Saturday, May 30, :00 PM - 9:00 PM The Peabody Orlando Orlando, Florida Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options This program is supported by an educational grant from

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clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Overview  This presentation consists of 2 separate talks that were presented as part of a satellite symposium in Orlando, Florida –Platinum-Sensitive Recurrent Ovarian Cancer (Nonplatinum Doublets) – Bradley J. Monk, MD, FACOG, FACS –Platinum-Sensitive Recurrent Disease: Role of Biologics and Secondary Cytoreduction? – Thomas J. Herzog, MD

Bradley J. Monk, MD, FACOG, FACS Associate Professor and Director of Research Gynecologic Oncology Chao Family Comprehensive Cancer Center University of California Irvine Medical Center Orange, California Platinum-Sensitive Recurrent Ovarian Cancer (Nonplatinum Doublets)

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Case Presentation

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options What is the appropriate chemotherapy?  Carboplatin + gemcitabine  Carboplatin + paclitaxel  Carboplatin + pegylated liposomal doxorubicin  PLD + trabectedin  Chemotherapy doublet with bevacizumab  Other

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Current Controversies in Treating Platinum- Sensitive Recurrent Ovarian Cancer  When to initiate therapy  Single drug vs combination  Platinum doublet vs nonplatinum doublet  Choice of agent(s)  Sequencing of agent(s)  Adding a targeted agent  When to discontinue therapy

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Carboplatin vs Carboplatin + Gemcitabine PlatinumCarbo + Gemcitabine P Value Platinum sensitive 100% Response rate 31%47%.0016 Median PFS 5.8 mos8.6 mos.0031 Median OS 17.3 mos18.0 mos.73  N = 366 (356 evaluable) PFS Time (Mos) Reprinted with permission. ©2006 American Society of Clinical Oncology. All rights reserved. Pfisterer J, et al. J Clin Oncol. 2006;24: Progression-Free Probability Log-rank P =.0038 HR: 0.72 ( ) Gemcitabine/carboplatin median: 8.6 mos Carboplatin median: 5.8 mos Gem/carboplatin (N = 178) Carboplatin (N = 178)

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Median PFS, MosGemcitabine/ Carboplatin Carboplatin Platinum-free interval (6-12 mos) Platinum-free interval (> 12 mos) Prior platinum and paclitaxel Prior platinum (no paclitaxel) Pfisterer J, et al. ASCO Abstract Summary of Subgroup Analysis

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options A new treatment option for sarcoma patients following European Commission approval on September 20, 2007: Trabectedin is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuitable to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients. Trabectedin Trabectedin (ET-743)

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OVA-301: Methods—Study Design Phase III Trial PLD 30 mg/m² 90-min infusion followed by Trabectedin* 1.1 mg/m² 3-hr infusion q 3 wks PLD 50 mg/m 2 90-min infusion q 4 wks RANDOMIZATIONRANDOMIZATION Monk BJ, et al. ESMO Abstract LBA4. ClinicalTrials.gov. NCT *Premedication with dexamethasone is required.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OVA-301 Demographics PLD (n = 335) Trab + PLD (n = 337) Race, n (%) White Asian Black Other 259 (77) 71(21) 3 (1) 2 (1) 265 (79) 66 (20) 2 (1) 4 (1) Median age, yrs (%) < 65 yrs  65 yrs ECOG, % PS 0/1 PS 2 57/ /29 3 Platinum sensitivity, % Platinum sensitive Platinum resistant Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Independent Radiologist  All radiologists blinded to treatment and clinical data  2 radiologists determined response and PD by RECIST –Agreement  results final –Disagreement  adjudication by third radiologist  Combined with data on death to determine PFS

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OVA-301 Primary Endpoint: PFS Indep Rad (All Measurable Analysis Set)  PFS events: 389 –PLD: 5.8 mos –Trabectedin + PLD: 7.3 mos –HR: 0.79 ( ); P =.0190  No. censored: 256 Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options PFS Investigator, all randomized Indep onc, all randomized Investigator, all measurable Indep rad, all measurable Analysis Set N P Value HR* 95% CI *HR: trabectedin + PLD vs PLD Favoring Trabectedin + PLD Favoring PLD Monk BJ, et al. ESMO Abstract LBA4.  PFS HR and 95% CI; unstratified (study ET743-OVA-301, by analysis set)

