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Ovarian Cancer: Standards of Care and New Opportunities Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research Department of Gynecologic Oncology.

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Presentation on theme: "Ovarian Cancer: Standards of Care and New Opportunities Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research Department of Gynecologic Oncology."— Presentation transcript:

1 Ovarian Cancer: Standards of Care and New Opportunities Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research Department of Gynecologic Oncology M.D. Anderson Cancer Center

2 Ovarian Cancer: Liner Notes  Globally 7 th most incident and lethal cancer –New cases: 225,000 annually –Deaths: 140,000 annually  Burden of disease is greater in developed countries  The incidence increases with age  Almost 75% of cases present with advanced stage III / IV disease  Risk of relapse of advanced stage disease is as high as 70% CA Cancer, 2013

3 Ovarian Cancer: Natural History Symptoms Diagnosis Chemotherapy #1 Staging Evaluation ? SLL Progression Chemo #2 Chemo #3+ SupportiveCare Death SecondarySurgery Maintenance Duration Progression-Free Survival (12-28 mos) Post Progression Survival (12-38 mos)

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5 Surgical Management of Primary Ovarian Cancer  Theoretical: –Reduced the volume of hypoxic, poorly perfused cells –Host immunocompetence is improved with lower tumor burden –Recruitment of residual cells into G1 potentiating the effects of cytotoxic therapy –Removal of chemoresistant clones  Practical: –“Biology vs Brawn”

6 % Progression- free Survival 0 mm 1-10 mm > 10 mm HR (95%CI) 1-10 mm vs. 0 mm: 2.52 (2.26;2.81) >10 mm vs mm:1.36 (1.24;1.50) log-rank: p < % Overall Survival 0 mm 1-10 mm > 10 mm HR (95%CI) 1-10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs mm:1.34 (1.21; 1.49) log-rank: p < The Impact of Residual Tumor: What Is Optimal Debulking? Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) N = 3126 pts Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) N = 3126 pts DuBois, Cancer (2009)115:1234

7 Primary Approach: What’s Best? N Engl J Med (2010) 363:943 PDS: 12 mos NACT: 12 mos HR: 0.99 ( ) PDS: 29 months IDS: 30 months HR: 0.98 (0.85, 1.14) PFS OS

8 Neoadjuvant Chemotherapy in Ovarian Cancer 9/21/109/21/10 1/20/111/20/11

9 Primary Approach: What’s Best? N Engl J Med (2010) 363:943 PDS: 12 mos NACT: 12 mos HR: 0.99 ( ) PDS: 29 months IDS: 30 months HR: 0.98 (0.85, 1.14) PFS OS

10 CHORUS Chemotherapy Or Upfront Surgery RCOG ICON-8OV.21 Neoadjuvant Chemotherapy X 3-4 courses Randomized IV-ArmIP-Arm Pac/Carbo + Pac/Carbo (IP) + Pac (d8)Pac (IP, d8) Neoadjuvant Chemotherapy X 3-4 courses Randomized IV-ArmIP-Arm Pac/Carbo + Pac/Carbo (IP) + Pac (d8)Pac (IP, d8) Pre-randomization Strata for NACT or PDS RandomizedPre-randomization Randomized StandardPac/Carbo Exp A DD-Pac/Carbo Exp B DD - Pac/DD-Carbo

11 Principle Approach: I º Therapy ChemotherapyGOG-111 Cisplatin 75 mg/m 2 Cytoxan 750mg/m 2 Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 GOG-158 Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 Carboplatin AUC 7.5 Paclitaxel 175 mg/m 2 GOG-172 Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 Day1: IV Paclitaxel 135 mg/m 2 Day 2: IP Cisplatin 100mg/m 2 Day 8: IP Paclitaxel 60 mg/m 2 McGuire New Engl J Med (1996) 334:1 Ozols, J Clin Oncol (2003) 21:3194 Armstrong New Engl J Med (2006) 354:34 OS Cytoxan/Cisplatin Cytoxan/Cisplatin Paclitaxel/Cisplatin PFS

12 International Phase III Experience CPCPG CP  PLD CT  CP CG  CP PLD-CCETotal GOG0182-ICON SCOTROC AGO-GINECO NSGO-EORTC-NCIC-GEICO MITO AGO-GINECO-GERCOR- NSGO NCIC-EORTC-GEICO OV MITO Regimen Total: No Significant Effect More ≠ Better Different ≠ Better

