GOG0172: The DingsGOG0172: 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

• 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

• Epithelial Ovarian CancerEpithelial Ovarian Cancer• Stage IC/II any gradeStage IC/II any grade• Stage IA/B high gradeStage IA/B high grade• No prior therapyNo prior therapy

Open:Open: 20-Mar-9520-Mar-95Closed:Closed: 25-May-9825-May-98Accrual:Accrual: 457 pts457 pts

x 3x 3

x 6x 6Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (3 h) (3 h)Carboplatin AUC=7.5Carboplatin AUC=7.5

IIII

II

GOG157: Ovarian (adjuvant)GOG157: Ovarian (adjuvant)GOG157: Ovarian (adjuvant)GOG157: Ovarian (adjuvant)

Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (3 h) (3 h)Carboplatin AUC=7.5Carboplatin AUC=7.5

• Only 70% met eligibility criteria (133 excluded)Only 70% met eligibility criteria (133 excluded)• 107/457 (23%) were incompletely staged107/457 (23%) were incompletely staged• Hematologic toxicity and neuropathy increased with 6 cyclesHematologic toxicity and neuropathy increased with 6 cycles

Bell JG, et al. Bell JG, et al. Gynecol OncolGynecol Oncol 102:432-9, 2006 102:432-9, 2006

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72 84 96Months on Study

Pro

port

ion

Sur

vivi

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GOG157: Ovarian (adjuvant)GOG157: Ovarian (adjuvant)

Carbo-Paclitaxel (x6)Carbo-Paclitaxel (x6)(n = 214) 83% @ 5 y(n = 214) 83% @ 5 y

Carbo-Paclitaxel (x3)Carbo-Paclitaxel (x3)(n = 213) 81% @ 5 y(n = 213) 81% @ 5 y

Hazard Ratio = 1.0295% CI = 0.662 – 1.57, p=0.94(includes 107 surgical exclusions)

Bell JG, et al. Bell JG, et al. Gynecol OncolGynecol Oncol 102:432-9, 2006 102:432-9, 2006

Cisplatin 75 mg/mCisplatin 75 mg/m22

Cyclophosphamide 650 mg/mCyclophosphamide 650 mg/m22

Cisplatin 75 mg/mCisplatin 75 mg/m22

Paclitaxel 135 mg/mPaclitaxel 135 mg/m22 (24 h) (24 h)

• Epithelial Ovarian CancerEpithelial Ovarian Cancer• Suboptimal Stage III/IVSuboptimal Stage III/IV• No prior therapyNo prior therapy

Open:Open: 13-Apr-9013-Apr-90Closed:Closed: 02-Mar-9202-Mar-92Accrual:Accrual: 410 pts410 pts

II

IIII

McGuire, et al. McGuire, et al. N Engl J MedN Engl J Med 334:1-6, 1996 334:1-6, 1996

GOG111: Ovarian (suboptimal III/IV)GOG111: Ovarian (suboptimal III/IV)GOG111: Ovarian (suboptimal III/IV)GOG111: Ovarian (suboptimal III/IV)

Cisplatin 100 mg/mCisplatin 100 mg/m22

Cisplatin 75 mg/mCisplatin 75 mg/m22

Paclitaxel 135 mg/mPaclitaxel 135 mg/m22 (24 h) (24 h)

• Epithelial Ovarian CancerEpithelial Ovarian Cancer• Suboptimal Stage III/IVSuboptimal Stage III/IV• No prior therapyNo prior therapy• Crossover allowedCrossover allowed

Open:Open: 20-Mar-9220-Mar-92Closed:Closed: 09-May-9409-May-94Accrual:Accrual: 648 pts648 pts

II

IIIIII

IIII Paclitaxel 200 mg/mPaclitaxel 200 mg/m22 (24 h) (24 h)

Muggia, et al. Muggia, et al. J Clin OncolJ Clin Oncol 18:106, 2000 18:106, 2000

GOG132: Ovarian (suboptimal III/IV)GOG132: Ovarian (suboptimal III/IV)GOG132: Ovarian (suboptimal III/IV)GOG132: Ovarian (suboptimal III/IV)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60Months on Study

Pro

port

ion

Sur

vivi

ng .

