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Ovarian CancerCommittee Agenda
Summary of ongoing and recently closed trials Christian Marth
AGO-OVAR OP.4/Desktop III trial Phillipp Harter
ICON-8 Jonathan
Lederman
MucinousEOC – GOG 241 Jonathan
Lederman
NCIC CTG OV21: A Phase II/III Study of Intraperitoneal (Ip) Diane Provencher
Plus Intravenous (Iv) Chemotherapy Versus Iv Carboplatin
Plus Paclitaxel In Patients With Epithelial Ovarian Cancer
Optimally Debulked At Surgery Following Neoadjuvant
Intravenous Chemotherapy
DDPC-PREOC: A randomised phase III trial of weekly Ros Glasspool
carboplatin and paclitaxel versus pegylated liposomal
doxorubicin in recurrent, platinum resistant, epithelial ovarian cancer
Upfront Surgery vs Neoadjuvant Chemotherapy
Patients closed / 550
Leading EORTC
Participating NCIC CTG
Presentation IGCS 2008
EORTC 55971/CHORUS
NACT + IDS versus PDS: ITT
Median PFS
PDS: 12 months
IDS: 12 months
HR for IDS:0.99 (0.87, 1.13)
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment320 360 168 60 39 26 17 7 2
320 357 177 60 36 20 13 3 1
Upfront debulking surgery
Neoadjuvant chemotherapy
Progression-free survival
Carbo Paclitaxel +/- Gemcitabine
Patients closed 1742
Leading AGO-OVAR
Participating GINECO, NSGO
Presented ASCO 2009
AGO-OVAR-9
AGO Ovarian Cancer Study Group (AGO-OVAR)AGO Ovarian Cancer Study Group (AGO-OVAR)
GCIG Intergroup study (AGO-OVAR/GINECO/NSGO) Protocol # AGO-OVAR 9
RANDOMISATION q 21 x 6
Strata:
* FIGO stage
* post-op residual tumor
* Surgery
Interval-surgery y/n
* Center
Paclitaxel 175 mg/m² 3 h iv
Carboplatin AUC 5 iv
q 21 x 6
Gemcitabine 800 mg/m² d1+8 iv
Paclitaxel 175 mg/m² 3 h iv
Carboplatin AUC 5 iv *
* evaluated in preceding Phase II Study protocol # AGO-OVAR 8
0
0,25
0,5
0,75
1
0 6 12 18 24 30 36 42 48 54 60 66 72
Progression-free (RECIST & GCIG CA125) and Overall Survival Progression-free (RECIST & GCIG CA125) and Overall Survival by Therapy within Stratum 2+3 (FIGO IIB-IV)by Therapy within Stratum 2+3 (FIGO IIB-IV)
HR = 1.17 [95% CI: 1.05-1.31]
p = 0.0065
TCTC 793 pts. / 588 evts.793 pts. / 588 evts. median 16.0 [14.9-17.4] mos.median 16.0 [14.9-17.4] mos.
TCGTCG 774 pts. / 629 evts.774 pts. / 629 evts. median 14.7 [14.0-15.9] mos.median 14.7 [14.0-15.9] mos.
P r
o b
a b
i l
i t
y
0
0,5
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78
[[monthsmonths]]
HR = 1.03 [95% CI: 0.90-1.18]
p = 0.6955
TCTC 793 pts. / 401 evts.793 pts. / 401 evts. median 48.9 [43.1-51.2] mos.median 48.9 [43.1-51.2] mos.
TCGTCG 774 pts. / 404 evts.774 pts. / 404 evts. median 45.8 [40.0-49.5] mos.median 45.8 [40.0-49.5] mos.
Carbo Flat Dosing vs Intrapatient Dose Escalation
Patients closed 937Leading SGCTG
Participating ANZGOG
Report ASCO 2009
SCOTROC 4
... tria
l has
been closed
to
recruitment,
with no evidence of
benefit for
intra-patie
nt dose
escalation of c
arboplatin.
