MITO 7 ENGOT-OV10

WEEKLY vs EVERY 3 WEEK CARBOPLATIN + PACLITAXEL

IN PATIENTS WITH OVARIAN CANCER: RANDOMIZED MULTICENTRE STUDY

Carboplatin AUC 6 d1 q 21 Paclitaxel 175 mg/mq d1 q 21

Carboplatin AUC 2 dd 1-8-15 q 21 Paclitaxel 60 mg/mq dd 1-8-15 q 21

Three-weekly Carboplatin-Paclitaxel

Weekly Carboplatin-Paclitaxel

Primary : PFS & QoL Secondary: OS, RR, Toxicity

Patients closed 941 (8/2010) Leading AGO-OVAR Participating AGO-Austria, ANZGOG, BGOG, GEICO, GINECO, ICORG, JGOG,KGOG, MANGO, MITO, NSGO, NYCC, California Consortium

AGO-OVAR 16

Primary chemotherapy Placebo

Pazopanib

Carbo Paclitaxel +/- BIBF 1120 (Vargatef) Patients closed 1366 (7/2011) Leading AGO-OVAR

Participating AGO-Austria, BGOG, GEICO, GINECO, MANGO, MITO, NSGO, US Oncology

AGO-OVAR 12

Jacobus Pfisterer

Paclitaxel 175 mg/m² Carboplatin AUC5 q21 Tage

Bevacizumab 15mg/kg q21

15 months

= 22 cycles

Paclitaxel 175 mg/m² Carboplatin AUC5 q21 Tage

Bevacizumab 15mg/kg q21

30 months

= 44 cycles

AGO-OVAR 17 Study design

AGO-GINECO-NSGO

R

N= 900

1:1

Strata ♦Residual disease (yes vs no) ♦FIGO stage (IIB-III vs IV) ♦Center

Primary endpoint: PFS Sec. endpoints: RR, OS, QoL, Safety LKP: Prof. J. Pfisterer

819/900 patients

Gemcitabine 1000 mg/m² d1 and 8

Carboplatin AUC 4 d 1 q3w

Bevacizumab 15mg/kg q3w until PD

Pegylated Liposomal Doxorubicin 30 mg/m² d1

Carboplatin AUC 5 d1 q4w

Bevacizumab 10mg/kg q2w

R

N = 654

1:1

Stratification Factors Platinum free interval (6-12 months vs. > 12

months) In case of debulking surgery for recurrence:

residual tumour (yes vs. no) In case of no debulking surgery for recurrence: all pts. categorized to residual tumor = yes prior antiangiogenetic treatment (yes vs. no) participating study group

Bevacizumab 15mg/kg q3w until PD

• Superiority test for PFS of Bevacizumab/PLD/Carboplatin

• Hazard Ratio < 0.79 First Patient In: Q2 2013 (first site activation June 2013)

AGO-OVAR 2.21 ENGOT ov18

GINECO, AGO-Austria, SGCTG, ANZGOG

Shanghai GOG AGO-OVAR OP.4 /

DESKTOP III Study Design

♦ Participating Groups • AGO Study Group (Leading Group) • AGO-A (Austria) • BGOG (Belgium) • CRCTU (UK) • GEICO (Spain) • GINECO (France)

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 platinum-based

chemotherapy* recommended

* Recommended platinum-based chemotherapy regimens: - carboplatin/paclitaxel - carboplatin/gemcitabine - carboplatin/pegliposomal doxorubicin - or other platinum combinations in prospective trials

no surgery

• KGOG (Korea) • MITO/MaNGO (Italy) • NSGO (Scandinavia) • Shanghai GOG (China) • Single site in Greece

188/408 pts

José María Del Campo

A Multicenter Randomized Double Blind Phase III Trial

of Nintedanib (BIBF 1120)/Placebo combined with Carboplatin and Paclitaxel in Patients With Recurrent

