a randomized phase ii study of …...background • paclitaxel/carboplatin (pc) is a standard...

A randomized phase II study of paclitaxel/carboplatin/bevacizumab,

paclitaxel/carboplatin/temsirolimus and

ixabepilone/carboplatin/bevacizumab as initial therapy for

measurable stage III or IVA; stage IV or recurrent endometrial cancer,

GOG-86P

C Aghajanian, VL Filiaci, DS Dizon, J Carlson, MA Powell, AA

Secord, KS Tewari, D Bender, DM O’Malley, A Stuckey, J

Rotmensch, DA Levine, HA Lankes, KN Moore

Background

• Paclitaxel/carboplatin (PC) is a standard initial therapy for

advanced endometrial cancer (EC)

• GOG209, a randomized noninferiority trial of initial therapy

(n=1381), showed that PC was not inferior to TAP in terms of

PFS and OS

• Bevacizumab, temsirolimus and ixabepilone have shown

single agent activity in recurrent EC

TAP, Paclitaxel + Doxorubicin + Cisplatin

Gynecol Oncol 2012,125(3) Suppl 1:S2-188, page 771; J Clin Oncol 2011;29:2259-65; Gyn Oncol 2013;129:22-7; J Clin Oncol 2011;29:3278-85; Gynecol

Oncol 2014;132:585-92; J Clin Oncol 2009;27:3104-8

GOG86P: Schema

Endometrial Cancer

No prior chemotherapy

-Stage III or IVA (measurable disease)

-Stage IVB (measurable disease or not)

-Recurrent (measurable disease or not)

Paclitaxel 175 mg/m2 IV 3 hours

Carboplatin AUC 6 IV

Bevacizumab 15 mg/kg IV*

Bevacizumab 15 mg/kg IV

Paclitaxel 175 mg/m2 IV 3 hours


Temsirolimus 25 mg IV days 1 & 8*

Temsirolimus 25 mg IV days 1, 8 and 15

Ixabepilone 30 mg/m2 IV 1 hour


Bevacizumab 15 mg/kg IV*

Bevacizumab 15 mg/kg IV

One Cycle = 3 weeks

Treatment until disease progression or adverse events prohibit further therapy

*Starting cycle 2 when within 12 weeks of surgery

EBRT, External Beam Radiation Therapy

Stratification:

•performance status (< 1 vs 2)

•recurrent disease (yes/no)

•measurable disease (yes/no)

•prior EBRT (yes/no)

Open: 9/14/09

Closed: 1/9/12

6 cycles Maintenance

GOG86P: Statistical Design

• Primary endpoint: PFS

• Secondary endpoints: ORR, OS, safety – Matched group from GOG209 PC Arm used as historical control

– 3 experimental Arms of GOG86P are compared individually to historical control

– RECIST 1.1

– Common Terminology Criteria for Adverse Events (CTCAE) v3.0

• Planned sample size: 330

• PFS: 35% decrease (HR=0.65) considered significant – 12 month PFS from 39% to 54%

– 58 PFS events in an experimental arm, 85% power, 3.9% type I error

– 6, 18 week time intervals evaluated to lessen bias (as comparisons made to matched group from GOG209)

GOG86P: Patient Characteristics PC + Bevacizumab PC + Temsirolimus IC + Bevacizumab

Enrolled (n=349) 116 115 118

Eligible and Treated (n=329) 108 111 110

Median Age, years (range) 62 (36-87) 63 (38-82) 65 (37-89)

Performance Status 0-1 106 (91%) 109 (95%) 113 (96%)

Stage

III (measurable disease) 12 (10%) 13 (11%) 10 (9%)

IV 58 (50%) 58 (51%) 62 (52%)

Recurrent 46 (40%) 44 (38%) 46 (39%)

Histology (Central pathology review)

Endometrioid, grade 1 17 (15%) 13 (11%) 15 (13%)



Serous 16 (14%) 26 (23%) 31 (26%)

Clear Cell 6 (5%) 4 (3%) 6 (5%)

Other 11 (9%) 18 (16%) 17 (14%)

PC, paclitaxel + carboplatin; IC, ixabepilone + carboplatin

GOG86P: Patient Characteristics PC + Bevacizumab PC + Temsirolimus IC + Bevacizumab

Eligible and Treated (n=329) 108 111 110

Prior EBRT

No 99 (85%) 95 (83%) 98 (83%)

Yes 17 (15%) 20 (17%) 20 (17%)

Measurable Disease

No 27 (23%) 30 (26%) 33 (28%)

Yes 89 (77%) 85 (74%) 85 (72%)

GOG86P: Treatment Exposure

Treatment Delivered PC + Bevacizumab

(n=116)

