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
Closed Trials
EORTC 55971/CHORUS
Upfront Surgery
vs
Neoadjuvant Chemotherapy
Patients
closed / 550
Leading
EORTC
Participating
NCIC CTG
Presentation
IGCS 2008
NACT + IDS versus PDS: ITT
Progression-free survival
100
Median PFS
90
80
PDS: 12 months
70
60
IDS: 12 months
50
40
HR for IDS:0.99 (0.87, 1.13)
30
20
10
0
(years)
0
O N
320 360
320 357
1
2
3
Number of patients at risk :
168
60
39
177
60
36
4
5
6
7
8
26
20
17
13
7
3
2
1
Treatment
Upfront debulking surgery
Neoadjuvant chemotherapy
AGO-OVAR-9
Carbo Paclitaxel +/- Gemcitabine
Patients
closed 1742
Leading
AGO-OVAR
Participating
Presented
GINECO, NSGO
ASCO 2009
GCIG Intergroup study (AGO-OVAR/GINECO/NSGO)
Protocol # AGO-OVAR 9
Strata:
* FIGO stage
* post-op residual
tumor
* Surgery
Interval-surgery y/n
* Center
R
A
N
D
O
M
I
S
A
T
I
O
N
Gemcitabine 800 mg/m² d1+8
iv
Paclitaxel 175 mg/m² 3 h iv
Carboplatin AUC 5 iv *
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
AGO Ovarian Cancer Study Group (AGO-OVAR)
Progression-free (RECIST & GCIG CA125) and Overall Survival
by Therapy within Stratum 2+3 (FIGO IIB-IV)
TC
793 pts. / 588 evts.
median 16.0 [14.9-17.4] mos.
TC
TCG 774 pts. / 629 evts.
median 14.7 [14.0-15.9] mos.
TCG 774 pts. / 404 evts.
median 45.8 [40.0-49.5] mos.
1
1
Probability
793 pts. / 401 evts.
median 48.9 [43.1-51.2] mos.
0,75
0,5
0,5
0,25
0
0
0
6
12
18
24
30
36
42
48
54
60
66
72
0
6
12
18
24
30
36
42
48
54
60
66
72
[months]
HR = 1.17 [95% CI: 1.05-1.31]
p = 0.0065
HR = 1.03 [95% CI: 0.90-1.18]
p = 0.6955
78
SCOTROC 4
Carbo Flat Dosing vs Intrapatient Dose Escalation
Patients
Leading
closed 937
SGCTG
Participating
ANZGOG
Report
ASCO 2009
Tarceva Trial EORTC 55041
Tarceva consolidation 2 years
Primary Chemotherapy
Control
Patients
closed / 835
Leading
EORTC
Participating
AGO-AUSTRIA, ANZGOG, GINECO,
MRC/NCIC, MANGO
ICON-7
TC
±
BEVACIZUMAB
Patients
closed / 1520
Leading
MRC/NCRI
Participating
NCIC CTG, AGO OVAR, GINECO, GEICO
EORTC, ANZGOG, NSGO
GOG 218
CT vs CT + Bevacizumab
Placebo vs
CT + Bevacizumab concurrent and extended
Patients
closed / 1800
Leading
GOG
Participating
ECOG, NCCTG, NSABP, SWOG
AGO-OVAR-OP.2 DESKTOP II
Evaluation of predictive factors for complete
resection in platinum-sensitive recurrent
ovarian cancer
Patients
closed/412
Leading
AGO-OVAR
Participating
AGO-AUSTRIA, MITO,
selected Canadian+Australian
centers
Report
IGCS 2008
AGO-OVAR-OP.2 DESKTOP II
08/06 – 03/08: Screening of 516 pts with
platinum-sensitive relapse in 46 centres
Study collective: AGO score + 1st relapse
129 pts (87%)
Score positive
+
First relapse
76%
Complete
resection
Frequency of complete resection by
applying the AGO Score
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
Progression-Free Survival (ITT)
Median PFS, mo
HR (95% CI)
CD
CP
11.3
9.4
0.82 (0.72, 0.94)
Log-rank p-value (superiority)
0.005
P-value (non-inferiority)
<0.001
Open Trials
AGO – OVAR OP.3 (LION)
Lymphadenectomy In Ovarian Neoplasms
epithelial invasive
ovarian cancer
System. Lymphadenectomy
 pelvic
FIGO IIB - IV
ECOG 0/1 and
no CI against LNE
no visible extraand intra-abdominal
tumor residuals
 para-aortic
R
80/ 640
no Lymphadenectomy
no bulky lymph nodes
Endpoints: OS, PFS, QoL
Strata: centre, PS ,age
Supported by Deutsche Forschungsgemeinschaft
AGO-OVAR-OP.4 DESKTOP III
Cytoreductive surgery vs NO surgery
in platinum-sensitive recurrent EOC
Patients
0 / 385
Leading
AGO-OVAR
Participating
?