Tarceva consolidation 2 yearsPrimary Chemotherapy
Control
Patients closed / 835
Leading EORTC
Participating AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO
Tarceva Trial EORTC 55041
TC ± BEVACIZUMAB
Patients closed / 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 closed / 1800
Leading GOG
Participating ECOG, NCCTG, NSABP, SWOG
GOG 218
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
AGO-OVAR-OP.2 DESKTOP II
Study collective: AGO score + 1st relapse129 pts (87%)
08/06 – 03/08: Screening of 516 pts with platinum-sensitive relapse in 46 centres
Score positive+
First relapse
Frequency of complete resection by applying the AGO Score
76%Completeresection
TC vs C + CaelyxPatients closed / 976
Leading GINECO
Participating AGO-AUSTRIA, AGO-OVAR, ANZGOG, EORTC, MANGO, MITO, NCIC/CTG, NSGO
Presentation ASCO 2009
CALYPSO
Progression-Free Survival (ITT)
CD CP
Median PFS, mo 11.3 9.4
HR (95% CI) 0.82 (0.72, 0.94)
Log-rank p-value (superiority) 0.005
P-value (non-inferiority) <0.001
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 Strata: centre, PS ,age
Lymphadenectomy In Ovarian Neoplasms
AGO – OVAR OP.3 (LION)
80/ 640
Supported by Deutsche Forschungsgemeinschaft
Cytoreductive surgery vs NO surgery in platinum-sensitive recurrent EOC
Patients 0 / 385
Leading AGO-OVAR
Participating ?
AGO-OVAR-OP.4 DESKTOP III
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 > 12 months
- 1st line platinum
based chx: yes vs no
RANDOM
Cytoreductivesurgery
platinum-basedchemotherapy*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
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, prognostic factors
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 OR 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
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
Inclusion criteria (2):
A positive AGO-score: Obligatory requirements for a positive AGO recurrence score in platinum-sensitive disease:
(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 possible (estimated by an experienced surgeon). Intra-abdominal disease has to be excluded by MRI/CT, if other surgical approaches for extra-abdominal recurrences only are planned
- Age > 18 years, signed and written informed consent
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
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)
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
Datamanagemt: e-CRF (MACRO)
Randomisation: Fax
Central Monitoring/Queries: AGO
Statistics: HR 0.7 favouring surgery
Sample size: 408 patients/244 events
Recruitment: 36 months
IDMSC: R. Coleman (chair), J. Berek, D Chi, J. Paul (statistics)
The next steps:
Protocol finalized (-> review participating groups)
Ethical approval for Germany:12/09 -> FPI 01/2010
Identifikation of interested GCIG-groups/single centres
-> representatives contact:
p.harter@gmx.de
office-wiesbaden@ago-ovar.de
Again limited funding - participating groups have to pay local costs
(DESKTOP II model – Presentation/Publication/Co-authorship)
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
Carbo Paclitaxel +/- BIBF 1120 (Vargatef)
Patients 0 / 1300 (2:1 random)
Leading AGO-OVAR
Participating AGO Austria, BGOG, GINECO,
MANGO, MITO, NSGO, US Oncology
AGO-OVAR-12
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 paclitaxel patients with advanced ovarian cancer
AGO-OVAR12
R
CT
CT
CT
CT
CT
CT
CT
CT
CT
CT
CT
CT
= Vargatef 2 x 200 mg po qd
= Placebo
120 weeks
C = Carboplatin AUC 5-6 d1
T = Paclitaxel 175 mg/m2 (3h) d1
q21d / 6 courses
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
SURGERY
n=1300
Pazopanib consolidation 1 yrFirst 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
AGO-OVAR 16
AGO-OVAR16A 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
Survival Follow-up(post-PD)