13 Moving The Bar: Primary Therapy  Dose-dense therapy  IP Chemotherapy  Biologics: Anti-angiogenesis, PARPi, angiopoeitin inhibitors Establishing a Front-Line Adjuvant Standard

14 Dose Dense: Weekly Therapy Ovarian Epithelial, PP, FT FIGO Stage II-IV Ovarian Epithelial, PP, FT FIGO Stage II-IV Paclitaxel 180mg/m 2 Paclitaxel 180mg/m 2 Carboplatin AUC 6.0 Carboplatin AUC 6.0 q 21 days (6-9 cycles) q 21 days (6-9 cycles) Dose density: 60 mg/m 2 /wk Paclitaxel 80mg/m 2, days 1, 8, 15 Paclitaxel 80mg/m 2, days 1, 8, 15 Carboplatin AUC 6.0, day 1 Carboplatin AUC 6.0, day 1 q 21 days (6-9 cycles) q 21 days (6-9 cycles) Dose density: 80 mg/m 2 /wk (+33%) Stratification; Residual disease: 1cm FIGO Stage : II vs. III vs. IV Histology : clear cell/mucinous vs serous/others RR Katsumata, Lancet 2009

15 JGOG 3016: Long-Term Follow-Up Katsumata N, ASCO Abstract 5003, 2012

16 iPocc JGOG Trial: Schema Epithelial Ovarian Cancer Stages II-IV Including Bulky Tumor Paclitaxel 80 mg/m 2 IV Day 1,8,15 Carboplatin AUC 6 IV Q21, 6-8 Cycles Paclitaxel 80 mg/m 2 IV Day 1,8,15 Carboplatin AUC 6 IP Q21, 6-8 Cycles Primary Endpoint: PFSSecondary Endpoint: OS, Toxicity, QOL Accrual Goal: 746 pts / 511 events Dose dense−TCip Dose dense−TCiv RANDOMIZATION

17 GOG-0218 study schema Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Stage III optimal (macroscopic) Stage III optimal (macroscopic) Stage III Stage III suboptimal suboptimal Stage IV Stage IVn=1873 Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Stage III optimal (macroscopic) Stage III optimal (macroscopic) Stage III Stage III suboptimal suboptimal Stage IV Stage IVn=1873 Stratification variables: GOG performance status GOG performance status Stage/debulking status Stage/debulking status RANDOMRANDOMIIZEZERANDOMRANDOMIIZEZEI RANDOMRANDOMIIZEZERANDOMRANDOMIIZEZEI 1:1:1 15 months Paclitaxel 175 mg/m 2 Carboplatin AUC 6 Placebo IArm Cytotoxic (6 cycles) Maintenance (16 cycles) (CP + PLA → PLA) Carboplatin AUC 6 Paclitaxel 175 mg/m 2 Placebo Bevacizumab 15 mg/kg II (CP + BEV → PLA) Bevacizumab 15 mg/kg Carboplatin AUC 6 Paclitaxel 175 mg/m 2 III (CP + BEV  BEV) Burger et al. N Engl J Med 2011;365: Establishing a Front-Line Adjuvant Standard

18 Stratification variables: Stage & extent of debulking: I–III debulked ≤1cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III Timing of intended treatment start ≤4 vs >4 weeks after surgery GCIG group Schema Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing Paclitaxel 175 mg/m 2 Carboplatin AUC 5/6 Paclitaxel 175 mg/m 2 18 cycles R n=1528* Bevacizumab 7.5 mg/kg q3w 1:1 *Dec 2006 to Feb 2009 Establishing a Front-Line Adjuvant Standard Perrin, N Engl J Med 2011;365:

19 Anti-VEGF Targeting: Frontline PFSPFS Perren, NEJM (2011) 365:2484 Burger, NEJM (2011) 365:2473 HR: vs 13.9 mos Median  : 3.5 mos HR: vs 19.8 mos Median  : 2.4 mos GOG 218 ICON7

20 Anti-VEGF Targeting: Frontline Overall Survival Perren, NEJM (2011) 365:2484 Burger, NEJM (2011) 365:2473 GOG 218 ICON7

