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UPDATE ON GCIG TRIALS FOR EPITHELIAL OVARIAN
CANCER Christian Marth

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Ovarian Cancer
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Ovarian Cancer
Diagnosis
Surgery
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Closed Trials
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EORTC 55971/CHORUS
Upfront Surgery vs Neoadjuvant
Chemotherapy Patients closed / 550 Leading
EORTC Participating NCIC CTG
Presentation planned at IGCS 2008
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Randomised trial comparing primary debulking
surgery (PDS) with neoadjuvant chemotherapy
(NACT) followed by interval debulking (IDS) in
stage IIIC-IV ovarian,fallopian tube and
peritoneal cancer.
7
Randomised EORTC-GCG/NCIC-CTG trial on NACT IDS
versus PDSSurgical characteristics (PP1)
PDS (n 329) NACT -gt IDS (n 339)
Postoperative mortality (lt 28 days) 2,7 0,6
Postoperative sepsis 8 2
Fistula (bowel/GU) 1,2 / 0,3 0,3 / 0,6
Operative time (minutes) 180 180
Red blood cell transfusion 51 53
Hemorhage Grade 3/4 7 1
Venous Gr 3/4 2,4 0,3
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NACT IDS versus PDS ITT
Median PFS PDS 12 months IDS 12 months
HR for IDS0.99 (0.87, 1.13)
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Ovarian Cancer
First-line Chemotherapy
Consolidation
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AGO-OVAR-9
Carbo Paclitaxel /- Gemcitabine Patients
closed 1742 Leading AGO-OVAR Participati
ng GINECO, NSGO,
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GCIG Intergroup study (AGO-OVAR/GINECO/NSGO)
Protocol AGO-OVAR 9
RANDOMISATION
Gemcitabine 800 mg/m² d18 iv Paclitaxel 175
mg/m² 3 h iv Carboplatin AUC 5 iv

• Strata
• FIGO stage
• post-op residual
• tumor
• Surgery
• Interval-surgery y/n
• Center

q 21 x 6
Paclitaxel 175 mg/m² 3 h iv Carboplatin AUC
5 iv
q 21 x 6
evaluated in preceding Phase II Study protocol
AGO-OVAR 8
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Progression-free Survival (RECIST GCIG CA125)
by Therapy within Stratum 23 (FIGO IIB-IV)
Kaplan-Meier
TC 793 pts. / 588 evts. median 16.0 14.9-17.4
mos. TCG 774 pts. / 629 evts. median 14.7
14.0-15.9 mos.
HR 1.17 95 CI 1.05-1.31 Logrank test p
0.0065
months
Patients at risk
793 699 511 351 270 225 191 152 95 43 14 2 774 6
85 483 307 228 185 155 116 72 36 12 2
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Overall Survival by Therapy within Stratum 23
(FIGO IIB-IV)
TC 793 pts. / 401 evts. median 48.9 43.1-51.2
mos. TCG 774 pts. / 404 evts. median 45.8
40.0-49.5 mos.
P r o b a b i l i t y
HR 1.03 95 CI 0.90-1.18 p 0.6955
months
Patients at risk
793 750 705 638 557 489 420 338 226 89 31 5 774 74
0 693 628 554 484 411 322 208 87 28 5
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SCOTROC 4
Carbo Flat Dosing vs Intrapatient Dose
Escalation Patients closed 932 Leading
SGCTG Participating ANZGOG
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Tarceva Trial EORTC 55041
Tarceva consolidation 2 years Primary
Chemotherapy Control Patients
closed / 835 Leading EORTC Participating
AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO
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ICON-7
TC BEVACIZUMAB Patients
closed / 1520 Leading MRC/NCRI Participating
NCIC CTG, AGO OVAR, GINECO, GEICO EORTC,
ANZGOG, NSGO
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GOG 218
CT vs CT Bevacizumab Placebo vs CT
Bevacizumab concurrent and extended Patients
closed / 1800 Leading GOG Participating
ECOG, NCCTG, NSABP, SWOG
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Ovarian Cancer
Platinum-sensitive Recurrence Surgery Chemotherapy
Platinum-resistant Recurrence
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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 CanadianAustralian
centers Report IGCS 2008
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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)
Score negative 255 pts (49)
Surgery 148 pts (57)
No surgery 113 pts (43)
No surgery 175 pts (69)
Surgery 80 pts (31)
Study collective AGO score 1st relapse 129 pts
(87)
1st relapse 64 pts (80)
2nd relapse 19 pts (13)
2nd relapse 16 pts (20)
Selection process 228 pts (44.2) had
cytoreductive surgery for recurrent OC -gt
Primary study collective (AGO score , 1st
relapse) 129 pts (25)
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AGO DESKTOP OVAR II SURGICAL RESULTS
Frequency of complete resection by applying the
AGO Score
DESKTOP Hypothesis
complete resection in 76 of the study
collective AGO score could predict complete
resection in at least 2 out of 3 patients
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AGO DESKTOP OVAR II CONCLUSIONS

