Investigating the Role of Anti-Angiogenic Agents in Ovarian

Cancer

Carol Aghajanian, M.D.

Chief, Gynecologic Medical Oncology

Memorial Sloan-Kettering Cancer Center

Phase III: GOG 218

Stage III* or IV, Stage III* or IV, Ovarian, primary Ovarian, primary

peritoneal, or peritoneal, or fallopian tube cancerfallopian tube cancer

• Activated: 9/26/05 Activated: 9/26/05

• Accrual goal: 1800 ptsAccrual goal: 1800 pts

• Primary end point: PFSPrimary end point: PFS

Carboplatin/Paclitaxel - cycles 1-6Carboplatin/Paclitaxel - cycles 1-6Concurrent Placebo - cycles 2-6Concurrent Placebo - cycles 2-6

Placebo - cycles 7-22Placebo - cycles 7-22

Carboplatin/Paclitaxel – cycles 1-6 Carboplatin/Paclitaxel – cycles 1-6 Concurrent Bevacizumab – cycles 2-6 Concurrent Bevacizumab – cycles 2-6

Placebo – cycles 7-22Placebo – cycles 7-22

Carboplatin/Paclitaxel – cycles 1-6 Carboplatin/Paclitaxel – cycles 1-6 Concurrent Bevacizumab – cycles 2-6Concurrent Bevacizumab – cycles 2-6

Bevacizumab – cycles 7-22Bevacizumab – cycles 7-22

*optimal (gross residual) or suboptimal

Phase III: ICON7

Carboplatin: AUC6; Paclitaxel 175mg/m2

Cycles: 21 days

High risk early High risk early stage/Advanced stagestage/Advanced stage

Ovarian, primary Ovarian, primary peritoneal, or fallopian peritoneal, or fallopian

tube cancertube cancer

Carboplatin/Paclitaxel x 6 cyclesCarboplatin/Paclitaxel x 6 cycles

ObservationObservation

Carboplatin/Paclitaxel x 6 cyclesCarboplatin/Paclitaxel x 6 cyclesBevacizumab 7.5 mg/kg x 5-6 cyclesBevacizumab 7.5 mg/kg x 5-6 cycles

Bevacizumab 7.5 mg/kg x 12 cyclesBevacizumab 7.5 mg/kg x 12 cycles

Target Accrual: 1520

Primary endpoint: PFS

IP Therapy: Randomized Trials

IV ARM IP ARM P value

GOG 104 IV cyclophosphamide + IV or IP CDDP

OS 41 mos 49 mos 0.02

GOG 114 IV Pac + IV CDDP or IV carbo then IV Pac + IP CDDP

PFS 22 mos 28 mos 0.01

OS 52 mos 63 mos 0.05

GOG 172 IV Pac + IV CDDP or IV/IP Pac + IP CDDP

PFS 18.3 mos 23.8 mos 0.05

OS 49.7 mos 65.6 mos 0.03

Alberts et al. NEJM 1996, Markman et al. JCO 2001, Armstrong et al. NEJM 2006

Modulating Toxicity of IP Therapy

New approaches to improve toxicity profile while maintaining efficacy– Dose/schedule modifications– Docetaxel instead of paclitaxel– IP Carboplatin instead of IP cisplatin– The role of bevacizumab

IP Chemotherapy: Modification

GOG 172

Modified

D1: IV Paclitaxel (135 mg/m2/24h)D2: IP Cisplatin (100 mg/m2)D8: IP Paclitaxel (60 mg/m2)

D1: IV Paclitaxel (135 mg/m2/3h)D2: IP Cisplatin (75 mg/m2)D8: IP Paclitaxel (60 mg/m2)

D1IV

D2IP

D1IV

D2IP

D8IP

D8IP

Phase I - GOG 9916

9916Part A

9916Part C

D1: IV Paclitaxel (175 mg/m2/3h)D1: IP Carboplatin (AUC 6)D8: IP Paclitaxel (60 mg/m2)

D1: IV Paclitaxel (175 mg/m2/3h)D1: IP Carboplatin (AUC 6)D1: IV Bevacizumab (15 mg/kg)*D8: IP Paclitaxel (60 mg/m2)