GOG111 & 132: Ovarian (subopt III/IV)GOG111 & 132: Ovarian (subopt III/IV)

GOG-111 (n = 184)GOG-111 (n = 184)CDDP 75 and Paclitaxel 135CDDP 75 and Paclitaxel 135Median = 37 mMedian = 37 m

GOG-132 (n = 201)GOG-132 (n = 201)CDDP 75 and Paclitaxel 135CDDP 75 and Paclitaxel 135Median = 27 mMedian = 27 m

Muggia, et al. Muggia, et al. J Clin OncolJ Clin Oncol 18:106, 2000 18:106, 2000McGuire, et al. McGuire, et al. N Engl J MedN Engl J Med 334:1-6, 1996 334:1-6, 1996

10 m10 m

GOG158: Ovarian (optimal III)GOG158: Ovarian (optimal III)GOG158: Ovarian (optimal III)GOG158: Ovarian (optimal III)

Cisplatin 75 mg/mCisplatin 75 mg/m22

Paclitaxel 135 mg/mPaclitaxel 135 mg/m22 (24 h) (24 h)

Carboplatin AUC 7.5Carboplatin AUC 7.5Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (3 h) (3 h)

• Epithelial Ovarian CancerEpithelial Ovarian Cancer• Optimal Stage IIIOptimal Stage III• No prior therapyNo prior therapy• Elective Second-LookElective Second-Look• Non-Inferiority DesignNon-Inferiority Design

Open:Open: 03-Apr-9503-Apr-95Closed:Closed: 26-Jan-9826-Jan-98Accrual:Accrual: 792 pts (evaluable)792 pts (evaluable)

II

IIII

Ozols, et al. Ozols, et al. Proc J Clin OncolProc J Clin Oncol 21:3194, 2003 21:3194, 2003

GOG172: Ovarian (optimal III)GOG172: Ovarian (optimal III)GOG172: Ovarian (optimal III)GOG172: Ovarian (optimal III)

Cisplatin 75 mg/mCisplatin 75 mg/m22

Paclitaxel 135 mg/mPaclitaxel 135 mg/m22 (24 h) (24 h)

Cisplatin 100 mg/mCisplatin 100 mg/m22 IP d1 IP d1Paclitaxel 135 mg/mPaclitaxel 135 mg/m22 (24 h) IV d1 (24 h) IV d1Paclitaxel 60 mg/mPaclitaxel 60 mg/m22 IP d8 IP d8

• Epithelial Ovarian CancerEpithelial Ovarian Cancer• Optimal Stage IIIOptimal Stage III• No prior therapyNo prior therapy• Elective Second-LookElective Second-Look

Open:Open: 23-Mar-9823-Mar-98Closed:Closed: 29-Jan-0129-Jan-01Accrual:Accrual: 416 pts (evaluable)416 pts (evaluable)

II

IIII

Armstrong, et al. Armstrong, et al. NEJMNEJM 354:34-43, 2006 354:34-43, 2006

CDDP (IV) Paclitaxel (IV)CDDP (IV) Paclitaxel (IV)(n = 400)(n = 400)

Ozols, et al. Ozols, et al. J Clin Oncol J Clin Oncol 21:3194, 2003 21:3194, 2003

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60Months on Study

Ove

rall

Sur

viva

l .GOG172 & 158: Exploratory AnalysisGOG172 & 158: Exploratory AnalysisGOG172 & 158: Exploratory AnalysisGOG172 & 158: Exploratory Analysis

Armstrong, et al. Armstrong, et al. NEJMNEJM 354:34-43, 2006 354:34-43, 2006

CDDP (IV) Paclitaxel (IV)CDDP (IV) Paclitaxel (IV)(n = 210)(n = 210)

CDDP (IP) Paclitaxel (IP+IV)CDDP (IP) Paclitaxel (IP+IV)(n = 206)(n = 206)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60Months on Study

Ove

rall

Sur

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l .GOG: Combined Exploratory AnalysisGOG: Combined Exploratory AnalysisGOG: Combined Exploratory AnalysisGOG: Combined Exploratory Analysis

Ozols, et al. Ozols, et al. Gynecol OncolGynecol Oncol 103:1-6, 2006 103:1-6, 2006

GOG172 to GOG158:HR = 0.81 (95% CI 0.59 – 1.11)

Ovarian Cancer: Biologic OpportunitiesOvarian 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

• 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 StudiesGOG-DTC: Ovary, Biologic Studies

Study Closed Reagents Chair Response & Comments

160160 Jan-00Jan-00 TrastuzumabTrastuzumab BookmanBookman 3/41 (7.3%)3/41 (7.3%) InactiveInactive

170-B170-B Mar-99Mar-99 IL-12 (IV)IL-12 (IV) HurteauHurteau 1/26 (3.8%)1/26 (3.8%) InactiveInactive

170-C170-C Jun-02Jun-02 GefitinibGefitinib SchilderSchilder 1/27 (3.7%)1/27 (3.7%) TK-mutTK-mut