Platinum-Sensitive Ovarian Cancer ENGOT-ov19/GEICO-1204 study

Leading Group: GEICO

Eric Pujade / Freyer

18

ALIENOR DESIGN : 60 patients

Bevacizumab 15mg/Kg every 3 weeks

Paclitaxel alone

80mg/m², IV, at D1, D8 and D15

every 4 weeks

Paclitaxel 80mg/m², IV, D1, D8 and D15

every 4 weeks +

Bevacizumab 10mg/kg, IV, D1 and D15

RANDOMISATION

Maximum of 6 cycles Up to 1 year or until PD / intolerance

Arm A

Arm B

Standard

surveillance

Standard of care

PD or Toxicity

Bevacizumab 15mg/Kg every 3 weeks

Standard of care

PD or Toxicity

At the investigator discretion

Population : 5 patients included, 1st patient Jan 2013 Patients with an histologically confirmed diagnosis of ovarian sex-cord stromal tumor in relapse after at least 1 platinum-based chemotherapy and measurable disease by RECIST.

PRIMARY OBJECTIVE: Clinical benefit rate (non-progression rate after 6 months of treatment)

21

Arm A : carboplatine AUC 5-6 + paclitaxel 175mg/m² q21 X 6 cycles

Arm B : carboplatine AUC 5-6 q21 q21 X 6 cycles

Arm C : carboplatine AUC 2 + paclitaxel 60 mg/m² weekly q28 (d1, d8, d15) x 6 cycles

Patient >70 years old GVS* > 3

*GVS = Geriatric Vunerability Score : - score ADL < 6 - score IADL < 25 - score HADS > 14 - albuminemia < 35g/L - Lymphopenia < 1G/L GVS = Σ factors with vulnerable score 240 patients to be enrolled Primary endpoint: To compare the rate of success to deliver 6 courses of chemotherapy without progression at 6 months or unacceptable toxicity*

Michael Bookman

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Optimal and Suboptimal Disease (through April 2011) • Primary Endpoint: PFS (Analysis 2014)

GOG0252: IP Therapy

Open: 27-Jun-2009 Closed: 29-Oct-2011 Accrual: 1560 pts (250 suboptimal) Walker J. for GOG, pending

Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 IV (d1,8,15) Bevacizumab (C2-6)

Cisplatin 75 mg/m2 (IP) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2-6)

I

III

II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1,8,15) Bevacizumab (C2-6)

Bevacizumab q21d x 16

Bevacizumab q21d x 16

Bevacizumab q21d x 16

IV Carbo IP Carbo IP Cisplatin

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Suboptimal residual disease, amended to permit NACT-ICS • Primary Endpoint: PFS (Analysis Planned July 2013) • Incorporation of early perfusion-based CT imaging (ACRIN 6695)

GOG0262: Dose-Dense Integration

Open: 27-SEP-2010 Closed: 08-FEB-2012 (ACRIN JUN-2013) Target Accrual: 700 pts (with imaging) Chan J. for GOG, pending

Carboplatin AUC=6 Paclitaxel 80 mg/m2 (d1,8,15) +/- Bevacizumab (C2-6)$

I

II

Bevacizumab q21d$

Bevacizumab q21d$

Carboplatin AUC=6 Paclitaxel 175 mg/m2 (d1) +/- Bevacizumab (C2-6) $

$ Use of Bevacizumab to be determined by patient and physician choice prior to randomization

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Stage III-IV, PDS or NACT-IDS • Stratified by Carboplatin AUC, Stage and residual disease, PDS vs IDS • Primary Endpoint: PFS 90% power for HR=0.77 (OS Secondary) • GOG Partners Protocol with ENGOT and AMGEN

GOG3001: CP +/- Trebananib (Trinova3)

Open: 26-JUL-2012 Closed: (ongoing) Target Accrual: 2000+ Monk B. for GOG, pending

Carboplatin AUC = 5 or 6 Paclitaxel 175 mg/m2 (d1) + Trebananib 15 mg/kg IV Weekly

I

II

Trebananib IV Weekly x 18 m

Placebo IV Weekly x 18 m

Carboplatin AUC = 5 or 6 Paclitaxel 175 mg/m2 (d1) + Placebo IV Weekly

2:1

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Clinical Stage I-IV, PS 0-3, Elect PCS or NACT-ICS • Elect single-agent or combination chemotherapy with PKs • Age >70 with no more than 25% age <75 • Primary Endpoints: Completion of 4 cycles without DLT

and impact of IADL score on treatment

GOG0273: Elderly Patients

Open: 15-AUG-2011 Closed: Arm I,III MAY-2013 Accrual: 185 pts Von Gruenigen V. for GOG, pending