• 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

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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
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Ovarian Cancer
Diagnosis
Surgery
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AGO OVAR OP.3 (LION)
Lymphadenectomy In Ovarian Neoplasms
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
System. Lymphadenectomy

• pelvic
• para-aortic

R
n 640
no Lymphadenectomy
Endpoints OS, PFS, QoL Strata centre, PS
,age
Supported by Deutsche Forschungsgemeinschaft
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Participating groups/sites AGO Study Group (24
centres initiated) MITO (11 centres planned
ethical approval 06/09) KGOG AGO Austria Single
sites Leuven
Recruitment 26 / 640 pts
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Ovarian Cancer
First-line Chemotherapy
Consolidation
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JGOG-3017 Clear Cell Carcinoma
CT vs CDDP Irinotecan Patients
360 / 652 Leading JGOG Participating GIN
ECO, GOG, KGOG, MITO, SGCTG
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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 Toru Sugiyama, MD (Iwate Medical
University) Study Co-Chair Seiji Isonishi, MD
(Jikei University School of Medicine)
Fumitoshi Terauchi, MD (Toho University)
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International Cooperative Phase III Study for
Clear Cell Carcinoma
TC Paclitaxel 175 mg/m2 (d1)
Carboplatin AUC 6 (d1) Every 3 wk x 6
-Clear Cell Ca -Stage IIV
RANDOMIZATION
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
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JGOG3017/GCIG Trial
JGOG 345 KGOG 15
As of 5/27/2009
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MucinousEOC
oxaliplatin capecitabine bevacizumab vs
carboplatin paclitaxel bevacizumab
Patients 0/332 Leading NCRI/SGCTG
GOG Participating AGO OVAR, GINECO, MaNGO,
NSGO, KGOG
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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
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2x2 Factorial Trial Design
mEOC FIGO stages IIIV OR recurrent stage I No
previous chemotherapy gt18yrs PS0-2
Randomise
(332 patients 83 patients in each arm)
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
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
Clinical 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, AUC6,
if GFR has been measured, AUC5 Bevacizumab can
be omitted from the first cycle of if
chemotherapy must be started within 4 weeks of
surgery.
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MITO-7
Weekly CT vs 3-weekly CT (QoL) Patients 25
/ 500 Leading MITO Participating MaNGO,
AGO-OVAR
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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
• Risk of progression at 18 months as primary
  end-point

Carboplatin AUC 6 Paclitaxel 175 mg/mq
day 1 - every 21days
RANDOM
Carboplatin AUC 2 Paclitaxel 60 mg/mq
day 1,8 15 - every 21days
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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

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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)

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Administrative information and status of the trial

• NCI of Naples is the sponsor
• Study started November 10 2008
• The expected duration of the study 20 months
• 49 centers (43 MITO 6 MANGO), 5 open
• 25 patients enrolled

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Pathway to diagnosis of ovarian cancer an
observational retrospective multicentered study
MITO Nursing
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Study objectives

• Describe frequency and duration of symptoms in
  the 12 months preceding ovarian cancer diagnosis
• Describe time intervals (weeks) of sentinel
  events
• onset of first persistent symptoms
• first physician visit
• Cyto-histological diagnosis of ovarian cancer
• Classify diagnostic delays according to the
  expanded Andersens model of total patient delay.

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Methods

• Patient compilation of ovarian cancer symptom
  survey
• Review of clinical documentation
• Directed patient interview1
• Corner J, Hopkinson J, Fitzsimmons D, Barcaly s,
  Muers M (2005). Is late diagnosis of lung cancer
  inevitable? Interview study of patients
  recollections of symptoms before diagnosis.
  Thorax 60 314-39.