First-line Chemotherapy
(allow ip, neoadj) Placebo
(12 months)
Pazopanib (12 months)
If not PD
Treatment PeriodR
ANDOMIZE
Observation (to PD)
ScreeningBaseline
Post-Treatment Period
Follow-up Period
Carbo Topo vs Chemo (CT or CG) in recurrent Platinum-sensitive ovarian cancer
Patients 508 / 550
Leading NOGGO/AGO-OVAR
Participating AGO-AUSTRIA, GEICO
HECTOR
CT vs CDDP + Irinotecan
Patients 396 / 652
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)
RA
ND
OM
IZA
TIO
NTC
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
First line weekly carboplatin and paclitaxel vs every 3 weeks
carboplatin/paclitaxel in patients with ovarian cancer:
Phase III multicenter trial
MITO - 7
Trial design
• Aim of the trial is to compare the quality of life of weekly somministration of carboplatin plus carboplatin (experimental arm) versus every 3 weeks administration of the same drugs (standard arm) in 1°-line advanced ovarian, tubal and peritoneal cancer
RANDOM
Carboplatin AUC 2Paclitaxel 60 mg/mq
day 1,8 15 - every 21days
Carboplatin AUC 6Paclitaxel 175 mg/mq
day 1 - every 21days
Statistics
• Phase 3 open-label multicentre trial• Quality of life as primary end-point
– Difference in FACT-O after 9 weeks: 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)
Collaborative Nursing Study MITO12Pathway to diagnosis of ovarian cancer in Italian
women: an exploratory study
Primary Objectives• Describe the frequency and duration of symptoms in
the 12 months preceding the diagnosis of ovarian cancer (Goff symptoms survey)
• Describe time intervals of sentinel events– Onset of persistent symptoms– First physician visit– Diagnosis of ovarian cancer
• Describe the pathway to diagnosis according to Andersen’s model of “total patient delay”
PLD vs CT cross-overin 6-12 m platinum-free interval
Patients 18 / 253
Leading MITO
Participating MaNGO, AGO-OVAR, Belgium
MITO-8
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
MITO8 – Groups involved
• MaNGo (8 centers)
• Belgium (15 centers)
• AGO (funding application approved;
soon ready to go)
• Others?
• 18 patients enrolled (5 in September)
ICON6: A randomised trial of concurrent (with platinum based chemotherapy) and maintenance
cediranib (AZD2171, Recentin) in women with platinum-sensitive relapsed ovarian cancer.
Gynaecologic Cancer Intergroup TrialStage 1 MRC/NCRI, NCIC
Stage 2 ANZ-GOG, IMN, EORTC, GINECO, GEICO, MANGO, NSGO, ICMB and others
ICON 6 Start up slidesOct 2009
ICON 6 Design schema
Arm AReference arm
6 cycles of chemotherapy
plusPlacebo
No Progressive disease
Maintenancecediranib after chemotherapy
Maximum 18 months from
randomisation
Arm BChemotherapy
Pluscediranib
during Chemotherapy
Arm CChemotherapy
pluscediranib
during Chemotherapy
No Progressive diseasePlacebo
Maximum 18 months from
randomisation
No Progressive diseasePlacebo
Maximum 18 months
from randomisation
2:3:3 RANDOMISATION
ICON 6 Start up slidesOct 2009
Outcome measures
Stage I- Safety• Safety analysis after ~ 33 patients entered
into Arms B & C at 20mg doseStage II – Activity• ~ 50 deaths, 90 events, ~ 450 patients• Progression free survival (PFS)• Overall survival (OS)Stage III- Confirmation of Efficacy• Overall survival (OS)• Progression-free survival (PFS)• Toxicity• Quality of life, Health Economics,
Translational substudies
ICON6 Cediranib Dose Reduction
• Cediranib dose initially selected at 30mg/d in ICON6. Reduced to 20 mg
• Stage I re-started• Stage I now completed 103 patients
entered (11 UK; 6 CDN)• Stage II being prepared with expansion
of chemotherapy options to be discussed by ITMG Sunday 11th Oct- Belgrade
ICON 6 Start up slidesOct 2009
Recruitment Prediction
• Based on recruitment to date450 new patients by Oct 2010 (550 patients in total)