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options PFS According to Platinum-Free Interval Monk BJ, et al. ESMO Abstract LBA4. HR (PLD + trabectedin vs PLD) and 95% CI (log scale)  HR and 95% CI (study ET743-OVA-301, PFS, independent review, all measurable or randomized subjects) PFI (Mos) > > 12 Combo % CI Mono 78/109 55/86 57/117 90/117 68/91 63/122 Combo 74/109 69/122 48/93 82/115 73/123 49/94 HR Mono Favoring PLD + Trabectedin Favoring PLD Reviewer Indep rad Indep onc Median (Mos)Events/N

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OVA-301: Primary Endpoint PFS—PFI > 6 Mos Indep Rad (All Measurable* Subjects)  PFS events: 226 –PLD: 7.5 mos –Trabectedin + PLD: 9.2 mos –HR: 0.73 ( ); P =.0170  No. censored: 191 Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OVA-301: OS (Interim Analysis)  OS events: 300 –PLD: 19.4 mos –Trabectedin + PLD: 20.5 mos –HR: 0.85 ( ); P =.1506  No. censored: 372 Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options PLD (N = 335) Trabectedin + PLD (N = 337) P Value Independent radiologist review, n (%) Platinum sensitive CR + PR48 (22.6)77 (35.3).0042 Platinum resistant CR + PR15 (12.2)16 (13.4).8484 Investigator review, n (%) Platinum sensitive CR + PR69 (32.5)103 (47.2).0022 Platinum resistant CR + PR20 (16.3)27 (22.7).2554 *All randomized subjects. OVA-301: Best Overall Response* (by Platinum Sensitivity) Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OVA-301: Selected Adverse Events Adverse Events, %PLD (n = 330)* Trabectedin + PLD (n = 333)* Grade 3Grade 4Grade 3Grade 4 Hand-foot syndrome18140 Mucositis/stomatitis11< 130 Cardiac disorders< 1 2 Fatigue5< 18 Vomiting4012< 1 Nausea40100 Febrile neutropenia*2< 162 Neuropathy00< 10 Alopecia (  grade 2) 42 NCI CTC Version 3.0. *Number treated. Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OVA-301 Grade 3/4 Laboratory Abnormalities NCI CTC Version 3.0 Laboratory Abnormalities, %PLD (n = 330) Trabectdedin + PLD (n = 333) Grade 3Grade 4Grade 3Grade 4 HematologyNeutrophils WBC Platelets Hemoglobin62136 BiochemistryALT increase20465 AST increase1< 1122 CPK increase0011 Alkaline phosphatase1020 Bilirubin< 10 0 Creatinine10< 1 TransfusionsBlood1211 Platelet210 Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Krasner CN, et al. ASCO 2009; Abstract OVA-301: QLQC30 Global Health Status Scale Mean Score Over Time,* All Randomized Subjects  QoL was a secondary endpoint in OVA-301 –EORTC Quality of Life 30-Question Questionnaire (QLQ ‑ 30) used to evaluate global health status to assess QoL  No difference in QoL between the trabectedin/PLD combination regimen vs PLD *Higher is better

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Platinum-Sensitive Recurrent Ovarian Cancer: Positive Randomized Trials in Perspective StudyNPrior Taxane, % % PFI > 12 Mos, % Measurable Disease RR,* % PFS, Mos OS, Mos GordonPLD123NS Measurable ParmarCarbo + paclitaxel Italy (not MRC CTU or AGO) 6612*29 PfistererCarbo + gemcitabine SWOG (measurable or assessable) 478.6*18 MonkPLD + trabectedin RECIST479.7 † 20.5 (not mature) *By investigator. † By independent radiologist. Monk BJ, et al. ESMO Abstract LBA4.

