Investigating the Role of Anti-Angiogenic Agents in Ovarian Cancer

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Investigating the Role of Anti-Angiogenic Agents
in Ovarian Cancer

• Carol Aghajanian, M.D.
• Chief, Gynecologic Medical Oncology
• Memorial Sloan-Kettering Cancer Center

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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
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

• Activated 9/26/05
• Accrual goal 1800 pts
• Primary end point PFS

optimal (gross residual) or suboptimal
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Phase III ICON7
Carboplatin/Paclitaxel x 6 cycles Observation
High risk early stage/Advanced stage Ovarian,
primary peritoneal, or fallopian tube cancer
Carboplatin/Paclitaxel x 6 cycles Bevacizumab 7.5
mg/kg x 5-6 cycles Bevacizumab 7.5 mg/kg x 12
cycles
Target Accrual 1520 Primary endpoint PFS
Carboplatin AUC6 Paclitaxel 175mg/m2 Cycles
21 days
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IP Therapy Randomized Trials
Alberts et al. NEJM 1996, Markman et al. JCO
2001, Armstrong et al. NEJM 2006
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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

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IP Chemotherapy Modification
GOG 172
D1 IV Paclitaxel (135 mg/m2/24h) D2 IP
Cisplatin (100 mg/m2) D8 IP Paclitaxel (60 mg/m2)
D1 IV
D2 IP
D8 IP
Modified
D1 IV Paclitaxel (135 mg/m2/3h) D2 IP Cisplatin
(75 mg/m2) D8 IP Paclitaxel (60 mg/m2)
D1 IV
D2 IP
D8 IP
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Phase I - GOG 9916
D1 IV Paclitaxel (175 mg/m2/3h) D1 IP
Carboplatin (AUC 6) D8 IP Paclitaxel (60 mg/m2)
9916 Part A
D1 IV
D8 IP
D1 IP
9916 Part B
D1 IV Docetaxel (75 mg/m2/1h) D1 IP Carboplatin
(AUC 6) D8 IP Paclitaxel (60 mg/m2)
D1 IP
D1 IV
D8 IP
9916 Part C
D1 IV Paclitaxel (175 mg/m2/3h) D1 IP
Carboplatin (AUC 6) D1 IV Bevacizumab (15
mg/kg) D8 IP Paclitaxel (60 mg/m2)
D1 IV
D1 IP
D8 IP
beginning cycle 2, day 1 and continuing for 17
total cycles
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Phase I - GOG 9917
D1 IV Paclitaxel (175 mg/m2/3h) D1 IP
Carboplatin (AUC 6)
9917 Part A
D1 IV
D8 IP
D1 IP
9917 Part B
D1 IV Paclitaxel (175 mg/m2/3h) D1 IP
Carboplatin (AUC 6) D1 IV Bevacizumab 15 mg/kg
D1 IP
D1 IV
D8 IP
beginning cycle 2, day 1 and continuing for 17
total cycles
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MSKCC 06-064
Modified GOG-0172
D1 IV Paclitaxel (135 mg/m2/3h) D2 IP Cisplatin
(75 mg/m2) D8 IP Paclitaxel (60 mg/m2)
D1 IV
D2 IP
D8 IP
06-064
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)
D1 IV
D2 IP
D8 IP
PI Dr. Jason Konner
beginning cycle 2, day 1 and continuing through
cycle 22
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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

Isonishi et al. J Clin Oncol 26 2008, abs 5506
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Phase III GOG 0252
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
RANDOMIZE
Stage II or III (lt1cm residual), Ovarian, primary
peritoneal, or fallopian tube cancer
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

• Accrual goal 1100 pts
• Primary end point PFS

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Relapse Therapy Past

• Primary treatment

RELAPSE
lt 6 months
gt 6 months
Platinum Resistant
Platinum Sensitive
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Bevacizumab in Recurrent Ovarian Cancer
1Burger et al. JCO 2007, 2Garcia et al. JCO
2008, 3Cannistra et al. JCO 2007
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AVF2949g Risk Factors for GI Perforation
Radiographic
Prior Treatment
P lt 0.05
P lt0.1
Cannistra, et al JCO 2007
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Single Agent Activity of Bevacizumab
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Ovarian Cancer Biologics
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ASCO 2008
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VEGF-TRAP
VEGF Trap 2 mg/kg IV q 2 weeks
Recurrent ovarian cancer 3 - 4 lines treatment
Platinum-resistant Resistant Topotecan and/or
Liposomal Doxorubicin
Randomized (11) 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
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Recurrent Disease Platinum Sensitive
ICON41
AGO2
1ICON4 Lancet 2003 and 2Pfisterer et al JCO 2006
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OCEANS STUDY PHASE III
Gemcitabine 1000 mg/m² days 1 and 8 Carboplatin
AUC 4 day 1 Bevacizumab 15 mg/kg day 1 q 21
days x 6
RANDOMIZATION
Bevacizumab until PD
Gemcitabine 1000 mg/m² days 1 and 8 Carboplatin
AUC 4 day 1 Placebo IV day 1 q 21 days x 6
Placebo until PD
Up to 10 cycles of gemcitabine/carboplatin
allowed
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OCEANS STUDY

• Recurrent Ovarian Cancer
• gt 6 months off platinum
• Measurable disease
• Strata
• Platinum-free interval (gt6-12, gt 12 months)
• Cytoreductive surgery for recurrent ovarian
  cancer (yes/no)
• Primary Objective
• PFS (Investigator determined) HR 0.73
• Sample size
• 450 pts

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GOG 213 PHASE III
Surgical Candidate?
Yes
No
Randomize
Surgery
No Surgery
Randomize
Paclitaxel Carboplatin Bevacizumab
Paclitaxel Carboplatin
Primary endpoint OS Target accrual 660
Maintenance Bevacizumab
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ICON6
Carboplatin/Paclitaxel x 6 cycles Concurrent
Placebo Maintenance Placebo
First platinum-sensitive 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
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Future Directions

• Combinations
• GOG 186G Randomized Phase II study of
  bevacizumab/everolimus vs. bevacizumab/placebo
• Novel Agents

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Selected Combinations in Trials
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Combination of anti-angiogenesis agents
preliminary toxicity data (Phase I experience)
Exposures in more pts and for longer duration may
reveal additional serious toxicities that are
relatively low-frequency
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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