• Stage 2 data maturityExpected 90 PFS events and 50 deaths in control arm would be observed by April 2011
CLINICAL TRIAL
TR QoL
HE
Other groups
ICON 6 Start up slidesOct 2009
Summary
• Academic GCIG Trial with MRC/NCRI Group as lead group
• Coordinated by MRC CTU• Sponsored by MRC (UK)• UK CTAAC funding for MRC CTU• Administrative support from AZ for international
coordination• Grant from AZ to cover coordination by GCIG groups
and some per patient support• After publication data may be used by AZ to support
license extension• AZ support for TR sample collection at Stage 2 -
under discussion
Collaborative Nursing Study MITO12Pathway to diagnosis of ovarian cancer in Italian
women: an exploratory study
Primary Objectives• Describe the frequency and duration of symptoms in
the 12 months preceding the diagnosis of ovarian cancer (Goff symptoms survey)
• Describe time intervals of sentinel events– Onset of persistent symptoms– First physician visit– Diagnosis of ovarian cancer
• Describe the pathway to diagnosis according to Andersen’s model of “total patient delay”
Weekly Paclitaxel vs weekly Paclitaxel and Pazopanib in patients with
resistant/refractoryovarian cancer:
Phase II randomized multicenter trial
MITO - 11
Trial design
• Aim of the trial is to compare the PFS of weekly paclitaxel vs weekly paclitaxel and pazopanib
RANDOM
Pazopanib 800 mg/dayPaclitaxel 80 mg/mq
day 1,8 15 - every 28days
Paclitaxel 80 mg/mq
day 1, 8, 15 - every 28 days
Statistics
• Phase 2 open-label multicentre trial
• Assuming a median PFS in the control arm equal to 3
months (Kristensen ASCO 2008) and a median PFS
in the experimental arm equal to 4.6 months
(corresponding to a Hazard ratio of 0.65) 61 events
are required (East 5 software). With a possible
accrual rate of 4 patients/month, 72 patients (36 for
each arm) will be enrolled in about 1.5 year
• Planned to start December 2009
IP Trial under Planning in JGOG
IntraPeritoneal therapy for Ovarian Cancer with Carboplatin (iPocc)
Phase II/III Design
EligibilityOvarian, Peritoneal and Fallopian TubeStage II, III, and IVOptimal and Suboptimal
Targeting Accrual 754 during 3 years120 patients for Phase II componentFirst enrollment January 2010
iPocc Trial DesignEpithelial Ovarian, Peritoneal,
Fallopian Tube CancerStages II-IV
Optimal, SuboptimalExcluding Clear Cell Carcinoma
Paclitaxel 80 mg/m2 IV WeeklyCarboplatin AUC 6 IV
Q21, 6-8 Cycles
Paclitaxel 80 mg/m2 IV WeeklyCarboplatin AUC 6 IP
Q21, 6-8 Cycles
Randomization
Primary Endpoint: PFSSecondary Endpoint: OS, Toxicity, QOL, Cost
oxaliplatin + capecitabine ± bevacizumab vs carboplatin + paclitaxel ± bevacizumab Patients 0/332
Leading NCRI/SGCTG GOG
Participating AGO OVAR, GINECO, MaNGO, NSGO, KGOG
MucinousEOC
A GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/- bevacizumab
compared with oxaliplatin and capecitabine +/- bevacizumab as first line chemotherapy in patients with mucinous Epithelial Ovarian Cancer (mEOC)
Cancer Research UK & UCL Cancer Trials Centre
Cancer Research UK & UCL Cancer Trials Centre
The mEOC study is a multi-national collaboration with the Gynecologic Oncology Group, USA (GOG -0241)
• Primary Aims: Does chemotherapy with oxaliplatin + capecitabine improve the survival of patients with mucinous ovarian cancer, compared to standard chemotherapy with carboplatin + paclitaxel.
• In addition whether bevacizumab improves overall survival of patients with mucinous epithelial ovarian cancer.
• Secondary Objectives: Progression free survival, response rates, toxicity, quality of life (QoL)
• QoL: All patients will be assessed using FACT-O TOI, FACT/GOG-NTX Subscale and EQ-5D QoL questionnaires.
• Translational research: Patients may opt to donate a sample of their tumour taken at time of surgery, for future research.
