Transcript Investigating the Role of Anti

Investigating the Role of AntiAngiogenic Agents in Ovarian
Cancer
Carol Aghajanian, M.D.
Chief, Gynecologic Medical Oncology
Memorial Sloan-Kettering Cancer Center
Phase III: GOG 218
Carboplatin/Paclitaxel - cycles 1-6
Concurrent Placebo - cycles 2-6
Placebo - cycles 7-22
Stage III* or IV,
Ovarian, primary
peritoneal, or
fallopian tube cancer
• Activated: 9/26/05
Carboplatin/Paclitaxel – cycles 1-6
Concurrent Bevacizumab – cycles 2-6
Placebo – cycles 7-22
Carboplatin/Paclitaxel – cycles 1-6
Concurrent Bevacizumab – cycles 2-6
Bevacizumab – cycles 7-22
• Accrual goal: 1800 pts
• Primary end point: PFS
*optimal (gross residual) or suboptimal
Phase III: ICON7
Carboplatin/Paclitaxel x 6 cycles
High risk early
stage/Advanced stage
Ovarian, primary
peritoneal, or fallopian
tube cancer
Observation
Target Accrual: 1520
Carboplatin/Paclitaxel x 6 cycles
Bevacizumab 7.5 mg/kg x 5-6 cycles
Primary endpoint: PFS
Bevacizumab 7.5 mg/kg x 12 cycles
Carboplatin: AUC6; Paclitaxel 175mg/m2
Cycles: 21 days
IP Therapy: Randomized Trials
IV ARM
GOG 104
OS
GOG 114
IP ARM
P value
IV cyclophosphamide + IV or IP CDDP
41 mos
49 mos
0.02
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
D1 D2
IV IP
D8
IP
Modified
D1 D2
IV IP
D8
IP
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)
Phase I - GOG 9916
9916
Part A
9916
Part B
9916
Part C
D1 D1
IV IP
D1 D1
IV IP
D1 D1
IV IP
D8
IP
D8
IP
D8
IP
D1: IV Paclitaxel (175 mg/m2/3h)
D1: IP Carboplatin (AUC 6)
D8: IP Paclitaxel (60 mg/m2)
D1: IV Docetaxel (75 mg/m2/1h)
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)
*beginning cycle 2, day 1 and continuing for 17 total cycles
Phase I - GOG 9917
9917
Part A
9917
Part B
D1: IV Paclitaxel (175 mg/m2/3h)
D1: IP Carboplatin (AUC 6)
D1 D1
IV IP
D1 D1
IV IP
D8
IP
D8
IP
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
Modified
GOG-0172
D1 D2
IV IP
D8
IP
06-064
D1 D2
IV IP
PI: Dr. Jason Konner
D8
IP
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)
*beginning cycle 2, day 1 and continuing through cycle 22
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
TC
319
17.2 mos
TC-T- T
312
28.0 mos
P value
HR
95% CI
0.0015
0.714
0.581-0.879
0.0496
0.735
0.540-1.000
2 year OS
TC
319
77.7%
TC-T-T
312
83.6%
Isonishi et al. J Clin Oncol 26: 2008, abs 5506
Phase III: GOG 0252
Stage II or III
(<1cm residual),
Ovarian,
primary
peritoneal, or
fallopian tube
cancer
R
A
N
D
O
M
I
Z
E
• Accrual goal: 1100 pts
• Primary end point: PFS
Paclitaxel 80 mg/m2/1h IV, Days 1, 8, 15, Cycles 1-6
Carboplatin AUC 6 IV, Day 1, Cycles 1-6
Bevacizumab 15 mg/kg IV, Cycles 2-22
Paclitaxel 80 mg/m2/1h IV, Days 1, 8, 15, Cycles 1-6
Carboplatin AUC 6 IP, Day 1, Cycles 1-6
Bevacizumab 15 mg/kg IV, Cycles 2-22
Paclitaxel 135 mg/m2/3h IV, Day 1, Cycles 1-6
Cisplatin 75 mg/m2 IP, Day 2, Cycles 1-6
Paclitaxel 60 mg/m2 IP, Day 8, Cycles 1-6
Bevacizumab 15 mg/kg IV, Cycles 2-22
Relapse Therapy: Past
Primary treatment
RELAPSE
< 6 months
Platinum Resistant
> 6 months
Platinum Sensitive
Bevacizumab in Recurrent Ovarian Cancer
Study
N
Treatment RR PF 6 mo Prior Rx
(%)
(%)
GIP
GOG
62
BV 15
mg/kg IV
q 3 wk
21
40.3
42% platinum
resistant, 1-2
priors
0
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%)
170-D1
NCI
57892
1Burger
et al. JCO 2007, 2Garcia et al. JCO 2008, 3Cannistra et al. JCO 2007
AVF2949g: Risk Factors for GI Perforation
Radiographic
Prior Treatment
P < 0.05
Cannistra, et al JCO 2007
P <0.1
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: Biologics
STUDY AGENT
N
170-C
170-D
170-E
170-F
170-G
170-H
170-I
170-J
170-K
170-M
27
3.7
14.8
62
21
40.3
56
1.8
16.1
59
3.4
23.7
26
0
7.7
27
3.7
7.4
Both stages of accrual completed
27
7.4
11.1
Closed after first stage
First stage accrual completed
Gefitinib
Bevacizumab
Imatinib
Sorafenib
Lapatinib
Vorinostat
Temsirolimus
Enzastaurin
Mifepristone
Dasatinib
RR (%) PFS at 6 months (%)
ASCO 2008
Agent/
Abstract No.
Sorafenib
(5537)
Cediranib
(5501)
Cediranib
(5521)
Sunitinib
(5522)
N
RR (%)
59 3.4 (2/59)
PFS
Prior RX
23.7% PF 1-2 priors
at 6 mo
32 18.8 (6/32)
-
1-3 priors
26 7.7 (2/26) – Pl-S
34 0 – Pl-R
17 11.8 (2/17)
-
1-2 priors
-
1-2 priors
VEGF-TRAP
VEGF Trap
Recurrent ovarian cancer
2 mg/kg IV
3 - 4 lines treatment
q 2 weeks
Platinum-resistant
Resistant: Topotecan
and/or Liposomal
Doxorubicin
Randomized (1:1)
Double-Blinded
N = 200
VEGF Trap
4 mg/kg IV
q 2 weeks
Primary endpoint: RR
Preliminary results: 8% (blinded pooled summary of first 162 patients)
50% of patients with 4 prior chemotherapy regimens
Tew et al. ASCO 2007
Recurrent Disease: Platinum Sensitive
ICON41
AGO2
1ICON4
Lancet 2003 and 2Pfisterer et al JCO 2006
OCEANS STUDY –PHASE III
R
A
N
D
O
M
I
Z
A
T
I
O
N
Gemcitabine 1000 mg/m²
days 1 and 8
Carboplatin AUC 4 day 1
Bevacizumab 15 mg/kg day 1
Bevacizumab
until PD
q 21 days x 6
Gemcitabine 1000 mg/m²
days 1 and 8
Carboplatin AUC 4 day 1
Placebo IV day 1
q 21 days x 6
*Up to 10 cycles of gemcitabine/carboplatin allowed
Placebo
until PD
OCEANS STUDY
 Recurrent Ovarian Cancer

