Transcript GOG0182ICON5

GOG0172: The Dings
• The recommended regimen is not feasible
– Substitution of carboplatin for cisplatin
– Reduce cisplatin from 100 mg/m2 to 75 mg/m2
– Change paclitaxel infusion and/or schedule
– Need for 6 cycles not established
• Role of intraperitoneal delivery not established
– Trial design flawed (too many variables)
– Dose-intensity hypothesis not validated
– Potential role of biology, angiogenesis, microenvironment
• This should not be our research priority
GOG157: Ovarian (adjuvant)
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Epithelial Ovarian Cancer
Stage IC/II any grade
Stage IA/B high grade
No prior therapy
I
Paclitaxel 175 mg/m2 (3 h) x 3
Carboplatin AUC=7.5
II
Paclitaxel 175 mg/m2 (3 h)
x6
Carboplatin AUC=7.5
• Only 70% met eligibility criteria (133 excluded)
• 107/457 (23%) were incompletely staged
• Hematologic toxicity and neuropathy increased with 6 cycles
Open:
Closed:
Accrual:
20-Mar-95
25-May-98
457 pts
Bell JG, et al. Gynecol Oncol 102:432-9, 2006
GOG157: Ovarian (adjuvant)
Carbo-Paclitaxel (x6)
(n = 214) 83% @ 5 y
Proportion Surviving .
1.0
0.8
Carbo-Paclitaxel (x3)
(n = 213) 81% @ 5 y
0.6
0.4
Hazard Ratio = 1.02
95% CI = 0.662 – 1.57, p=0.94
(includes 107 surgical exclusions)
0.2
0.0
0
12
24
36
48
60
72
84
96
Months on Study
Bell JG, et al. Gynecol Oncol 102:432-9, 2006
GOG111: Ovarian (suboptimal III/IV)
I
Cisplatin 75 mg/m2
Cyclophosphamide 650 mg/m2
II
Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2 (24 h)
• Epithelial Ovarian Cancer
• Suboptimal Stage III/IV
• No prior therapy
Open:
Closed:
Accrual:
13-Apr-90
02-Mar-92
410 pts
McGuire, et al. N Engl J Med 334:1-6, 1996
GOG132: Ovarian (suboptimal III/IV)
I Cisplatin 100 mg/m2
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•
•
•
Epithelial Ovarian Cancer
Suboptimal Stage III/IV
No prior therapy
Crossover allowed
II Paclitaxel 200 mg/m2 (24 h)
2
Cisplatin
75
mg/m
III
Paclitaxel 135 mg/m2 (24 h)
Open:
Closed:
Accrual:
20-Mar-92
09-May-94
648 pts
Muggia, et al. J Clin Oncol 18:106, 2000
GOG111 & 132: Ovarian (subopt III/IV)
Proportion Surviving .
1.0
GOG-111 (n = 184)
CDDP 75 and Paclitaxel 135
Median = 37 m
0.8
0.6
10 m
GOG-132 (n = 201)
CDDP 75 and Paclitaxel 135
Median = 27 m
0.4
0.2
0.0
0
12
24
36
48
60
Months on Study
McGuire, et al. N Engl J Med 334:1-6, 1996
Muggia, et al. J Clin Oncol 18:106, 2000
GOG158: Ovarian (optimal III)
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•
•
•
•
Epithelial Ovarian Cancer
Optimal Stage III
No prior therapy
Elective Second-Look
Non-Inferiority Design
2
Cisplatin
75
mg/m
I
Paclitaxel 135 mg/m2 (24 h)
II Carboplatin AUC 7.52
Paclitaxel 175 mg/m (3 h)
Open:
Closed:
Accrual:
03-Apr-95
26-Jan-98
792 pts (evaluable)
Ozols, et al. Proc J Clin Oncol 21:3194, 2003
GOG172: Ovarian (optimal III)
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•
•
•
Epithelial Ovarian Cancer
Optimal Stage III
No prior therapy
Elective Second-Look
2
Cisplatin
75
mg/m
I
Paclitaxel 135 mg/m2 (24 h)
II
Open:
Closed:
Accrual:
Cisplatin 100 mg/m2 IP d1
Paclitaxel 135 mg/m2 (24 h) IV d1
Paclitaxel 60 mg/m2 IP d8
23-Mar-98
29-Jan-01
416 pts (evaluable)
Armstrong, et al. NEJM 354:34-43, 2006
GOG172 & 158: Exploratory Analysis
CDDP (IP) Paclitaxel (IP+IV)
(n = 206)
Overall Survival.
1.0
0.8
0.6
CDDP (IV) Paclitaxel (IV)
(n = 210)
0.4
CDDP (IV) Paclitaxel (IV)
(n = 400)
0.2
0.0
0
12
24
36
48
60
Months on Study
Ozols, et al. J Clin Oncol 21:3194, 2003
Armstrong, et al. NEJM 354:34-43, 2006
GOG: Combined Exploratory Analysis
1.0
Overall Survival.