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Platinum ± Paclitaxel (Parmar et al) Carboplatin ± Gemcitabine (Pfisterer et al) Trabectedin ± PLD (Monk et al) N Primary endpointOSPFS Prior taxane, % mos PFI, % PFS assessmentInvestigator Indep radiologist/ investigator Risk of progression  24%  28%  27%/38% Risk of death  18%No  18% Added toxicityMyelo, neuroMyeloMyelo, LFTs Active Agents: Platinum-Sensitive Patients

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Thank You!

Thomas J. Herzog, MD Director, Division of Gynecologic Oncology Columbia University College of Physicians and Surgeons New York, New York Platinum-Sensitive Recurrent Disease: Role of Biologics and Secondary Cytoreduction?

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Background: Recurrent Ovarian Cancer  Nearly 70% of advanced-stage cancers relapse  Many pts will have biologic exposure frontline  Secondary cytoreduction appears to benefit a subset of pts  Toxicity and resource availability may influence choice of therapy  Phase III data are emerging

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Primary Treatment End of frontline therapy 0 mos6 mos12 mos Refractory ResistantSensitive Platinum Sensitivity

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Secondary Cytoreductive Surgery in Pts With Platinum-Sensitive Disease Chi DS, et al. Cancer. 2006;106: DFISingle SiteMultiple Sites: No Carcinomatosis Carcinomatosis 6-12 mosOffer SCConsider SCNo SC mosOffer SC Consider SC > 30 mosOffer SC

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Harter P, et al. Ann Surg Oncol. 2006;13: Combination of PS, early FIGO stage initially or no residual tumor after first surgery, and absence of ascites could predict complete resection in 79% of pts DESKTOP-OVAR: Predictors of Successful Surgery (= Complete Resection) Multivariate Analysis Pre-Op VariableOR95% CIP Value PS (ECOG 0vs > 0) <.001 Residual disease 1st surgery (0 vs > 0) <.001 Or initial FIGO stage (I/II vs III/IV) No ascites (cutoff 500 mL) <.001

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Harter P, et al. Ann Surg Oncol. 2006;13: No residual Median OS: 45.2 mos Residual > 10 mm Median OS: 19.7 mos Residual 1-10 mm Median OS: 19.6 mos DESKTOP-OVAR I Results: What Is the Surgical Endpoint? Mos Survival Probability

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Complete resection in 76% of the study collective = AGO score could predict complete resection in at least 2 out of 3 pts DESKTOP Hypothesis AGO DESKTOP OVAR II: Surgical Results Frequency of complete resection by applying the AGO Score 08/06-03/08: Screening of 516 pts with platinum-sensitive relapse in 46 centres Score Positive All Pts Score Positive 1st Relapse Score Positive 2nd Relapse Study collective: AGO score + 1st relapse 129 pts (87%)

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options A randomized trial evaluating cytoreductive surgery in pts with platinum-sensitive recurrent ovarian cancer Platinum-sensitive recurrent cancer of the ovaries, fallopian tubes, or peritoneum PFI > 6 mos No previous chemotherapy for this 1st relapse Complete resection seems feasible and positive AGO score:  ECOG PS 0  No ascites > 500 mL  Previous complete debulking or initial FIGO I/II (if data available) RANDOMIZERANDOMIZE Cytoreductive surgery Platinum-based chemotherapy* recommended *Recommended platinum-based chemotherapy regimens:  Carboplatin/paclitaxel  Carboplatin/gemcitabine  Carboplatin/pegliposomal doxorubicin (if CALYPSO trial shows equivalence to carboplatin-paclitaxel)  Or other platinum combinations in prospective trials No surgery AGO-OVAR DESKTOP III

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options ClinicalTrials.gov. NCT PI: Coleman GOG-213 YesNo Surgery No surgery Carboplatin Paclitaxel Carboplatin Paclitaxel Bevacizumab Bevacizumab To chemotherapy randomization Randomize Surgical candidate? Recurrent ovarian, PPT, and FT cancer TFI ≥ 6 mos Randomize

The Role of Biologics

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options ClinicalTrials.gov. NCT PI: Coleman YesNo Surgery No surgery Carboplatin Paclitaxel Carboplatin Paclitaxel Bevacizumab Bevacizumab To chemotherapy randomization Randomize Surgical candidate? Recurrent ovarian, PPT, and FT cancer TFI ≥ 6 mos Randomize GOG-213