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
R
A
N
D
O
M
Cytoreductive
surgery
no surgery
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
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)
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
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-12
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-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 paclitaxel patients with advanced ovarian cancer
S
U
R
G
E
R
Y
R
C
C
C
C
C
C
T
T
T
T
T
T
= Vargatef 2 x 200 mg po qd
C
= Carboplatin AUC 5-6
d1
T
= Paclitaxel 175 mg/m2 (3h)
d1
q21d / 6 courses
n=1300
C
C
C
C
C
C
T
T
T
T
T
T
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
= Placebo
 120 weeks
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
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
Screening
Baseline
First-line
Chemotherapy
(allow ip, neoadj)
If not PD
R
A
N
D
O
M
I
Z
E
Treatment
Period
Pazopanib
(12 months)
Placebo
(12 months)
Post-Treatment
Period
Follow-up
Period
Observation
(to PD)
Survival
Follow-up
(post-PD)
HECTOR
Carbo Topo vs Chemo (CT or CG) in recurrent
Platinum-sensitive ovarian cancer
Patients
508 / 550
Leading
NOGGO/AGO-OVAR
Participating
AGO-AUSTRIA, GEICO
JGOG-3017 Clear Cell Carcinoma
CT
vs
CDDP + Irinotecan
Patients
396 / 652
Leading
JGOG
Participating
GINECO, GOG, KGOG,
MITO, SGCTG
JGOG3017/GCIG
Ovarian Trial Protocols
Randomized Phase III Trial of Paclitaxel plus
Carboplatin (TC) Therapy versus Irinotecan plus
Cisplatin (CPT-P) Therapy as a First Line Chemotherapy
for Clear Cell Carcinoma of the Ovary
Study Chair
Study Co-Chair
Toru Sugiyama, MD (Iwate Medical University)
Seiji Isonishi, MD (Jikei University School of Medicine)
Fumitoshi Terauchi, MD (Toho University)
-Clear Cell Ca
-Stage I~IV
RANDOMIZATION
International Cooperative Phase III
Study for Clear Cell Carcinoma
TC
Paclitaxel 175 mg/m2 (d1)
Carboplatin AUC 6 (d1)
Every 3 wk x 6
CPT-11/CDDP
CPT-11 60 mg/m2 (d1, 8, 15)
Cisplatin 60 mg/m2 (d1)
Every 4 wk x 6
225 patients in each arm, 450 total for 3 years
326 patients in each arm, 652 total for 4.25 years
JGOG3017/GCIG TRIAL
MITO-7
Weekly CT vs 3-weekly CT (QoL)
Patients
65 / 500
Leading
MITO
Participating
MaNGO, AGO-OVAR
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
Carboplatin AUC 6
Paclitaxel 175 mg/mq
RANDOM
day 1 - every 21days
Carboplatin AUC 2
Paclitaxel 60 mg/mq
day 1,8 15 - every 21days
Statistics
• Phase 3 open-label multicentre trial
• Quality of life as primary end-point
– Difference in FACT-O 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)
MITO7 – Groups involved
• MaNGo (8 centers)
• Others?
• 65 patients enrolled (12 in September)
Collaborative Nursing Study MITO12
Pathway 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”
MITO-8
PLD vs CT cross-over
in 6-12 m platinum-free interval
Patients
18 / 253
Leading
MITO
Participating
MaNGO, AGO-OVAR, Belgium
Liposomal doxorubicin stealth vs
carboplatin/taxol in recurrent ovarian
cancer patients with platinum-free
interval between 6-12 months
MITO - 8
Trial design
• The objective of this trial is the efficacy determined
through analysis of overall survival (OS) of the
different sequence (CP→PLD vs PLD→CP) in
recurrent ovarian cancer patients with platinum-free
interval 6-12 months
RANDOM
LIPOSOMAL
DOXORUBICIN 40 mg/mq
CARBOPLATIN AUC 5 +
PACLITAXEL 175 mg/mq
day1 every 28 days
day1 every21gg
Cross-over at
Progression
LIPOSOMAL
DOXORUBICIN
40 mg/mq
day1 every 28 days
CARBOPLATIN AUC 5 +
PACLITAXEL 175 mg/mq
day1 every 21 days
Statistics
• Median Overall Survival:
• expected (control arm): 18 months
• auspicated (experimental arm): 27 months
• Alpha error: 0.05, bilateral
• Power: 80%
• 193 events (progression) are needed
• 253 patients are to be enrolled (planned in 4 yr)