PC + Temsirolimus

(n=115)

IC + Bevacizumab

(n=118)

Chemotherapy

Median number of cycles, range

Paclitaxel/Ixabepilone

6 (0-6) 6 (0-6) 6 (0-6)

Median number of cycles, range

Carboplatin

6 (0-6) 6 (0-6) 6 (0-6)

Bevacizumab/Temsirolimus

Median number of cycles, range 12 (0-78) 8 (0-62) 9 (0-53)

GOG86P: Overview of AEs

Patients, %

PC + Bevacizumab

n=112

PC + Temsirolimus

n=113

IC + Bevacizumab

n=114

Any AE, Any grade 100 100 100

Any AE, Grade > 3 93.7 98.2 95.6

Any AE, Grade 5 3.6 5.3 5.3

AE Leading to Study Drug

Discontinuation

26.8 (bev) 23 (tem) 24.6 (bev)

15.8 (ixa)

SAE 42.8 50.4 46.5

GOG86P: AEs of Special Interest

Patients, %

PC +

Bevacizumab

n=112

PC +

Temsirolimus

n=113

IC + Bevacizumab

n=114

Fisher’s Exact

Test

(2 sided)*

ATE, grade > 3 0.9 0 0.9 p=0.554

VTE, grade > 3 8 9.7 7.9 p=0.681

Non-CNS Bleeding, grade > 3 2.7 0.9 4.4 p=0.281

GI Fistula, Leak, Perforation, Any grade 2.7 1.8 4.4 p=0.505

HTN, grade > 3 16.1 2.7 16.7 p<0.001

Proteinuria, grade > 3

5.4 0 4.4 p=0.018

Pneumonitis, any grade 0 6.2 0.9 p=0.002

Mucositis, oral, grade > 2 4.5 15.9 2.6 p<0.001

Rash, grade > 2 2.7 16.8 3.5 p<0.001

Hypertriglyceridemia, grade > 3 0 4.4 0 p=0.004

*Test comparing PC or IC + bevacizumab vs PC + temsirolimus

GOG86P: PFS Hazard

Ratio

92.2% Hazard Ratio

Confidence Limits

Arm 1 0.805 0.633 1.023

Comparison to Historical Reference

Hazard

Ratio

92.2% Hazard Ratio

Confidence Limits

Arm 2 1.222 0.961 1.554

Hazard

Ratio

92.2% Hazard Ratio

Confidence Limits

Arm 3 0.871 0.685 1.107

GOG86P: Objective Response Rate

Measurable Disease Patients

PC + Bevacizumab

(n=116)

PC + Temsirolimus

(n=115)

IC + Bevacizumab

(n=118)

GOG209 PC

Historical Reference

(n= 462)

Complete Response (CR) 22 (24.7%) 14 (16.5%) 9 (10.6%) 40 (10.8%)

Partial Response (PR) 31 (34.8%) 33 (38.8%) 36 (42.4%) 149 (40.4%)

Objective Response

Rate (CR + PR)

53 (59.5%) 47 (55.3%) 45 (52.9%) 189 (51.2%)

GOG86P: OS Arm Median Point Estimate

1 34.0 (p<0.039)

2 25.0

3 25.2

Reference 22.7

Translational science

Gene

Endometrioid, G1

(n=37)

Endometrioid, G2

(n=69)

Endometrioid, G3

(n=59)

Serous

(n=45)

PTEN 73% 71% 58% 9%

PIK3CA 38% 54% 53% 29%

TP53 14% 20% 44% 87%

ARID1A 38% 48% 39% 2%

CTNNB1 57% 32% 31% 2%

PIK3R1 27% 26% 19% 7%

KRAS 19% 20% 24% 2%

CHD4 27% 12% 20% 11%

PPP2R1A 11% 4% 5% 29%

FBXW7 0% 6% 10% 16%

MTOR 5% 9% 14% 4%

POLE 11% 6% 8% 2%

Top mutated genes by histology

(primary samples only, n=219)

25 most commonly mutated genes from TCGA endometrial cancer project

sequenced to a minimum mean depth of 600X

Profile of serous cases (n=45)

Douglas A. Levine, Fanny Dao

Conclusions

• PFS is not significantly increased in any Arm

• OS is significantly increased in the PC + Bevacizumab Arm when compared with historical controls

• No new safety signals

• Integration of the translational research findings and clinical endpoints is ongoing

Thank you

We gratefully acknowledge:

All the patients and their caregivers who

participated in this trial,

All the Investigators and staff who contributed

their time and effort to this study,

and NRG Oncology

a randomized phase ii study of …...background • paclitaxel/carboplatin (pc) is a standard...

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