Neoadjuvant Chemotherapy in Ovarian Cancer Key issues in trial design

Key Issue #1 What are the most current consensus recommendations on developing large phase III trials in ovarian cancer? What are the most current consensus recommendations on developing large phase III trials in ovarian cancer?

3 rd International Ovarian Cancer Consensus Conference 3 rd - 5 th September 2004, Black Forest, Germany 1-A 1:Is there a need to strictly define the extent and type of surgery for patients in first-line trials? Tissue should be obtained for histopathologic diagnosis to confirm the presence of primary ovarian or peritoneal carcinoma. Staging should be performed according to FIGO guidelines. For example, this includes at least lymph node sampling and peritoneal staging in early stage invasive disease (FIGO I – IIA). Up-front maximal surgical effort at cytoreduction with the goal of no residual disease should be undertaken. Level of Acceptance: 13 / 13

3 rd International Ovarian Cancer Consensus Conference 3 rd - 5 th September 2004, Black Forest, Germany 4-A4:Which regimen / kind of regimens can be regarded as standard comparator for future first-line trials? Within a given trial the chemotherapy regimen should be standardized and consistent with respect to drugs, dose, and schedule. The recommended standard comparator for trials on medical treatment in advanced ovarian cancer (FIGO IIB-IV) is carboplatin- paclitaxel The recommended regimen is carboplatin with a dose of AUC and paclitaxel 175 mg/m²/ 3h given every three weeks for 6 courses Level of Acceptance: 13 / 13

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Per protocol population (PP1) ITTPDS N = 361 NACT -> IDS N = 357 Disabling disease11 Histology41 Disease stage32 CA125/CEA ratio13 No pelvic mass-FNA10 Did not start allocated R/135 Other96 Remaining (PP1)329339

AIOM 2000 GOG 182: OS based on Residual Disease

Multivariate analysis for OS(PP1) P values Optimal debulking Histological type (9 categories) Largest tumor size at randomisation Figo Stage (IIIc vs IV) Country (14 categories) Age WHO PSNS Differentiation GradeNS Treatment armNS

Key Issue # 2 What is the primary hypothesis? What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will improve OS or PFS

AIOM 2000 NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14)

GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) ( ) ( ) ( ) ( ) Bookman, ASCO 2006, #5002

GOG 172 – IV vs. IP Overall survival

Key Issue # 2 What is the primary hypothesis? What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will improve OS or PFS Question # 1: Can we develop a rational superiority trial incorporating neoadjuvant chemotherapy?

Key Issue # 2 What is the primary hypothesis? What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical characteristics (PP1) PDS (n = 329) NACT -> IDS (n = 339)* Postoperative mortality (< 28 days) 2,7%0,6% Postoperative sepsis8%2% Fistula (bowel/GU)1,2% / 0,3%0,3% / 0,6% Operative time (minutes)180 Red blood cell transfusion51%53% Hemorhage Grade 3/47%1% Venous Gr 3/42,4%0,3%

Key Issue # 2 What is the primary hypothesis? What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Question # 2: What is the best trial design based on a primary endpoint of QOL?

Key Issue # 2 What is the primary hypothesis? What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Neoadjuvant chemotherapy will allow more patients to receive optimal surgery and optimal chemotherapy Neoadjuvant chemotherapy will allow more patients to receive optimal surgery and optimal chemotherapy

Randomised EORTC-GCG/NCIC-CTG trial on NACT+ IDS versus PDS Protocol Compliance (PP1) PDS (n = 329) NACT -> IDS (n = 339) Primary debulking100 %0% Interval debulking19%90% Second look surgery5%4% At least 6 courses CT83%86%

AIOM 2000 GOG 182: Residual Disease after Primary Surgery

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical findings and results (PP1) PDS (n = 329) NACT -> IDS (n = 339)* Metastases before > 2 cm95%68% Metastases before > 10 cm62%27% No residual after surgery21%53% ≤ 1 cm after surgery46%82% * % calculated on the 306 patients who underwent IDS.

Key Issue # 2 What is the primary hypothesis? What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Neoadjuvant chemotherapy will allow more patients to receive optimal surgery and optimal chemotherapy Neoadjuvant chemotherapy will allow more patients to receive optimal surgery and optimal chemotherapy Question # 3: Is there a patient population where this would have an impact on outcome?

Key Issue # 3 Neoadjuvant chemotherapy should be applied to all advanced ovarian cancer patients Neoadjuvant chemotherapy should be applied to all advanced ovarian cancer patientsOR Neoadjuvant chemotherapy should be only for select populations: Neoadjuvant chemotherapy should be only for select populations: Elderly Elderly Poor performance status Poor performance status Extensive disease Extensive disease Medical co-morbidities Medical co-morbidities

GOG 182 Median age on trial 58 (62 in neoadjuvant trial) Median age on trial 58 (62 in neoadjuvant trial) Only 14% of patients ≥ 70 Only 14% of patients ≥ 70 Less than 5% ≥ 75 Less than 5% ≥ 75 Performance status 0, 1, 2 Performance status 0, 1, 2 15% were stage IV 15% were stage IV Clearly a large patient population is not being enrolled onto current trials due to advanced age and poor performance status

Key Issue # 3: Special Populations Question # 4: How to best determine extensive disease? Question # 4: How to best determine extensive disease? Radiographic, CA-125 Radiographic, CA-125 Question # 5: What is the best way to incorporate neoadjuvant chemotherapy into advanced age and poor performance populations? Question # 5: What is the best way to incorporate neoadjuvant chemotherapy into advanced age and poor performance populations? Endpoints Endpoints Inclusive study design Inclusive study design

Key Issue # 4: Surgical Timing Question # 6: What is the best timing for surgery in patients undergoing neoadjuvant chemotherapy (3 vs. 6 months)? Question # 6: What is the best timing for surgery in patients undergoing neoadjuvant chemotherapy (3 vs. 6 months)? Which patients should not undergo surgical intervention? Which patients should not undergo surgical intervention?

Key Issue # 5: Endpoints Question # 7: What are the appropriate endpoints and how should they be measured? Question # 7: What are the appropriate endpoints and how should they be measured? OS/PFS OS/PFS QOL QOL Surgical morbidity Surgical morbidity Response Response Clinical Clinical Radiologic Radiologic Serum Markers Serum Markers Surgical complete response Surgical complete response

Key Issue # 6: Proof-of-Concept designs Using neoadjuvant chemotherapy for proof-of- concept type studies Using neoadjuvant chemotherapy for proof-of- concept type studies Novel strategies Novel strategies Novel cytotoxic or biologic agents Novel cytotoxic or biologic agents Molecular mechanisms and biomarkers Molecular mechanisms and biomarkers Question # 8: Can we develop a standard queue for proof-of-concept studies in advanced ovarian cancer patients?