21 vs 17 3 months’ difference 13.3 vs months’ difference 3 months’ difference Time (months) GOG-0218 ICON7 (III suboptimal and IV subgroup) GOG-0218 and ICON7: Restricted Means Estimate – Benefit During Exposure Only? Research Arm

22 GOG Ovarian Strategy: Suboptimal (> 1 cm Residual) Neoadjuvant allowed CT Perfusion Scan IV Paclitaxel 80 mg/m 2 weekly IV Carboplatin AUC 6 q 3 wk IV Bevacizumab 15 mg/kg (optional) IV Paclitaxel 175 mg/m 2 IV Carboplatin AUC 6 IV Bevacizumab 15 mg/kg (optional) Bevacizumab q 3 wk (If chosen) Maintenance to Progression N: 702/625 (OPEN only for ACRIN Component Primary endpoint: PFS

23 Phase III GOG 252 Schema IV Paclitaxel 80 mg/m 2 days 1, 8, 15 IV Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w † IV Paclitaxel 80 mg/m 2 days 1, 8, 15 IP Carboplatin AUC 6 day 1 Bevacizumab 15 mg/kg q3w † IV Paclitaxel 135 mg/m 2 day 1 IP Cisplatin 75 mg/m 2 day 2 IP Paclitaxel 60 mg/m 2 day 8 Bevacizumab 15 mg/kg q3w † RANDOMIZATION N = 1250 RANDOMIZATION Walker JL. Am Soc Clin Oncol Ed Book. 2009: N: 1554 (CLOSED) Primary endpoint: PFS Cycles 1-6* Cycles 7-22* Bevacizumab 15 mg/kg q3w *Each cycle is 3 weeks; † Begin cycle 2. Bevacizumab 15 mg/kg q3w

24 Other Pursuits in Front-Line Therapy  VEGF TKI’s –Nintedanib (BIBF1120)  PARPi –Veliparib (OVM1102)  Angiopoeitin inhibitors –TRINOVA-3: Trebananib (AMG-386)

25 Bottom Line…  Determine good candidates for surgery –Potential for better selection tools, e.g. Laparoscopy  Optimal radical resection –Goal: R0  Adjuvant therapy –IP and dose dense are my favorite options –Good place for clinical trial

26 Maintenance: The Stakes are High! Symptoms Diagnosis Chemotherapy #1 Staging Evaluation ? SLL Progression Chemo #2 Chemo #3+ SupportiveCare Death SecondarySurgery Maintenance What we know… Rate of response is high (CR + PR) >75% Rate of response is high (CR + PR) >75% Second assessment operations find disease > 40% of CR’s Second assessment operations find disease > 40% of CR’s Clinical CR’s have >50% recurrence risk at 2 years Clinical CR’s have >50% recurrence risk at 2 years Pathological CR’s have >40% risk at 2 years Pathological CR’s have >40% risk at 2 years Option applies to CR’s and documented PR’s Option applies to CR’s and documented PR’s

27 Maintenance Therapy Scorecard Maintenance Beneficial? StrategyNoYes Prolonged Initial Therapy ✓ Short Duration / Non-Cross Resistant Chemotherapy ✓ High-Dose Chemotherapy ✓ Intraperitoneal ✓ Interferon-  ✓ Anti-CA-125 Ab ✓ Biologic Agent (MMPI, bevacizumab*) ✓✓*✓* Paclitaxel (6 months) ✓ Paclitaxel (1 year) ✓#✓# Erlotinib ✓

28 Maintenance Trials: Ongoing  Bevacizumab (GOG 252, 262)  Pazopanib (OVAR-16)  Nintedanib (BIBF 1120)  Trebananib (TRINOVA-3)  CVAC: Muc-1 Dendritic Cell vaccine  PARPi,  pvKLH + OPT-821 [GOG-255] (II° maintenance)  FAKi (GSK ) – GOG concept approved 8/11 EOC, PP, FT cancer Paclitaxel X 12 mos Paclitaxel CTI-2103 CTI-2103 NoTreatmentNoTreatment PaclitaxelCarboplatinPaclitaxelCarboplatin GOG-212GOG-212 N = 1100 patients Survival primary endpoints QOL endpoints 28