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options OCEANS Trial (Phase III) Pts with platinum- sensitive recurrent 1.Epithelial ovarian carcinoma 2.Primary peritoneal carcinoma 3.Fallopian tube carcinoma (N = 450) Gemcitabine 1000 mg/m² Days 1 and 8 + Carboplatin AUC 4 Day 1 + Placebo IV Day 1 q 21 days x 6 Gemcitabine 1000 mg/m² Days 1 and 8 + Carboplatin AUC 4 Day 1 + Bevacizumab 15 mg/kg Day 1, q 21 days x 6* ClinicalTrials.gov. NCT Placebo to 51 wks Bev to 51 wks Up to 10 cycles Bev to PD Unblind  Primary objective: NCI CTCAE > grade 1 GI perforation  Secondary objective: PFS, OS *Up to 10 cycles allowed

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options ICON6 (Second-Line European Trial) Pts with platinum-sensitive ovarian cancer Relapsed > 6 mos following first-line platinum-based treatment Measurable disease (N = 33)* *Planned: phase II (N = 300), phase III (N = 2000) Platinum-Based Chemo (± Taxane) q 21 days x 6 cycles + oral Cediranib daily during chemo, then total of 18 mos Placebo Platinum-Based Chemo (± Taxane) q 21 days x 6 cycles + Placebo Platinum-Based Chemo (± Taxane) q 21 days x 6 cycles + oral Cediranib during chemo and until progression or 18 mos Randomized 2:3:3 ClinicalTrials.gov. NCT

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Bevacizumab x 15 mos Placebo x 15 mos Maintenance Phase N = 2000 pts Survival, PFS primary endpoints Biologic and QoL endpoints EOC, PP, FT cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab GOG-218 Primary Treatment Phase PI: Burger ClinicalTrials.gov. NCT Front-line Trials: GOG

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Bevacizumab (36 wks total) Open: Oct 20, 2006Closed: (ongoing) Target accrual: 1520 pts (2 Y) *Starting with C1 or C2. ClinicalTrials.gov. NCT RANDOMIZERANDOMIZE ICON 7: Frontline Bevacizumab  Epithelial ovarian, fallopian, or primary peritoneal cancer  Optimal or suboptimal cytoreduction, stage I-IV  GCIG trial (MRC, AGO, ANZGOG, GEICO, GINECO, NCIC, NSGO)  Primary endpoint: PFS II Paclitaxel 175 mg/m 2 3 hrs + Carboplatin AUC 6 + Bevacizumab 7.5 mg/kg q 21 days* x 6 I Paclitaxel 175 mg/m 2 3 hrs + Carboplatin AUC 6 + Placebo q 21 days* x 6

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Primary endpoint: PFS Secondary endpoints: 3-yr PFS, OS, QoL Pazopanib 800 mg/day for 52 wks ClinicalTrials.gov. NCT Placebo 800 mg/day for 52 wks Pts with debulked stage II-IV ovarian, FT, or PP carcinoma and ≥ 5 cycles platinum/taxane therapy (Planned N = 900) AGO-OVAR16 (Phase III)

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options *Pts stratified according to the degree of residual disease following initial diagnosis and surgical debulkment. Primary endpoint: PFS Secondary endpoints: abnormal CA-125, OS Sorafenib 400 mg PO BID, continuous dosing ClinicalTrials.gov. NCT Placebo 400 mg PO BID, continuous dosing Stratification* Pts with FIGO stage III/IV ovarian epithelial cancer or PPC who have achieved clinical CR after standard platinum/taxane therapy (Planned N = 240) Study (Phase IIb Maintenance)

clinicaloptions.com/oncology Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options  Secondary cytoreduction needs to be individualized  Level of evidence is lacking and GOG-213 may not definitively answer question  Biologics increasingly used frontline  Need to resolve role of bevacizumab retreatment or continued treatment when changing chemotherapy platform Conclusions: Recurrence

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