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 Trial
Stage 1 MRC/NCRI, NCIC
Stage 2 ANZ-GOG, IMN, EORTC, GINECO, GEICO, MANGO,
NSGO, ICMB and others
ICON 6 Design schema
2:3:3 RANDOMISATION
Arm A
Reference arm
6 cycles of
chemotherapy
plus
Placebo
No Progressive
disease
Placebo
Maximum 18
months
from randomisation
Arm B
Chemotherapy
Plus
cediranib
during
Chemotherapy
No Progressive
disease
Placebo
Maximum 18
months from
randomisation
Arm C
Chemotherapy
plus
cediranib
during
Chemotherapy
No Progressive
disease
Maintenance
cediranib after
chemotherapy
Maximum 18
months from
randomisation
ICON 6 Start up slides
Oct 2009
Outcome measures
Stage I- Safety
• Safety analysis after ~ 33 patients entered
into Arms B & C at 20mg dose
Stage 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
ICON 6 Start up slides
Oct 2009
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 slides
Oct 2009
Recruitment Prediction
• Based on recruitment to date
450 new patients by Oct 2010 (550 patients in total)
• Stage 2 data maturity
Expected 90 PFS events and 50 deaths in control arm
would be observed by April 2011
TR
QoL
CLINICAL
TRIAL
Other
groups
HE
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
ICON 6 Start up slides
Oct 2009
Planned Trials
Collaborative Nursing Study MITO12
Pathway 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”
MITO 12 – Groups involved
• MaNGo (8 centers)
• Others?
• 58 patients enrolled
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
Paclitaxel 80 mg/mq
RANDOM
day 1, 8, 15 - every 28 days
Pazopanib 800 mg/day
Paclitaxel 80 mg/mq
day 1,8 15 - every 28days
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
JGOG IP Trial
IP vs IV carboplatin + weekly Paclitaxel
Patients
Leading
Participating
JGOG
Intraperitoneal Trial
Under Planning at JGOG
IP Trial under Planning in JGOG
 IntraPeritoneal therapy for Ovarian Cancer with
Carboplatin (iPocc)
 Phase II/III Design
 Eligibility
 Ovarian, Peritoneal and Fallopian Tube
 Stage II, III, and IV
 Optimal and Suboptimal
 Targeting Accrual 754 during 3 years
 120 patients for Phase II component
 First enrollment January 2010
iPocc Trial Design
Epithelial Ovarian, Peritoneal,
Fallopian Tube Cancer
Stages II-IV
Optimal, Suboptimal
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, Co
AGO-OVAR-OP DESKTOP IV
recurrent ovarian cancer
Patients
0/?
Leading
AGO-OVAR
Participating
?
MucinousEOC
oxaliplatin + capecitabine ± bevacizumab
vs carboplatin + paclitaxel ± bevacizumab
Patients
0/332
Leading
NCRI/SGCTG GOG
Participating
AGO OVAR, GINECO, MaNGO,
NSGO, KGOG
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
Trial Objectives
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 EQ5D QoL questionnaires.
•
Translational research: Patients may opt to donate a sample of their tumour taken at time
of surgery, for future research.
Cancer Research UK & UCL Cancer Trials Centre
2x2 Factorial Trial Design
mEOC FIGO stages II–IV OR recurrent stage I; No previous chemotherapy; >18yrs; PS=0-2
Randomise
(332 patients – 83 patients in each arm)
Carboplatin AUC 5/6*
Paclitaxel 175mg/m2
6 x 21-day cycles
Oxaliplatin 130
mg/m2 Capecitabine
850mg/m2 bd
6 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
Clinical assessment every 6 weeks
for 36 weeks
Telephone call at week 3 between
every 6-week visit
Oxaliplatin 130 mg/m2
Capecitabine 850mg/m2
bd
6 x 21-day cycles
Bevacizumab 15mg/kg
given every 3 weeks for
5 or 6** cycles
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.
Trial Criteria
Exclusion 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
•
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
Cancer Research UK & UCL Cancer Trials Centre
ICON-8
TC dose dense / 3weekly ± BEVACIZUMAB
Patients
0 / 2000
Leading
MRC/NCRI
Participating
?