Trial Objectives
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 x 21-day cycles
Oxaliplatin 130 mg/m2 Capecitabine
850mg/m2 bd6 x 21-day cycles
Carboplatin AUC 5/6* Paclitaxel 175mg/m2
6 x 21-day cycles
Bevacizumab 15mg/kg given every 3 weeks for 5 or 6** cycles
Oxaliplatin 130 mg/m2
Capecitabine 850mg/m2
bd6 x 21-day cycles
Bevacizumab 15mg/kg given every 3 weeks for
5 or 6** cycles
Clinical assessment every 6 weeks for 36 weeks
Telephone call at week 3 between every 6-week visit Bevacizumab 15mg/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, 1 month after completion of cycle 6, then 3 monthly for Year 1
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.
Cancer Research UK & UCL Cancer Trials Centre
Trial Criteria
Inclusion Criteria: • Histological diagnosis of mucinous
ovarian carcinoma• FIGO stage II-IV• Aged 18 or above• Life expectancy >3 months• No previous chemotherapy or
radiotherapy• Recurrent stage I• ECOG performance status 0, 1 and 2• Fit for protocol treatments• Urine dipstick for proteinuria <2+• Adequate coagulation parameters
Exclusion Criteria: • Histological diagnosis of non-mucinous
ovarian carcinoma• Previous history of malignancy except
cervical carcinoma in situ, and basal cell carcinoma of the skin
• Concurrent uncontrolled medical condition• Previous chemotherapy, radiotherapy or
any investigational treatment for ovarian or rectal cancer.
• Symptoms or history of peripheral neuropathy
• Previous history of malabsorption or other conditions preventing oral treatment
• Clinically significant cardiac disease, including M.I. in last 12 months
• Criteria excluding bevacizumab therapy
Cancer Research UK & UCL Cancer Trials Centre
Targets: Planned start date – November 2009; Planned end date – May 2014
European Sites: Interest from sites in
UK, Denmark, Finland, Sweden, Norway, France, Italy & Germany.
Approximately 40 UK sites interested. Trial is in set-up, no centres are open.
Chief Investigator: Prof. Martin Gore
Sponsor: University College London
http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=4667
Contact Email: mEOC@ctc.ucl.ac.uk
ICON8
Outline Proposal for the next international, first-line ovarian cancer trial
A proposal by the NCRI and SGCTG
Initial Outline Proposal
• To answer questions around– Weekly paclitaxel (JOG, ASCO 2008 abs)– Bevacizumab (ICON7/GOG218 abs 2010)– Immediate & delayed primary surgery (EORTC
55971, IGCS 2008 abs, CHORUS – ongoing)
• Aim to maximise eligible population and questions answered– Initial application for 6 arm adaptive multi-arm multi-
stage design investigating dose-fractionated chemotherapy and bevcizumab declined• Suggestion from CTAAC to reapply with simpler three arm
trial without bevacizumab
Randomisation
ARM1: C q 3/52 P q 3/52(current std)
ARM2: C q 3/52 P q 1/52
ARM3: C q 1/52 P q 1/52
Current Proposal
(A) Immediate Primary Surgery (IPS)
(B) Delayed Primary Surgery (DPS)
Surgery (IPS)
Surgery (DPS)
Chemotherapy(ARM 1-3 x 6)
Chemotherapy(Arm 1-3 x 3)
Chemotherapy (Arm 1-3 x 3)
One trial with pre-specified
stratification for IPD v DPS
Plan to use lower dose of paclitaxel than JOG for arm 2: Carboplatin AUC6 d1Paclitaxel 60mg/m2 d 1,8,15 q3w
JOG study 60% received 6 cycles, 48% required at least one dose reduction and 76% had at least one delay, doses used carboplatin AUC6 and paclitaxel 80 mg/m2
Outcome Measures
• Primary– Stage I
• Feasibility of using dose-fractionated arms with both IPS and DPS