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Pathway to diagnosis of ovarian cancer an
exploratory study
Time Intervals in weeks
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Coordinating centreClinical Trials Unit
National Cancer Institute Naples

• https//uosc.fondazionepascale.it
• Web-based procedures
• Register to be authorized user
• Identify study of interest (MITO nursing)
• Download documents and submit for Ethics
  Committee evaluation
• Study data entry
• Research nurse coordinator jane.bryce_at_uosc.fonda
  zionepascale.it

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JGOG IP Trial
IP vs IV carboplatin weekly Paclitaxel
Patients Leading JGOG Participating

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Planned Japanese IP Trial
Epithelial Ovarian Cancer Stages II-IV Excluding
Clear Cell Carcinoma
Randomization
Paclitaxel 80 mg/m2 IV Weekly Carboplatin AUC 6
IV Q21, 6-8 Cycles
Paclitaxel 80 mg/m2 IV Weekly Carboplatin AUC 6
IP Q21, 6-8 Cycles
Primary Endpoint PFS Secondary Endpoint OS,
Toxicity, QOL, Cost
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NCIC CTG OV.21
IP/IV Platinum/T vs IV CT optimally debulked
following NACT Patients 0 / 780 Leading
NCIC CTG Participating GEICO, NCRI, SWOG
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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

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Participating Centres

• Lead group NCIC CTG
• Collaborators NCRI (UK), GEICO (Spain)

Canada
UK
USA?
Spain
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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 trial neoadjuvantupfront with lower
  morbidity!!!
• Patients undergoing neoadjuvant chemotherapy not
  included in IP studies

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• Do EOC patients who have received neoadjuvant
  chemotherapy benefit from IP therapy?

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Basic Design
Patients with EOC
3-4 cycles neoadjuvant chemo
Initial surgery lt 1 cm residual
3 cycles IV Carbo/Taxol
3 cycles IP/IV platinum and taxol
Endpoints PFS and OS
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IV Carbo IV Taxol
IP Carbo (Taxol) IV Taxol
IP Cisplatin (Taxol) IV Taxol
Phase II
Then..
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This or..
IV Carbo IV Taxol
IP Carbo (Taxol) IV Taxol
IP Cisplatin (Taxol) IV Taxol
Phase II
Phase III
IP Carbo (Taxol) IV Taxol
IV Carbo IV Taxol
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This..
IV Carbo IV Taxol
IP Carbo (Taxol) IV Taxol
IP Cisplatin (Taxol) IV Taxol
Phase II
Phase III
IP Cisplatin (Taxol) IV Taxol
IV Carbo IV Taxol
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Phase II Endpoints for selecting IP arm.

• 9-month progression rate post randomization
• Completion rate of treatment
• Toxic effects
• Feasibility

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Phase III endpoints

• Primary Endpoint
• Progression free survival
• Secondary Endpoints
• Overall survival
• Toxic effects
• Quality of life

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Key Eligibility Criteria

• Histologically confirmed initial FIGO stage
  IIB-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.
• Adequate organ function
• ECOG 2 or less 7 days prior to randomisation

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Study Arms Phase II

• Arm 1
• Day 1Paclitaxel 135 mg/m2 IV day 1 plus
  carboplatin AUC 5 (measured)/ AUC 6
  (calculated) IV
• Day 8Paclitaxel 60 mg/m2 IV day 8
• Q 21 days x 3 cycles

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Study Arms Phase II

• Arm 2
• Day 1 Paclitaxel 135 mg/m2 IV plus
  Cisplatin 75 mg/m2 IP
• Day 8 Paclitaxel 60 mg/m2 IP
• Q 21 days x 3 cycles

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Study Arms Phase II

• Arm 3
• Day 1 Paclitaxel 135 mg/m2 IV plus
  carboplatin AUC 5 (measured)/ AUC 6
  (calculated) IV IP
• Day 8 Paclitaxel 60 mg/m2 IP
• Q 21 days x 3 cycles

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Statistics Phase III Portion

• Progression free survival
• Seek improvement of IP over control with hazard
  ratio of 0.8 (Median increase PFS 4.3 mo, 17
  21.3 mo)
• 80 power, 2-sided alpha 0.05
• Need 631 progression events
• To detect need additional 630 patients
  randomized after phase II completed
• Overall Survival Same numbers will detect hazard
  ratio of 0.80 once 631 deaths seen (10 month
  increase in median survival)
• Total no of patients 780

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Other points!!