29 Bottom Line…  Experimental but evidence of PFS impact has been demonstrated  I always have the conversation (longest of any counseling session) but it is only infrequently taken by the patient

30 Recurrent Therapy: Ovarian Cancer Symptoms Diagnosis Chemotherapy #1 Staging Evaluation ? SLL Progression Chemo #2 Chemo #3+ SupportiveCare Death Maintenance SecondarySurgery What we know (Recurrence): Nearly all patients will succumb to progression Options are plentiful Nothing a “homerun” What we know (Recurrence): Nearly all patients will succumb to progression Options are plentiful Nothing a “homerun”

31 Treatment Free Interval: Traditional Model Time from last platinum exposure (TFI) TreatmentCompletion 6 mos Platinum Resistant/Refractory Platinum Sensitive Non-Platinum Treatment Platinum Retreatment

32 Treatment-Free Interval and Survival Lauraine, Proc ASCO #829, Prog0-3 Non PD3-12 mos12-18 mos18+ mos PFS (days) OS (days) Response (%) Days Percentage

33 ControlExperimentalNTTP (wks)POS (wks)PComment PaclitaxelTopotecan22614 vs 23NS43 vs 61NS50% Cross-over Paclitaxel (bolus) Paclitaxel (weekly) vs 26NS34 vs 59NSLess toxicity w/ weekly PaclitaxelOxaliplatin8614 vs 12NS37 vs 42NS74% platinum resistant TopotecanPLD48117 vs 16NS57 vs 60NS54% resistant; OS benefit in sensitive PaclitaxelPLD21422 vs 22NS56 vs 46NSAll pts taxane-naïve TopotecanTreosulfan35722 vs vs nd – 3 rd line therapy PLDGemcitabine19516 vs 13NS59 vs 55NS PLDGemcitabine15316 vs 20NS55 vs 50NS resistant 56% platinum resistant PLD or Topotecan Canfosfamide46119 vs 9< vs 37 (PLD:62 vs Topo:47) <0.0001ASSIST-1 trial All 3 rd line PLDPatupilone80216 vs 16NS55 vs 57NSRR: 8% vs 18% (patupilone) Summary of Phase III Single Agent Trials: Resistant Ovarian Cancer

34 ControlExperimentalNTTP (wks)POS (wks)PComment PLD PLD + Trabectedin vs 17.4NSN/A RR: 16 vs 23% Summary of Phase III Combination Trials: PR Take home messages: Many choices Many choices No best cytotoxic agent No best cytotoxic agent Combinations with non-targeted cytotoxics add morbidity only Combinations with non-targeted cytotoxics add morbidity only

35 ControlExperimentalNTTP (wks)POS (wks)PComment PLD PLD + Trabectedin vs 17.4NSN/A RR: 16 vs 23% Chemo (Paclitaxel weekly, Gemcitabine, Topotecan) Chemo + Bevacizumab vs 29.1<0.001N/A RR: 12% vs 27% (RECIST) Summary of Phase III Combination Trials: PR

36 AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC) Recurrent EOC platinum resistant ≤ 2 prior therapies no clinical or radiologic evidence of bowel involvement Non-Platinum Chemotherapy RANDOMIZERANDOMIZE Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg Chemotherapy Options Paclitaxel 80 mg/m 2 d 1,8,15, 22 q28 Topotecan 4 mg/m 2 d 1, 8,15 q28 or Topotecan 1.25 mg/m 2 d 1-5 q21 PLD 40 mg/m 2 d 1 q28 Stratified chemotherapy PFI (< 3 vs 3-6 mo) prior anti-angiogenesis Treat to progression N = 361 Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

37 AURELIA: Patient Characteristics CharacteristicCT (n = 182)BEV + CT (n = 179) Median age, years6162 Serous/adenocarcinoma at diagnosis152 (84%)156 (87%) Histologic grade at diagnosis 1 2/3 9 (5%) 153 (84%) 10 (6%) 147 (82%) Prior anti-angiogenic therapy14 (8%)12 (7%) 2 prior chemotherapy regimens78 (43%)72 (40%) PFI < 3 months46 (25%)50 (28%) ECOG PS (54%) 80 (44%) 107 (60%) 70 (39%) Measurable Disease144 (79%)143 (80%) Ascites54 (30)59 (34) Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