– >80% receive 6 cycles (lower limit of 90% CI not < 60%)– >80% receive >90% planned dose intensity (lower limit of
90% CI not <60%)
• Toxicity (guide only at present)– If G2 neuropathy and G3/4 other toxicities >15% then need to
consider continuation– Special consideration in DPS arm for surgical 30d mortality
and morbidity
– Stage II: PFS and OS
Statistics
• Most current/planned trials (inc. ICON7, GOG218, MITO, JGOG trials) target HR of 0.75-0.80
• Assumption– median OS 36m for IPS and 30m DPS (poorer PS group) – = 34m overall
• For HR of 0.75, p=0.025 (2 main comparisons) and 90% power 1590 patients are required– Aim 2yr recruitment, 3yr follow up
• Open to option of prospective meta-analysis with other studies but ICON8 powered as single study
Current Situation
• Outline application for funding pending • Novelty of this trial is:
– weekly carboplatin and weekly paclitaxel arm– Inclusion of IPS and DPS patients
• Even if ICON7/GOG trials positive– Still many questions re dose, duration, cost-
effectiveness etc and bevacizumab not suitable for all
– Large eligible population for this study therefore hopefully fast recruitment
IP/IV Platinum/T vs IV CT optimally debulked following NACT
Patients 0 / 780
Leading NCIC CTG
Participating GEICO, NCRI, SWOG
NCIC CTG OV.21
A PHASE II/III STUDY OF INTRAPERITONEAL (IP) PLUS INTRAVENOUS (IV) CHEMOTHERAPY
VERSUS IV CARBOPLATIN PLUS PACLITAXEL IN PATIENTS WITH EPITHELIAL OVARIAN
CANCER OPTIMALLY DEBULKED AT SURGERY FOLLOWING NEOADJUVANT INTRAVENOUS
CHEMOTHERAPY:
A Gynecologic Cancer Intergroup (GCIG) Trial led by the NCIC CTG
NCIC CTG Protocol Number: OV.21
NCRI: UCL08/0379
GEICO: 0902
NCIC CTG STUDY CO-CHAIRS: HELEN MACKAYDIANE PROVENCHER
NCRI CO-CHAIR: CHRISTOPHER GALLAGHERGEICO CO-CHAIR: ANA OAKNIN
TRIAL COMMITTEE: MARK HEYWOODPHYSICIAN COORDINATOR: RALPH MEYER
BIOSTATISTICIAN: DONGSHENG TUQUALITY OF LIFE COORDINATOR: LORI BROTTO
COORDINATOR OF NURSING STUDY: LISA TINKERTRANSLATIONAL RESEARCH COORDINATOR:
JEREMY SQUIRESTUDY COORDINATOR: CHAD WINCH
SPONSOR: NCIC CTG
Rationale• 21.6% overall decrease in risk of death
after primary surgery with IP cisplatin-based treatment
• Cogent arguments against IP therapy
• Many EOC patients receive neoadjuvant systemic treatment before debulking is attempted.
• EORTC trial: neoadjuvant=upfront with lower morbidity!!! (abstract)
Although
Although
Our question
Do EOC patients who have received neoadjuvant chemotherapy/optimal cytoreduction benefit from shorter
course of IP therapy?
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
Basic 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
RR
Day 8th Day 8th
Optimal Optimal SurgerySurgery
ShorteShorter r
coursecourse
Phase IIPatients will be randomized to one of the following three arms:
Arm Agent(s) Dose Route DurationSchedule
Days Repeat
1
Paclitaxel135 mg/m2
IV
3 hours Day 1
Every 21 days
60 mg/m2 1 hour Day 8
Carboplatin
AUC 5if measured GFR
(use AUC 6 if calculated GFR)
30 minutes*
Day 1
2
Paclitaxel
135 mg/m2 IV 3 hours Day 1
60 mg/m2 IPBy gravity as rapidly
as possibleDay 8
Cisplatin 75 mg/m2 IPBy gravity as rapidly
as possibleDay 1
3
Paclitaxel
135 mg/m2 IV 3 hours Day 1
60 mg/m2 IPBy gravity as rapidly
as possibleDay 8
Carboplatin
AUC 5if measured GFR
(use AUC 6 if calculated GFR)
IPBy gravity as rapidly
as possible
Day 1
* or according to local practice
Phase II: Endpoints for selecting IP arm.
