Ovarian CancerCommittee Agenda Summary of ongoing and recently closed trials Christian Marth...

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 TrialsClosed Trials

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


Leading EORTC

Participating AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO

Tarceva Trial EORTC 55041

TC ± BEVACIZUMAB


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


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

Open TrialsOpen Trials

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


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


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


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


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


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)


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:

[email protected]

[email protected]

Again limited funding - participating groups have to pay local costs

(DESKTOP II model – Presentation/Publication/Co-authorship)


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

JGOG3017/GCIG TRIAL

Weekly CT vs 3-weekly CT (QoL)

Patients 65 / 500

Leading MITO

Participating MaNGO, AGO-OVAR

MITO-7

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)

MITO7 – Groups involved

• MaNGo (8 centers)

• Others?

• 65 patients enrolled (12 in

September)

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


• 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


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


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


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

Planned TrialsPlanned Trials

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”

MITO 12 – Groups involved


• 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

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 vs IV carboplatin + weekly Paclitaxel

Patients

Leading JGOG

Participating

JGOG IP Trial

Intraperitoneal TrialUnder Planning at JGOG

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

recurrent ovarian cancer

Patients 0/?

Leading AGO-OVAR

Participating ?

AGO-OVAR-OP DESKTOP IV

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


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.


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


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: [email protected]

TC dose dense / 3weekly ± BEVACIZUMAB

Patients 0 / 2000

Leading MRC/NCRI

Participating ?

ICON-8

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

Central activation

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

150 150 patientspatients

Transition: 150 Transition: 150 ptspts

Total : 830 Total : 830 ptspts

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


(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


(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.

Other points!!

• Quality of Life

• Correlative studies

• Economic analysis

• Nursing studies

PLEASE GET INVOLVED!!!!!!!!!!!

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

Trial Status

• Outline proposal submitted to the NIHR Health Technology Assessment (HTA) programme in July and decision expected Oct 2009.

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