• Quality of Life
• Correlative studies
• Economic analysis
• Nursing studies

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OV.21 Nursing Study

• Objectives
• Correlate nursing practices associated
  with IP therapy with treatment efficacy, toxic
  effects and quality of life.
• Rationale
• To date there are no trial based
  evidence that defines best nursing practice
  related to administration of IP chemotherapy
• Design
• Questionaire
• Patient positioning during and after
  administration of IP therapy
• The pre-warming of IP fluid
• The use of home hydration practices after
  administration of IP therapy.

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Plan

• Protocol at final stage of development
• Planned Health Canada submission May 2009
• Anticipated central activation July/August 2009
• IP guidelines developed to accompany study

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AGO-OVAR-12
Carbo Paclitaxel /- BIBF 1120 (Vargatef)
Patients 0 / 1300 (21 random) Leading
AGO-OVAR Participating AGO Austria, BGOG,
GINECO, MANGO, MITO, NSGO, US Oncology

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AGO-OVAR12
Multicenter, randomised, double-blind, Phase III
trial to investigate the efficacy and safety of
Vargatef (BIBF 1120) in combination with standard
treatment of carboplatin and paclitaxel compared
to placebo plus carboplatin and paclitaxelin
patients with advanced ovarian cancer
2
SURGERY
Vargatef / Placebo - no intake on days of
chemotherapy - dose 200 mg po bid (combi
mono) - dose adaptation in case of undue
toxicity - max. duration of 120 weeks in
non-progressing pts
q21d / 6 courses
1
n1300
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Participating groups
AGO Study Group AGO Austria BGOG GINECO MANGO MITO
NSGO US Oncology
First patient in September 2009 Recruitment
0/1300
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AGO-OVAR 16
Pazopanib consolidation 1 yr First Line
Chemotherapy Control Patients 0 /
900 Leading AGO-OVAR Participating AGO
Austria, ANZGOG, BGOG, GEICO, GINECO, ICORG,
JGOG, KGOG, MANGO, MITO, NSGO, US-Sites
California Consortium, NY GOG, SWOG
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AGO-OVAR16
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
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Participating groups
AGO Study Group AGO Austria ANZGOG BGOG GEICO GINE
CO ICORG JGOG KGOG MANGO MITO NSGO US-Sites
California Consortium, NY GOG, SWOG
First patient in June 2009 Recruitment 0/900
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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 design Randomisation weighted
in favour of research arms 122222 Number of
patients requires further discussion on what is
needed to demonstrate feasibility

• Aim of stage 1 is to establish which arms should
  be taken into stage 2 based.
• Primary outcome measures
• Toxicity
• Feasibility

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ICON8 Stage 2 trial design if ICON7 and GOG 218
are positive are positive for PFS Option 1 21
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
• PFS
• TOXICITY
• HE
• QOL
• TR

21 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)
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ICON 8 If bevacizumab trials negative for
PFS 3 arm 11 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
• PFS
• Toxicity
• HE
• QoL
• TR

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Ovarian Cancer
Platinum-sensitive Recurrence Surgery Chemotherapy
Platinum-resistant Recurrence
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AGO-OVAR-OP.4 DESKTOP III
Cytoreductive surgery vs NO surgery in
platinum-sensitive recurrent EOC Patients 0
/ 385 Leading AGO-OVAR Participating ?
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AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
A randomized trial evaluating cytoreductive
surgery in patients with platinum-sensitive
recurrent ovarian cancer

• Complete resection seems feasible and a positive
  AGO-score
• Strata
• Platinum-free-interval
• 6-12 vs gt 12 months
• 1st line platinum
• based chx yes vs no

Cytoreductive surgery
R A N D O M
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

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AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

• Primary objective
• - Overall survival
• Secondary objectives
• - Progression-free survival
• - Quality of Life EORTC QLQ 30 and NCCN FOSI
• - Rate of complete resection as prognostic factor
• - Complication rates of surgery
• Exploratory analysis of surgical characteristics
  
• and chemotherapy

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AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

• Inclusion criteria (1)
• Patients with 1st recurrence of platinum
  sensitive, invasive epithelial ovarian-,
  fallopian tube- or primary peritoneal cancer of
  any inital stage
• Progression-free interval of at least 6 months
  after end of last platinum based chemotherapy,
  recurrence within 6 months or later after primary
  surgery if the patient has not received prior
  chemotherapy in patients with FIGO I. Non
  cytostatic maintenance therapy not containing
  platinum will not be considered for this
  calculation