GOG172 to GOG158:
HR = 0.81 (95% CI 0.59 – 1.11)
0.8
0.6
0.4
0.2
0.0
0
12
24
36
48
60
Months on Study
Ozols, et al. Gynecol Oncol 103:1-6, 2006
Ovarian Cancer: Biologic Opportunities
• Unique Biology of the Müllerian Epithelium and Peritoneal Cavity
– Specialized relationship; spread via implantation
– Frequent production of ascites, associated with VEGF
– Negative immunoregulation (VEGF, IL-10, IL-6, IL-12, APC)
• Growth Factor Receptors
– EGF-R frequently expressed, mutations uncommon, frequency of
overexpression variable
– HER2/neu frequently expressed, high-level overexpression <15%,
gene amplification uncommon
– ER/PR/AR frequently expressed, variable functionality
– Other receptors less well characterized
• Growth Factor Production
– Frequent high-level expression of VEGF
– Increased expression of IL10, IL6, TNF, TGFα
GOG-DTC: Ovary, Biologic Studies
Study
Closed
Reagents
Chair
Response & Comments
160
Jan-00
Trastuzumab
Bookman
3/41 (7.3%)
Inactive
170-B
Mar-99
IL-12 (IV)
Hurteau
1/26 (3.8%)
Inactive
170-C
Jun-02
Gefitinib
Schilder
1/27 (3.7%)
TK-mut
170-D
Aug-04
Bevacizumab
Burger
12/62 (19.4%), 10+ m PFS
170-E
Aug-04
Imatinib
Schilder
Under Analysis (Stg 2)
170-F
Ongoing
BAY43-9006
Matei
Accrual in Process (Stg 2)
170-G
May-06
Lapatinib
Garcia
Under Analysis (Stg 1)
170-H
Apr-06
SAHA
Modesitt
Under Analysis (Stg 1)
170-J
Pending
Temserolimus
Behbakht
Under Development
170-I
Pending
Enzastaurin
Usha
Under Development
GOG0170D: Bevacizumab Phase II
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Epithelial Ovarian Cancer
≤ 2 Prior Therapies
RECIST Measurable
PS 0,1
Two-stage accrual design
Primary endpoint PFS @6 m
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•
Overall response rate 12/62 (19.4%), including 3 CR
42% of pts alive and free of progression at 6 m
Median number of cycles = 7, range = 1 to 29
Open:
Closed:
Accrual:
Apr-02
Aug-04
62 pts
I
Bevacizumab 15 mg/kg q3wk
Burger et al., Proc Ann Meet ASCO 24:A5009
Progression-Free Survival.
GOG0170D: Bevacizumab Phase II
1.0
GOG0170-D (n = 62)
PFS @ 6 m = 0.42
0.8
0.6
GOG0126 Series (n = 220)
Platinum-Resistant Disease
PFS @ 6 m = 0.16 ( SE 0.025)
0.4
0.2
0.0
0
6
12
18
Months on Study
Burger et al., Proc Ann Meet ASCO 24:A5009
GOG218: Ovarian (stage III-IV)
• Epithelial Ovarian or Primary Peritoneal Cancer
• Suboptimal Cytoreduction
• Collaborative design (GOG, NCI, Genentech)
I
Paclitaxel 175 mg/m2 (3 h)
Carboplatin AUC=6.0
Placebo q21d*
II
Paclitaxel 175 mg/m2 (3 h)
Carboplatin AUC=6.0
Bevacizumab 15 mg/kg q21d*
III
Paclitaxel 175 mg/m2 (3 h)
Carboplatin AUC=6.0
Bevacizumab 15 mg/kg q21d*
Open:
26-Sep-05
Closed:
--Target Accrual: 2000 pts (3 Y)
x6
Placebo
(14 m total)
x6
Placebo
(14 m total)
x6
Bevacizumab
(14 m total)
*starting with C2
Burger, et al.
If IP Therapy is Really So Important…
• Why has it been more than 2 years without an active GOG
phase III trial for women with ovarian cancer and optimal
cytoreductive surgery?
• Where is the funding to support scientific investigation of IP
therapy using generic off-patent medications (cisplatin and
paclitaxel)?
• Should our patients commit to increased toxicity and 2-3 days in
the hospital with each cycle of “recommended” therapy?
• Are we prepared to evaluate all new agents “IP” and “IV”?
• Should IP therapy have a higher priority than evaluation of
targeted agents, immunomodulation, and tumor molecular
profiling?
NCI Clinical Announcement
and potential risks
compared to standard IV chemotherapy
^
two cycles of
^
some
^
route
^
such as GOG0218 and ICON7,
^
^
(05-JAN-2006)