day 1Paclitaxel 135 mg/m2 (3 hr) IV day 1
Carboplatin AUC 5(6) IV day 1 Carboplatin AUC 5(6) IV day 1 Paclitaxel 60 mg/m2 IV day 8Paclitaxel 60 mg/m2 IV day 8
Arm 2: Arm 2: IP cisplatin based: IP cisplatin based: Paclitaxel 135 mg/m2 (3 hr) IV day 1 Paclitaxel 135 mg/m2 (3 hr) IV day 1 Cisplatin Cisplatin 7575 mg/m2 mg/m2 IPIP day 1 day 1Paclitaxel 60 mg/m2 Paclitaxel 60 mg/m2 IPIP day 8 day 8
Arm 3:Arm 3: IP carboplatin based: IP carboplatin based: Paclitaxel 135 mg/m2 (3 hr) IV d1Paclitaxel 135 mg/m2 (3 hr) IV d1 Carboplatin AUC 5(6) Carboplatin AUC 5(6) IPIP day 1 day 1Paclitaxel 60 mg/m2 Paclitaxel 60 mg/m2 IPIP day 8 day 8
Repeat q 3 wk
x 3 cycles
Phase II: Phase II: Endpoints for selecting IP arm Endpoints for selecting IP arm
• 9-month progression rate post 9-month progression rate post randomizationrandomization
• Completion rate of treatment Completion rate of treatment (feasibility): to assess toxic effects (feasibility): to assess toxic effects and technical issuesand technical issues
Standard TherapyStandard Therapy
Patients with EOC
3-4 cycles neoadjuvant chemo
Initial surgery: < 1 cm residual
3 cycles IV Carbo/Taxol
at 9 mo post debulking, normally expect ~40%
pts to have progressed (based on
NCIC CTG and NCRI data)9 mo
Phase III endpointsPhase III endpoints
Primary EndpointPrimary Endpoint::• Progression free survivalProgression free survival
Secondary EndpointsSecondary Endpoints::• Overall survivalOverall survival• Toxic effectsToxic effects• Quality of lifeQuality of life• Translational research Translational research • Health Economic evaluationHealth Economic evaluation
Key Eligibility CriteriaKey Eligibility Criteria• HistologicallyHistologically confirmed initial FIGO stage confirmed initial FIGO stage IIB-III IIB-III
(?IV)(?IV) EOC, peritoneal or fallopian tube cancer EOC, peritoneal or fallopian tube cancer
• 3-4 cycles neoadjuvant platinum based 3-4 cycles neoadjuvant platinum based chemotherapychemotherapy
• TAH,BSO and cytoreductive surgery with residual TAH,BSO and cytoreductive surgery with residual disease 1 cm or less. disease 1 cm or less. Must be completed ≤ 4 Must be completed ≤ 4 weeks prior prior to randomizationweeks prior prior to randomization
• Adequate organ functionAdequate organ function
• Imaging after surgery prior to first cycleImaging after surgery prior to first cycle
• ECOG 2 or less 7 days prior to randomizationECOG 2 or less 7 days prior to randomization
• QoL questionaireQoL questionaire
• Note: if randomized in OR, must satisfy safety Note: if randomized in OR, must satisfy safety related eligibility before IP treatment startsrelated eligibility before IP treatment starts
Key Ineligibility CriteriaKey Ineligibility Criteria
• Prior chemotherapy for ovarian cancer (other than Prior chemotherapy for ovarian cancer (other than neoadjuvant)neoadjuvant)
• Borderline histologyBorderline histology
• CCF/ventricular arrhythmiasCCF/ventricular arrhythmias
• Bowel obstructionBowel obstruction
• At surgeryAt surgery
Left sided bowel resectionLeft sided bowel resection
Extensive intra/post operative adhesionsExtensive intra/post operative adhesions
• Experience with prior chemotherapyExperience with prior chemotherapy
> grade 1 peripheral neuropathy> grade 1 peripheral neuropathy
prior allergic reactionprior allergic reaction
StatusStatus• Study approved by:Study approved by:
– NCIC CTG NCIC CTG – NCRI (Nov 12/08)NCRI (Nov 12/08)– GEICOGEICO– SWOG committee (but no CTEP submission yet)SWOG committee (but no CTEP submission yet)– Interest in other groups??? (NB: no external funding)Interest in other groups??? (NB: no external funding)
• Protocol drafted and in mature formProtocol drafted and in mature form• IP guideline first draftIP guideline first draft• Need:Need:
– CTEP review/approvalCTEP review/approval– CTA submissions etcCTA submissions etc– IP workshop?IP workshop?– EDC trainingEDC training