Carboplatin AUC=5 Paclitaxel 135 mg/m2 (d1) G-CSF

I x4

Carboplatin AUC=5 III x4

Optional ICS Optional ChemoRx

Carboplatin AUC=5 Paclitaxel 60 mg/m2/wk II* x4

*Submitted amendment JUN-13

OVM1102 PARPi: Proposed Phase III • High-grade extrauterine serous tumors, Stage I-C, II, III, IV • Election for neoadjuvant therapy with interval cytoreduction (biospecimens) • Election for intraperitoneal (IP) cisplatin or intravenous (IV) carboplatin • Primary endpoint PFS: (1) Entire Population (2) BRCA1/2 Population • Stratifications: Stage, Residual Disease, NACT-ICS, IP or IV

x 6 II Veliparib 400 mg PO BID

Paclitaxel 80 mg/m2 (1 h) D1,8,15 Carboplatin AUC 6 (IV)* Veliparib TBD PO#

x 6 I Paclitaxel 80 mg/m2 (1 h) D1,8,15 Carboplatin AUC 6 (IV)* Placebo TBD PO#

Placebo PO BID

Chemotherapy regimen pending results from GOG0262 (JUL-2013) Patients electing intraperitoneal therapy will receive cisplatin 75 mg/m2 D1 (IP) Paclitaxel 135 mg/m2 D1 (IV), Paclitaxel 60 mg/m2 D8 (IP) # Dose and schedule of PARPi with concurrent chemotherapy pending

Bell-Mcguinn K, et al. for GOG

Open: JAN 2014 Closed: JUN 2016 (2.5 y) Target Accrual: 2000 pts (340 BRCA1/2 +)

• Epithelial Ovarian, Fallopian, or Peritoneal Cancer • One prior therapy, Platinum-free interval > 6 months • Amended to permit carboplatin-gemcitabine DEC-2011 • Primary Endpoint: OS • Ongoing accrual to address surgical component

Open: 06-Dec-07 Closed: 29-Aug-11 (chemotherapy) Ongoing (surgical 155 pts) Target Accrual: 660 pts

GOG 0213: Secondary Cytoreduction

Coleman, et al. 2008

Secondary Cytoreduction

No Secondary Surgery

I

II

R1

Not Surgical Candidate III

Carboplatin AUC=5 Paclitaxel 175 mg/m2

(No further therapy)

Carboplatin AUC=5 Paclitaxel 175 mg/m2

Bevacizumab 15 mg/kg (continue until progression)

A

B

x 6-8

x 6-8

R2

K. Fujiwara

JGOG3017 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

Ovarian Clear Cell Carcinoma FIGO stage Ic-Ⅳ

RANDOMIZATION

Paclitaxel 175 mg/m2 IV, Day1 Carboplatin AUC 6 IV, Day1 Q21, 6 Cycles

Irinotecan 60 mg/m2 IV, Day1, 8, 15 Cisplatin 60 mg/m2 IV, Day1 Q28, 6 Cycles

Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, Response rate Accrual Goal: 662 patents

Planned publication: 2014 ASCO

iPocc Trial IntraPeritoneal therapy for Ovarian Cancer with Carboplatin

(GOTIC-001 / JGOG3019)

Epithelial ovarian, Fallopian tube or Primary peritoneal cancer

FIGO stage II−IV Including Bulky Tumor

RANDOMIZATION

Paclitaxel 80 mg/m2 IV Day1,8,15 Carboplatin AUC 6 IV

Q21, 6-8 Cycles

Paclitaxel 80 mg/m2 IV Day1,8,15 Carboplatin AUC 6 IP

Q21, 6-8 Cycles

Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL Accrual Goal: 685 patents

A Randomized Phase II/III Trial of 3 Weekly Intraperitoneal versus Intravenous Carboplatin in Combination with Intravenous Weekly Dose-Dense Paclitaxel

for Newly Diagnosed Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

236/685 patients

S. Pignata

MITO-8 Study Design Protocol 2.0

MITO, BGOG, MANGO, AGO

157/250 patients

The MITO-16/MANGO-OV2/ENGOT-OV17 Project:

Napoli

MITO 16/MANGO OV2 project A: the Phase IV trial

•Ovarian Ca •Stage IIIB-IV (FIGO) •ECOG 0-2 •Availability of samples for translational res. •No Beva contraindications • No previous treatments

Bevacizumab* 15mg/kg Paclitaxel

175mg/m2 Carboplatin

AUC 5 q3wks

If not PD Bevacizumab* 15 mg/Kg q 3wks

6 cycles

22 cycles

Started December 2012 70/400 patients enrolled

PHASE IV prospective study of first-line bevacizumab plus chemotherapy in advanced ovarian cancer patients (IIIB-IV) with translational objectives and conducted only in Italy

MITO 16/MANGO OV2 project B: the Phase III trial

•Ovarian Ca •Platinum-sensitive •Previous Bevacizumab •ECOG 0-2 •Availability of samples for translational res. •No Beva contraindications

R

CBDCA AUC5 + PAC 175 mg/m2 q3w or CBDCA AUC4, d1 + GEM 1000mg /m2, d1&8 q3w or CBDCA AUC5+PLD 30mg/m2 q4w

CBDCA AUC5 + PAC 175 mg/m2 q3w Plus bevacizumab** 15mg/kg q3w or CBDCA AUC4, d1 + GEM 1000mg /m2, d1&8 q3w Plus bevacizumab 15mg/kg q3w or CBDCA AUC5+PLD 30mg/m2 q4w Plus bevacizumab 10mg/kg q2w

ARM 1: 6 cycles

ARM 2*: 6 cycles

*Patients without PD after 6 cycles of combined treatment will receive Bevacizumab maintenance until PD **Bevacizumab will be provided by Roche ltd

n=400 pts International (MITO, MANGO, GINECO HECOG, SAKK)

A. Clamp / J. Ledermann / I. McNeish

49

Trial Design – 2x2 Factorial Randomise

(332 patients – 83 patients in each arm)

Carboplatin & Paclitaxel

6 x 21-day cycles

Oxaliplatin & Capecitabine 6 x 21-day cycles

Carboplatin & Paclitaxel 6 x 21-day cycles Bevacizumab given every 3 weeks for 5 or 6* cycles

Oxaliplatin &

Capecitabine 6 x 21-day cycles Bevacizumab given every 3 weeks for 5 or 6* cycles

Clinical assessment every 6 weeks for 36 weeks

Bevacizumab given every 3 weeks for 12 cycles Clinical assessment every 6 weeks for 36 weeks

Follow-up

*Bevacizumab can be omitted from the first cycle if chemotherapy must be started within 4 weeks of surgery

50

0

50

100

150

200

250

300

350

Jan-Dec 2010 (UK)

Jan-Dec 2011 (UK)

Jan-Dec 2012 (UK)

Jan-May 2013 (UK)

UK Total US Total Total accrual

No.

of p

atie

nts

Year

mEOC Trial Yearly Patient Accrual (UK)

Actual

Predicted

Recruitment

Considering to be conducted as a randomized phase II trial

ICON8

Arm A2 6 cycles

Arm A3 6 cycles

Arm A1 6 cycles

Randomise 1:1:1

Diagnosis of Stage IC-IV EOC/PPC/FTC After immediate primary surgery or planned to

receive NACT plus delayed primary surgery N=1485

Arm 3 Carboplatin AUC 2 q1w Paclitaxel 80mg/m2 q1w

Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w

Arm 1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m2 q3w

Arm 1 vs. Arm 2

Arm 1 vs. Arm 3

KGOG, ICORG, ANZGOG, GICOM, Mayo

ICON8: Revised Design

NB. Stage III with residual disease or IV still eligible for ICON8A so that patients with contra-indication to Bev or unable to access it are still eligible

