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: philipp.harter@hsk-wiesbaden.de

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