• 9-month progression rate post randomization
• Completion rate of treatment
• Toxic effects
• Feasibility
Statistics: Phase II Portion• 50 patients in each of the 3 arms: Assesses ONLY the IP
arms at time of analysis. Select the IP regimen for phase III based
• Efficacy:
– Assuming the highest 9 month PD rate in the two IP arms is 40%, using the “pick-the-winner” design we should have 90% chance to pick the true winner which has a 6 month PD rate at least 12% lower than the other.
– For the two IP arms, we will first test the null hypothesis that the true PD rate at 9 months is 52.5% or higher using a one-sided test at 0.05 level and then pick up the arm for phase III study by comparing their observed 9 month PD rates
Statistics: Phase II Portion
• Toxicity
• Tolerability criteria:
– Assess completion rate of IP treatment. Assume regimen would be interesting if >70% can complete 3 cycles and uninteresting if < 50% complete 3 cycles. Using these figures, arm(s) selected will be abandoned if >= 29/50 patients cannot complete IP therapy
• Accrual
How it will work!
DSMC to review efficacy then completion rate, toxicity and accrual.
Guideline for DSMC
• Both IP arms significant, examine completion rate for both:
– stopping rule not met in both arms WINNER = lowest PD rate
– one arm meets the stopping rule WINNER = Other arm
– If both arms meet the stopping rule NO WINNER study closes
Phase IIIPatients will be randomized to one of the following two arms:
Arm Agent(s) Dose Route Duration
Schedule
Days Repeat
1
Paclitaxel135 mg/m2
IV
3 hours Day 1
Every21 days
60 mg/m2 1 hour Day 8
Carboplatin
AUC 5if measured GFR
(use AUC 6 if calculated GFR)30 minutes* Day 1
2 The selected IP arm from Phase II (regimen as in above table)
Every21 days
* or according to local practice
Phase III endpoints
• Primary Endpoint:
• Progression free survival
• Secondary Endpoints:
• Overall survival
• Toxic effects
• Quality of life
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
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
i. Patient positioning during and after administration of IP therapy
ii. The pre-warming of IP fluid
iii. The use of home hydration practices after administration of IP therapy.
A randomised phase III trial of weekly carboplatin and paclitaxel versus pegylated liposomal doxorubicin in recurrent, platinum resistant, epithelial ovarian cancer
Patients 0 / ?
Leading SGCTG
Participating ?
DDPC-PREOC
A Randomised Phase III Trial of Weekly
Carboplatin and Paclitaxel versus Pegylated
Liposomal Doxorubicin In Recurrent, Platinum
Resistant, Ovarian Cancer
GCIG Belgrade Oct 2009
Ros Glasspool
DDPC- PREOC
Rationale for Trial• High RR and long PFS in phase II studies and retrospective series of dose
dense/ fractionated Paclitaxel/Carboplatin schedules
• Well tolerated
• No randomised trials
Regimen RR % PFS months OS months Ref
P90, C AUC4 day 1 and 8 q21
43 6.75 8 Cadron 2007
P90, C AUC4 Day 1, 8, 15 q28 x2
53 10 13 Van der Burg 2004
P80, C AUC 2Day 1, 8, 15 q28
37.5 3.2 Havrilesky2003
P70, C AUC 3Day 1, 8, 15 q 28
60 7.9 13.3 Sharma 2009
PLDH 12.3 2.1 13.3 Gordon 2001
PLDH TFI <12 m
16 3.7 12.9 Ferrandina 2008
PLDH 8.3 3.1 13.5 Mutch 2007
Trial Design
Carboplatin (AUC 3) and paclitaxel (80 mg/m2) for 3 weeks out of 4 for 6 cyclesPegylated Liposomal Doxorubicin (40 mg/m2) every 4 weeks for 6 cycles
RANDOMISE
250 patients with platinum resistant disease
Primary Endpoint: PFS
Secondary Endpoints: Overall SurvivalQuality of Life Health Economic AnalysisResponse RateToxicity/HypersensitivityDose Intensity Post progression therapy
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