ICON8 trials programme

ICON8A

Arm A2 6 cycles

Arm A3 6 cycles

Arm A1 6 cycles

Randomise 1:1:1

Stage IC-IV EOC/PPC/FTC

Arm A3 Carboplatin AUC 2 q1w Paclitaxel 80mg/m2 q1w

Arm A2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w

Arm A1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m2 q3w

N=1485 ICON8B

Stage III-IV EOC/PPC/FTC with residual disease after surgery or planned

for neoadjuvant chemotherapy

Arm B2 6 cycles

Arm B3 6 cycles

Arm B1 6 cycles

Randomise 1:1:1

16 cycles maintenance Bevacizumab

Arm B1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m2 q3w Bevacizumab 15mg/kg q3w

Arm B2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w

Arm B3 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w Bevacizumab 15mg/kg q3w

N=1170

Arm 1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m2 q3w Bevacizumab 15mg/kg q3w

Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w

Arm 3 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w Bevacizumab 15 mg/kg q3w

ICON 8B (n=1170)

Stage III-IV EOC/PPC/FTC

with residual disease after surgery or planned for neoadjuvant chemotherapy

Provencher

Basic Design A : Phase II Patients with EOC

3-4 cycles neoadjuvant chemo

Initial surgery: < 1 cm residual

3 cycles IV IV Taxol 135 mg/m2 IV Carboplatin AUC 5*

3 cycles IP/IV IV Taxol 135 mg/m2

IP Carboplatin AUC 5*

Day 8th

IV Taxol 60 mg/m2 Day 8th

IP Taxol 60 mg/m2

Optimal Surgery

Shorter course

3 cycles IP/IV IV Taxol 135 mg/m2 IP Cisplatin 75 mg/m2

Day 8th

IP Taxol 60 mg/m2

* Measured GFR: AUC 5; calculated GFR: AUC 6

Rando 90%

per op

OV.21 opened, Feb. 2009 N : 177 (05/2013) NCIC-CTG, MRC/NCRI , GEICO, SWOG

OV.21 On-going Study

150 patients

Transition: 150 patients

630 patients

Carboplatin in combination with paclitaxel and bevacizumab versus

carboplatin in combination with pegylated liposomal doxorubicin and

bevacizumab in primary advanced ovarian cancer FIGO IIB-IV

AGO-OVAR 19

Allocated

To HIPEC Allocated

To Control

Adjuvant chemotherapy (Paclitaxel & Carboplatin)

Follow up

Accessed for eligibility

Randomization

Enrollment

(Residual tumor <1cm

After Cytoreductive surgery)

QOL

assessment

HIPEC : Hyperthermic Intraperitoneal Chemotherapy QOL : Quality of Life

KGOG: HIPEC Enrollment (2010.03.02 ~ 2013.05.27)

Informed consent

118 cases

86 cases

40 cases

46 cases

83cases

32 cases excluded

Primary object: PFS

Secondary object OS Complications QOL

Phase III Study in BRCAm Platinum Sensitive Relapsed Ovarian Cancer Patients

PFS, time to 2nd progression, OS

Until progression or unacceptable toxicity or consent withdrawal

tablets

• High grade epithelial ovarian cancer (FT/PP)

• with BRCA mutation • at least 2 previous

courses of platinum-based Cx

• For the penultimate chemotherapy course (at least 4 cycles) should be defined as platinum sensitive In PR or CR or NED after completion

-264 patients in approx 20 countries Europe, US, Canada, Latin America, Russia, Australia and Japan

- First patient in planned for 3Q 2013

Study Design 2:1 randomization

Niraparib

Placebo Platinum Sensitive

Ovarian Cancer in Response

n=360+12 n=180

n=180

gBRCAmut

Non-gBRCAmut High-grade serous

Niraparib

Placebo

PFS sample size is determined based on the assumption that niraparib will result in an improvement in median PFS of 4.8 to 9.6 months (HR=0.50) for

each gBCRA cohort.

Phase 3 Randomized Double-Blind Trial of Maintenance with Niraparib Versus Placebo in

Patients with Platinum Sensitive Ovarian Cancer ENGOT-ov16

Study Sponsor: TESARO; ENGOT Lead Group: NSGO

Participating Groups: AGO Germany, BGOG Belgium , GINECO, AGO Austria, MaNGO MITO, GEICO, NCRI

Thank You!