D1IV

D1IP

D1IV

D1IP

D8IP

D8IP

9916Part B D1

IV

D1IP

D8IP

D1: IV Docetaxel (75 mg/m2/1h)D1: IP Carboplatin (AUC 6)D8: IP Paclitaxel (60 mg/m2)

*beginning cycle 2, day 1 and continuing for 17 total cycles

Phase I - GOG 9917

9917Part A

D1: IV Paclitaxel (175 mg/m2/3h)D1: IP Carboplatin (AUC 6)

D1IV

D1IP

D8IP

9917Part B D1

IV

D1IP

D8IP

D1: IV Paclitaxel (175 mg/m2/3h)D1: IP Carboplatin (AUC 6)D1: IV Bevacizumab 15 mg/kg*

*beginning cycle 2, day 1 and continuing for 17 total cycles

MSKCC 06-064

ModifiedGOG-0172

06-064

D1: IV Paclitaxel (135 mg/m2/3h)D2: IP Cisplatin (75 mg/m2)D8: IP Paclitaxel (60 mg/m2)

D1: IV Paclitaxel (135 mg/m2/3h)D1: IV Bevacizumab (15 mg/kg)*D2: IP Cisplatin (75 mg/m2)D8: IP Paclitaxel (60 mg/m2)

D1IV

D2IP

D1IV

D2IP

D8IP

D8IP

*beginning cycle 2, day 1 and continuing through cycle 22PI: Dr. Jason Konner

ASCO 2008: Phase III IV paclitaxel and carboplatin vs. dose dense (TC-T-T)

JGOG: 637 patients randomized, Stage III diagnosis

TC vs TC-T-T (80 mg/m2) weekly

Primary endpoint PFS– 0.8 power to detect 5 month difference

Treatment N Median PFS

P value HR 95% CI

TC 319 17.2 mos

TC-T- T 312 28.0 mos 0.0015 0.714 0.581-0.879

2 year OSTC 319 77.7%

TC-T-T 312 83.6% 0.0496 0.735 0.540-1.000

Isonishi et al. J Clin Oncol 26: 2008, abs 5506

Phase III: GOG 0252

Stage II or III Stage II or III ((<<1cm residual), 1cm residual),

Ovarian, Ovarian, primary primary

peritoneal, or peritoneal, or fallopian tube fallopian tube

cancercancer

• Accrual goal: 1100 ptsAccrual goal: 1100 pts

• Primary end point: PFSPrimary end point: PFS

Paclitaxel 80 mg/mPaclitaxel 80 mg/m22/1h IV, Days 1, 8, 15, Cycles 1-6/1h IV, Days 1, 8, 15, Cycles 1-6Carboplatin AUC 6 Carboplatin AUC 6 IVIV, Day 1, Cycles 1-6, Day 1, Cycles 1-6Bevacizumab 15 mg/kg IV, Cycles 2-22Bevacizumab 15 mg/kg IV, Cycles 2-22

Paclitaxel 80 mg/mPaclitaxel 80 mg/m22/1h IV, Days 1, 8, 15, Cycles 1-6/1h IV, Days 1, 8, 15, Cycles 1-6Carboplatin AUC 6 Carboplatin AUC 6 IPIP, Day 1, Cycles 1-6, Day 1, Cycles 1-6Bevacizumab 15 mg/kg IV, Cycles 2-22Bevacizumab 15 mg/kg IV, Cycles 2-22

Paclitaxel 135 mg/mPaclitaxel 135 mg/m22/3h IV, Day 1, Cycles 1-6/3h IV, Day 1, Cycles 1-6Cisplatin 75 mg/mCisplatin 75 mg/m22 IPIP, Day 2, Cycles 1-6, Day 2, Cycles 1-6Paclitaxel 60 mg/mPaclitaxel 60 mg/m22 IP, Day 8, Cycles 1-6 IP, Day 8, Cycles 1-6Bevacizumab 15 mg/kg IV, Cycles 2-22Bevacizumab 15 mg/kg IV, Cycles 2-22