DiscussionDiscussion
Statistics: Phase II PortionStatistics: Phase II Portion• 50 patients in each of the 3 arms 50 patients in each of the 3 arms
• Assesses ONLY the IP arms at time of analysis: Select Assesses ONLY the IP arms at time of analysis: Select the IP regimen based on the IP regimen based on efficacyefficacy and and tolerabilitytolerability
• EfficacyEfficacy: :
– The primary endpoint is the The primary endpoint is the rate of PD at 9 months post rate of PD at 9 months post randomizationrandomization
– 50 patients per arm: we have 90% power to detect the 50 patients per arm: we have 90% power to detect the “winner” the arm with “winner” the arm with true PD rate 12% lower than the true PD rate 12% lower than the otherother
– Also with this number, we have 80% power to test null Also with this number, we have 80% power to test null hypothesis that true PD rate is 52.5% or more (and thus hypothesis that true PD rate is 52.5% or more (and thus non-interesting---reject) non-interesting---reject) versusversus alternative that PD rate is alternative that PD rate is 35% or lower (interesting). 35% or lower (interesting).
• FeasibilityFeasibility: not feasible if fewer than 50% patients : not feasible if fewer than 50% patients can complete planned IP therapycan complete planned IP therapy
Statistics Phase III PortionStatistics Phase III Portion• Progression free survival:Progression free survival:
– Seek improvement of IP over control with Seek improvement of IP over control with hazard ratio of 0.8 (Median 17hazard ratio of 0.8 (Median 1721.3 mo) 21.3 mo)
– 80% power, 2-sided alpha 0.0580% power, 2-sided alpha 0.05
– Need 631 progression events (if Need 631 progression events (if one sidedone sided alpha: need 497 progression events)alpha: need 497 progression events)
– To detect need an To detect need an additionaladditional 630 patients 630 patients randomized (490 randomized (490 additionaladditional if if one-sided one-sided alpha) (assuming 200 patients per year alpha) (assuming 200 patients per year recruited) after phase II recruited) after phase II completed completed
– Overall Survival:Overall Survival: Same numbers will detect Same numbers will detect hazard ratio of 0.80 once 631 (or 497) hazard ratio of 0.80 once 631 (or 497) deaths seendeaths 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 PortionStatistics: Phase II Portion
• TolerabilityTolerability criteria: criteria:
– Assess completion rate of IP Assess completion rate of IP treatment. Assume regimen would be treatment. Assume regimen would be interesting if >70% can complete 3 interesting if >70% can complete 3 cycles and uninteresting if < 50% cycles and uninteresting if < 50% complete 3 cycles. Using these complete 3 cycles. Using these figures, arm(s) selected will be figures, arm(s) selected will be abandoned if >= 29/50 patients abandoned if >= 29/50 patients cannot complete IP therapy cannot complete IP therapy
Study QuestionStudy Question
• To determine if To determine if 3 cycles of IV/IP 3 cycles of IV/IP chemotherapychemotherapy improves progression free improves progression free (PFS) and overall survival (OS) compared to (PFS) and overall survival (OS) compared to 3 cycles of standard IV carboplatin/paclitaxel3 cycles of standard IV carboplatin/paclitaxel following following optimal debulking optimal debulking at initial surgery at initial surgery performed after 3-4 cycles neoadjuvant performed after 3-4 cycles neoadjuvant chemotherapy in patients with EOC.chemotherapy in patients with EOC.
• If positive, this trial would also offer If positive, this trial would also offer evidence to support the use of only 3 IP evidence to support the use of only 3 IP cycles of treatmentcycles of treatment
SGCTG/NCRIGCIG 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 SGCTGAndrew Clamp NCRIHani Gabra SGCTG