> 6 months off platinum
 Measurable disease

Strata:
– Platinum-free interval
(>6-12, > 12 months)
– Cytoreductive surgery for recurrent ovarian cancer
(yes/no)
 Primary Objective
– PFS (Investigator determined) – HR 0.73
 Sample size
– 450 pts
GOG 213 –PHASE III
Surgical Candidate?
Yes
Randomize
Surgery
No
No Surgery
Randomize
Paclitaxel
Carboplatin
Paclitaxel
Carboplatin
Bevacizumab
Primary endpoint: OS
Target accrual: 660
Maintenance
Bevacizumab
ICON6
Carboplatin/Paclitaxel* x 6 cycles
Concurrent Placebo
Maintenance Placebo
First platinumsensitive recurrence
Ovarian, primary
peritoneal, or
fallopian tube cancer
Carboplatin/Paclitaxel* x 6 cycles
Concurrent Cediranib
Maintenance Placebo
Carboplatin/Paclitaxel* x 6 cycles
Concurrent Cediranib
Maintenance 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
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
VEGF + mTOR
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
CCI-779 + Sunitinib
Not tolerable
(15 mg + 25 mg)
CCI-779 + Sorafenib
Dose reduction
Toxicities
DLT: Mucocutaneous
(no further development)
DLT: Mucocutaneous, Plts 
(for one agent)
BV + Sorafenib
Dose reduction
(both agents: 50%)
BV + Sunitinib
Not Tolerability at full
doses in RCC
BV + CCI-779
Full dose
DLT: HUS, HTN, proteinuria
SAEs: GI perf, fistula, bleeding
SAEs: HUS/TTP-like syndrome HTN
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