RANDOMIZE

Relapse Therapy: Past

Primary treatment

RELAPSE

< 6 months > 6 months

Platinum Resistant Platinum Sensitive

Bevacizumab in Recurrent Ovarian Cancer

Study N Treatment RR (%)

PF 6 mo (%)

Prior Rx GIP

GOG

170-D1

62 BV 15 mg/kg IV q 3 wk

21 40.3 42% platinum resistant, 1-2 priors

0

NCI

57892

70 BV 10 mg/kg IV q 2 wk + CTX 50 mg daily

24 56 40% platinum resistant, 1-3 priors

4 (5.7%)

AVF29493 44 BV 15 mg/kg IV q 3 wk

16 27.8 Platinum resistant, 1-3 priors

5 (11%)

1Burger et al. JCO 2007, 2Garcia et al. JCO 2008, 3Cannistra et al. JCO 2007

AVF2949g: Risk Factors for GI Perforation

Cannistra, et al JCO 2007 P <0.1

P < 0.05

Radiographic

Prior Treatment

Single Agent Activity of Bevacizumab

Tumor Type Dose ORR (PR+CR)

Ovarian Cancer 15mg/kg q3wk 16-21%

Renal Cell 10mg/kg q2wk 10%

Met Breast Cancer

3-20mg/kg q2wk 7%

NHL 10mg/kg q2wk 5%

CRC 10mg/kg q2wk 3%

HRPC 10mg/kg q2wk 0%

Ovarian Cancer: BiologicsSTUDY AGENT N RR (%) PFS at 6 months (%)

170-C Gefitinib 27 3.7 14.8

170-D Bevacizumab 62 21 40.3

170-E Imatinib 56 1.8 16.1

170-F Sorafenib 59 3.4 23.7

170-G Lapatinib 26 0 7.7

170-H Vorinostat 27 3.7 7.4

170-I Temsirolimus Both stages of accrual completed

170-J Enzastaurin 27 7.4 11.1

170-K Mifepristone Closed after first stage

170-M Dasatinib First stage accrual completed

ASCO 2008Agent/

Abstract No.

N RR (%) PFS Prior RX

Sorafenib

(5537)

59 3.4 (2/59) 23.7% PF at 6 mo

1-2 priors

Cediranib

(5501)

32 18.8 (6/32) - 1-3 priors

Cediranib

(5521)

26

34

7.7 (2/26) – Pl-S

0 – Pl-R

- 1-2 priors

Sunitinib

(5522)

17 11.8 (2/17) - 1-2 priors

VEGF-TRAPVEGF Trap

2 mg/kg IV

q 2 weeks

VEGF Trap

4 mg/kg IV

q 2 weeks

Recurrent ovarian cancer

3 - 4 lines treatment

Platinum-resistant

Resistant: Topotecan and/or Liposomal Doxorubicin

Randomized (1:1) Double-BlindedN = 200

Tew et al. ASCO 2007

Primary endpoint: RRPreliminary results: 8% (blinded pooled summary of first 162 patients)50% of patients with 4 prior chemotherapy regimens

Recurrent Disease: Platinum Sensitive

ICON41 AGO2

1ICON4 Lancet 2003 and 2Pfisterer et al JCO 2006

RRAANNDDOOMMIIZZAATTIIOONN

Gemcitabine 1000 mg/m²Gemcitabine 1000 mg/m²days 1 and 8days 1 and 8

Carboplatin AUC 4 day 1 Carboplatin AUC 4 day 1

Bevacizumab 15 mg/kg day 1Bevacizumab 15 mg/kg day 1

q 21 days x 6q 21 days x 6

Gemcitabine 1000 mg/m²Gemcitabine 1000 mg/m²days 1 and 8days 1 and 8

Carboplatin AUC 4 day 1Carboplatin AUC 4 day 1

Placebo IV day 1Placebo IV day 1

q 21 days x 6q 21 days x 6

OCEANS STUDY –PHASE III

BevacizumabBevacizumabuntil PDuntil PD

PlaceboPlacebountil PDuntil PD

*Up to 10 cycles of gemcitabine/carboplatin allowed

OCEANS STUDY

Recurrent Ovarian CancerRecurrent Ovarian Cancer > 6 months off platinum> 6 months off platinum Measurable diseaseMeasurable disease Strata:Strata:

– Platinum-free intervalPlatinum-free interval (>6-12, > 12 months) (>6-12, > 12 months)

– Cytoreductive surgery for recurrent ovarian cancer Cytoreductive surgery for recurrent ovarian cancer (yes/no)(yes/no)

Primary ObjectivePrimary Objective– PFS (Investigator determined) – HR 0.73PFS (Investigator determined) – HR 0.73

Sample sizeSample size– 450 pts450 pts

PaclitaxelPaclitaxelCarboplatinCarboplatinBevacizumabBevacizumab

PaclitaxelPaclitaxelCarboplatinCarboplatin

GOG 213 –PHASE III

MaintenanceMaintenanceBevacizumabBevacizumab

Surgical Candidate?Surgical Candidate?

RandomizeRandomize

No

Yes

RandomizeRandomize

SurgerySurgery No SurgeryNo Surgery

Primary endpoint: OS

Target accrual: 660

ICON6

First platinum-First platinum-sensitive recurrencesensitive recurrence

Ovarian, primary Ovarian, primary peritoneal, or peritoneal, or

fallopian tube cancerfallopian tube cancer

Carboplatin/Paclitaxel* x 6 cyclesCarboplatin/Paclitaxel* x 6 cyclesConcurrent PlaceboConcurrent Placebo

Maintenance PlaceboMaintenance Placebo

Carboplatin/Paclitaxel* x 6 cycles Carboplatin/Paclitaxel* x 6 cycles Concurrent CediranibConcurrent CediranibMaintenance PlaceboMaintenance Placebo

Carboplatin/Paclitaxel* x 6 cycles Carboplatin/Paclitaxel* x 6 cycles Concurrent CediranibConcurrent Cediranib Maintenance CediranibMaintenance Cediranib

*Carboplatin alone is allowed

Future Directions

Combinations– GOG 186G: Randomized Phase II

study of bevacizumab/everolimus vs. bevacizumab/placebo

Novel Agents

Selected Combinations in Trials

Targets Clinical trials Tumor types

VEGF + VEGFR BV + Sorafenib RCC, Ovarian, Melanoma

BV + Cederanib Phase I

BV + Sunitinib RCC

VEGF + mTOR BV + CCI-779* RCC, Ovary, Endometrial, HCC, NEC

Sorafenib + CCI-779 RCC, Melanoma, GBM

VEGF + PDGF BV + Imatinib* Melanoma, GIST, RCC

VEGFR + Integrin BV + Medi-552 RCC

BV + Cilengitide GBM

Angio + Tumor targets VEGF Ab or TKIs + EGFR, HER2, HDAC inhibitors,

Immunotherapy, etc

Combination of anti-angiogenesis agents – preliminary toxicity data (Phase I experience)

MTD Toxicities

CCI-779 + Sunitinib Not tolerable

(15 mg + 25 mg)

DLT: Mucocutaneous

(no further development)

CCI-779 + Sorafenib Dose reduction

(for one agent)

DLT: Mucocutaneous, Plts

BV + Sorafenib Dose reduction

(both agents: 50%)

DLT: HUS, HTN, proteinuria

SAEs: GI perf, fistula, bleeding

BV + Sunitinib Not Tolerability at full doses in RCC

SAEs: HUS/TTP-like syndrome HTN

BV + CCI-779 Full dose Nonspecific

Exposures in more pts and for longer duration may reveal additional serious toxicities that are relatively low-frequency

Conclusions Angiogenesis is an important target in Ovarian Cancer Initial treatment

– GOG 218– ICON7– IP Therapy

First Platinum-Sensitive Recurrence– Oceans– GOG 213– ICON6

Recurrent Disease– Multiple single agent phase II trials

Platinum resistant disease– Chemotherapy combinations– “First” platinum resistant recurrence

Combinations– Toxicity will limit the number of agents that can be given simultaneously– When dose reduction is required, optimal dose ratio unknown for optimal

therapeutic index