80
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

• Inclusion criteria (2)
• Complete resection seems feasible and a positive
  AGO-score
• (1) Performance status ECOG 0
• (2) Complete resection at 1st surgery (if
  unknown FIGO I/II). If report from 1st surgery
  is not available contact study chairman
• (3) Absence of ascites (cut off 500 ml
  radiological or ultrasound estimation)
• Complete resection of the tumor by median
  laparotomy seems feasible. Intra-abdominal
  disease has to be excluded by MRI/CT, if other
  surgical approaches for extra-abdominal
  recurrences only are planned
• Patient is willing to accept result of
  randomisation
• Age gt 18 years, signed and written informed
  consent

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AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

• Exclusion criteria (1)
• Patients with non-epithelial tumors or
  borderline tumors
• Patients without recurrence, but are scheduled
  for diagnostic/second-look surgery or debulking
  surgery after completion of chemotherapy
• Patients with second, third or later recurrence
• Patients with secondary malignancies who have
  been treated by laparotomy, as well as other
  neoplasms, if the treatment might interfere with
  the treatment of relapsed ovarian cancer or if
  major impact on prognosis is expected

82
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

• Exclusion criteria (2)
• Patients with so-called platinum-refractory
  tumor, i.e. progression during chemotherapy or
  recurrence within 6 months atfe end of former
  first platinum-containing chemotherapy
• Only palliative surgery planned
• Metastases not accessible to surgical removal
• Any concomitant disease not allowing surgery
  and/or chemotherapy
• Any medical history indicating excessive
  peri-operative risk
• Any current medication inducing considerable
  surgical risk (e.g. anticoagulant agents,
  bevacizumab)

83
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
Datamanagemt and Randomisation e-CRF
(MACRO) Central Monitoring Statistics HR 0.7
favouring surgery Sample size 385 patients/244
events Recruitment 36 months Participating
groups from GCIG - protocol will be sent out
soon to everybody Again no full funding -
participating groups have to pay local costs
84
HECTOR
Carbo Topo vs Chemo (CT or CG) in recurrent
Platinum-sensitive ovarian cancer Patients
452 / 550 Leading NOGGO/AGO-OVAR Partic
ipating AGO-AUSTRIA, GEICO
85
MITO-8
PLD vs CT cross-over in 6-12 m platinum-free
interval Patients 25 / 253 Leading
MITO Participating MaNGO, AGO-OVAR
86
Liposomal doxorubicin stealth vs
carboplatin/taxol in recurrent ovarian cancer
patients with platinum-free interval between 6-12
months
MITO - 8
87
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 day1 every 28 days
CARBOPLATIN AUC 5 PACLITAXEL 175 mg/mq 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
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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)

89
Administrative information and status of the trial

• NCI of Naples is the sponsor
• Study started November 10 2008
• The expected duration of the study 20 months
• 56 centers (43 MITO 7 MANGO, 6 Belgium), 12 open
• 3 patients enrolled
• AGO grant application ongoing

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Thank you for your attention http//www
.mito-group.it sandro.pignata_at_fondazionepascale.it

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(No Transcript)
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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.

93
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

94
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

95
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

96
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

• Trial Status
• 9 Centres Open 6 UK 3 Canada
• 31 patients recruited.

97
ICON6Multistage 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

OPEN 5 sites in UK 5 in Canada 1/08

• 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

98
SGCTG/NCRIGCIG 29th May 2008A
Randomised Phase III Trial of Weekly Carboplatin
and Paclitaxel versus Pegylated Liposomal
Doxorubicin In Recurrent, Platinum Resistant,
Ovarian CancerRos Glasspool SGCTGAndrew Clamp
NCRIHani Gabra SGCTG
99
Ovarian Cancer
100
UPDATE ON GCIG TRIALS FOR EPITHELIAL OVARIAN
CANCER

• GCIG has demonstrated to perform very efficient
  important clinical trials which have changed the
  standard of care in the treatment of ovarian
  cancer
• Main focus has been first-line chemotherapy
• Surgical questions have been raised recently
• Treatment options in platinum-resistant recurrent
  disease should be further develloped

101
Thank you for attention