170-D170-D Aug-04Aug-04 BevacizumabBevacizumab BurgerBurger 12/62 (19.4%), 10+ m PFS12/62 (19.4%), 10+ m PFS

170-E170-E Aug-04Aug-04 ImatinibImatinib SchilderSchilder Under Analysis (Stg 2)Under Analysis (Stg 2)

170-F170-F OngoingOngoing BAY43-9006BAY43-9006 MateiMatei Accrual in Process (Stg 2)Accrual in Process (Stg 2)

170-G170-G May-06May-06 LapatinibLapatinib GarciaGarcia Under Analysis (Stg 1)Under Analysis (Stg 1)

170-H170-H Apr-06Apr-06 SAHASAHA ModesittModesitt Under Analysis (Stg 1)Under Analysis (Stg 1)

170-J170-J PendingPending TemserolimusTemserolimus BehbakhtBehbakht Under DevelopmentUnder Development

170-I170-I PendingPending EnzastaurinEnzastaurin UshaUsha Under DevelopmentUnder Development

GOG0170D: Bevacizumab Phase IIGOG0170D: Bevacizumab Phase II

Bevacizumab 15 Bevacizumab 15 mg/kg q3wkmg/kg q3wk

• Epithelial Ovarian CancerEpithelial Ovarian Cancer• ≤≤ 2 Prior Therapies2 Prior Therapies• RECIST MeasurableRECIST Measurable• PS 0,1PS 0,1• Two-stage accrual designTwo-stage accrual design• Primary endpoint PFS @6 mPrimary endpoint PFS @6 m

Open:Open: Apr-02Apr-02Closed:Closed: Aug-04Aug-04Accrual:Accrual: 62 pts62 pts

II

Burger et al., Burger et al., Proc Ann Meet ASCOProc Ann Meet ASCO 24:A5009 24:A5009

• Overall response rate 12/62 (19.4%), including 3 CROverall response rate 12/62 (19.4%), including 3 CR• 42% of pts alive and free of progression at 6 m42% of pts alive and free of progression at 6 m• Median number of cycles = 7, range = 1 to 29Median number of cycles = 7, range = 1 to 29

0.0

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GOG0170D: Bevacizumab Phase IIGOG0170D: Bevacizumab Phase II

Burger et al., Burger et al., Proc Ann Meet ASCOProc Ann Meet ASCO 24:A5009 24:A5009

GOG0126 Series (n = 220)GOG0126 Series (n = 220)Platinum-Resistant DiseasePlatinum-Resistant DiseasePFS @ 6 m = 0.16 (PFS @ 6 m = 0.16 (SE 0.025)SE 0.025)

GOG0170-D (n = 62)GOG0170-D (n = 62)PFS @ 6 m = 0.42PFS @ 6 m = 0.42

• Epithelial Ovarian or Primary Peritoneal CancerEpithelial Ovarian or Primary Peritoneal Cancer• Suboptimal CytoreductionSuboptimal Cytoreduction• Collaborative design (GOG, NCI, Genentech)Collaborative design (GOG, NCI, Genentech)

GOG218: Ovarian (stage III-IV)GOG218: Ovarian (stage III-IV)GOG218: Ovarian (stage III-IV)GOG218: Ovarian (stage III-IV)

x 6x 6

Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (3 h) (3 h)Carboplatin AUC=6.0Carboplatin AUC=6.0Bevacizumab 15 mg/kg q21d*Bevacizumab 15 mg/kg q21d*

IIII

x 6x 6IIPaclitaxel 175 mg/mPaclitaxel 175 mg/m22 (3 h) (3 h)Carboplatin AUC=6.0Carboplatin AUC=6.0Placebo q21d*Placebo q21d*

Placebo(14 m total)

Placebo(14 m total)

Bevacizumab(14 m total)x 6x 6

Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (3 h) (3 h)Carboplatin AUC=6.0Carboplatin AUC=6.0Bevacizumab 15 mg/kg q21d*Bevacizumab 15 mg/kg q21d*

IIIIII

Open:Open: 26-Sep-0526-Sep-05Closed:Closed: ------Target Accrual:Target Accrual: 2000 pts (3 Y)2000 pts (3 Y) BurgerBurger, et al., et al.

*starting with C2*starting with C2

If IP Therapy is Really So Important…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?

• 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 (05-JAN-2006)NCI Clinical Announcement (05-JAN-2006)

and potential risks

^compared to standard IV chemotherapy

^

route

^

such as GOG0218 and ICON7,

^

Revised

14-Oct-2006

two cycles of

^some

^