ICON8
Outline Proposal for the next international, first-line
ovarian cancer trial
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 multistage design investigating dose-fractionated
chemotherapy and bevcizumab declined
• Suggestion from CTAAC to reapply with simpler three arm
trial without bevacizumab
Current Proposal
ARM1: C q 3/52
P q 3/52
(current std)
(A) Immediate Primary Surgery
(IPS)
Surgery
(IPS)
Randomisation
Chemotherapy
(ARM 1-3 x 6)
ARM2: C q 3/52
P q 1/52
(B) Delayed Primary Surgery
(DPS)
ARM3: C q 1/52
P q 1/52
Chemotherapy
(Arm 1-3 x 3)
Surgery
(DPS)
One trial with
pre-specified
stratification for
IPD v DPS
Chemotherapy
(Arm 1-3 x 3)
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, costeffectiveness etc and bevacizumab not
suitable for all
– Large eligible population for this study
therefore hopefully fast recruitment
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
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
Central activation
NCIC CTG STUDY CO-CHAIRS: HELEN MACKAY
DIANE PROVENCHER
NCRI CO-CHAIR: CHRISTOPHER GALLAGHER
GEICO CO-CHAIR: ANA OAKNIN
TRIAL COMMITTEE: MARK HEYWOOD
PHYSICIAN COORDINATOR: RALPH MEYER
BIOSTATISTICIAN: DONGSHENG TU
QUALITY OF LIFE COORDINATOR: LORI BROTTO
COORDINATOR OF NURSING STUDY: LISA TINKER
TRANSLATIONAL RESEARCH COORDINATOR:
JEREMY SQUIRE
STUDY COORDINATOR: CHAD WINCH
SPONSOR: NCIC CTG
Rationale
• 21.6% overall decrease in risk of death
after primary surgery with IP cisplatinbased 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)
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
R
Initial surgery: < 1 cm residual
3 cycles
IV Carbo/Taxol
3 cycles IP/IV
platinum and taxol
Day 8th
Day 8th
Endpoints: PFS and OS
Optimal
Surgery
Shorter
course
150 patients
Transition: 150 pts
Total : 830 pts
Phase II
Patients will be randomized to one of the following three arms:
Schedule
Arm
Agent(s)
Dose
Paclitaxel
1
Carboplatin
Days
135 mg/m2
3 hours
Day 1
60 mg/m2
1 hour
Day 8
IV
135 mg/m2
IV
3 hours
Day 1
60 mg/m2
IP
By gravity as rapidly
as possible
Day 8
75 mg/m2
IP
By gravity as rapidly
as possible
Day 1
135 mg/m2
IV
3 hours
Day 1
60 mg/m2
IP
By gravity as rapidly
as possible
Day 8
IP
By gravity as rapidly
as possible
2
Cisplatin
Paclitaxel
Carboplatin
Duration
AUC 5
if measured GFR
(use AUC 6 if calculated
GFR)
Paclitaxel
3
Route
AUC 5
if measured GFR
(use AUC 6 if calculated
GFR)
* or according to local practice
Repeat
Day 1
30 minutes*
Day 1
Every
21 days
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 III
Patients will be randomized to one of the following two arms:
Schedule
Arm
Agent(s)
Dose
Route
Duration
Days
135 mg/m2
3 hours
Day 1
60 mg/m2
1 hour
Day 8
Repeat
Paclitaxel
1
Carboplat
in
2
Every
21 days
IV
AUC 5
if measured GFR
(use AUC 6 if calculated GFR)
30 minutes*
The selected IP arm from Phase II (regimen as in above table)
* or according to local practice
Day 1
Every
21 days
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.
Other points!!
• Quality of Life
• Correlative studies
• Economic analysis
• Nursing studies
PLEASE GET
INVOLVED!!!!!!!!!!!
DDPC-PREOC
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
?
A Randomised Phase III Trial of Weekly
Carboplatin and Paclitaxel versus Pegylated
Liposomal Doxorubicin In Recurrent, Platinum
Resistant, Ovarian Cancer
DDPC- PREOC
GCIG Belgrade Oct 2009
Ros Glasspool
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
P90, C AUC4
Day 1, 8, 15 q28
x2
P80, C AUC 2
Day 1, 8, 15 q28
P70, C AUC 3
Day 1, 8, 15 q 28
PLDH
43
6.75
8
Cadron 2007
53
10
13
Van der Burg
2004
37.5
3.2
60
7.9
13.3
Havrilesky
2003
Sharma 2009
12.3
2.1
13.3
Gordon 2001
PLDH
TFI <12 m
PLDH
16
3.7
12.9
8.3
3.1
13.5
Ferrandina
2008
Mutch 2007
Trial Design
Carboplatin (AUC 3)
R
and paclitaxel (80
A
250
patients
mg/m2) for 3 weeks
N
with
platinum
out
of 4 for 6 cycles
D
Pegylated
resistant
disease
O
Liposomal
M
Doxorubicin (40
I
mg/m2) every 4
Secondary Endpoints:
Overall Survival
S
weeks
Quality
of Life for 6 cycles
Health Economic Analysis
E
Response Rate
Toxicity/Hypersensitivity
Dose Intensity
Post progression therapy
Primary Endpoi
Trial Status
• Outline proposal submitted to the NIHR Health Technology
Assessment (HTA) programme in July and decision expected Oct
2009.