38 AURELIA Progression-Free Survival Time (months) Estimated Probability BEV + CT CT Number at risk Events, n (%) Median PFS, months (95% CI) 166 (91%) 3.4 ( ) 135 (75%) CT (n = 182) BEV + CT (n = 179) 6.7 ( ) HR (unadjusted) (95% CI) Log-rnak P -value (2-sided, unadjusted) 0.48 ( ) < Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

39 Subgroup analysis of PFS a Unadjusted. b Missing n=8 SubgroupNo. of patients Median PFS, months HR a BEV + CT better CT better CTBEV + CT All patients Age, years<65 ≥ PFI, months b <3 3‒ Measurable disease, cm No (<1) Yes (1‒<5) Yes (≥5) AscitesYes No ChemotherapyPaclitaxel PLD Topotecan

40 Summary of best overall response rates  a Two-sided chi-square test with Schouten correction p=0.001 a p<0.001 a Patients (%)

41 AURELIA: Conclusions  No alarming safety signals –PLD – HFS, paclitaxel – neuropathy, all: myelosuppression)  Toxicity may relate to exposure (longer on experimental arms)  Bevacizumab augments outcomes (response, PFS) of standard chemotherapy  Paclitaxel may benefit to greater degree  Await OS data  CAVEATS –Not placebo-controlled –Pretreatment characteristics: 80% measurable, 30% ascites, 8% prior AA therapy –Each arm is equivalent to RP2

42 Bottom Line…  For platinum-resistant disease, I like: –Weekly paclitaxel ± bevacizumab –PLD –Gemcitabine + cisplatin (q 2 wk infusion)  Try HARD to get onto clinical trial –Lots of options with interesting new agents

43 NCCN Guidelines Version 2013 Therapy for Relapse > 6 months NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v Available at:

44 DESKTOP-I: Surgical Endpoint of Surgery at Relapse no residuals median OS 45.2 mo residuals > 10 mm residuals 1-10 mm Survival probability Months from Randomization

45 Secondary Cytoreduction: Multivariate Analysis Who Benefits? Tay, Obstet Gynecol 99:1008, 2002

46 Secondary Cytoreductive Surgery Chi DS, et al. Cancer. 2006;106(9): DFI = disease-free interval; mos = months; SC = secondary cytoreduction. DFISingle Site Multiple Sites: No Carcinomatosis Carcinomatosis 6-12 mosSuggest SCOffer SCNo SC mos Suggest SC Offer SC > 30 mosSuggest SC Goal of surgery: No gross residual disease

47 AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) EOC, FT, PP PFI > 6 No prior recurrence chemotherapy Complete resection seems feasible and positive AGO score: PS ECOG 0 No ascites > 500 ml Prior complete debulking or initial FIGO I/II Secondary Cytoreduction Chemo Regimens post-randomization Carboplatin/paclitaxel Carboplatin/gemcitabine Carboplatin/PLD No surgery N = 150/408 planned

48 PI: Coleman Recurrent Ovarian, PPT and FT Cancer TFI ≥ 6 mos Recurrent Ovarian, PPT and FT Cancer TFI ≥ 6 mos YesYesNoNo RandomizeRandomize SurgerySurgery No Surgery Carboplatin Paclitaxel or GemcitabineCarboplatin GemcitabineCarboplatin Pac or Gem BevacizumabCarboplatin Bevacizumab BevacizumabBevacizumab GOG-213GOG-213 To Chemotherapy Randomization Randomization RandomizeRandomize Surgical Candidate?

49 A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer RANRANDDOMIZOMIZEERANRANDDOMIZOMIZEEDE Cytoreductive surgery Platinum-based chemotherapy* Primary outcome: OS Secondary outcome: PFS, QoL, Complications No surgery SOC I Shanghai Gynecologic Oncology Group Available at: Accessed March 04, N=420 Platinum-sensitive, first relapse recurrent cancer of the ovaries, fallopian tubes, or peritoneum PFI > 6 mos No prior chemotherapy for this 1st relapse Complete secondary cytoreduction predicting score (iMODEL) FIGO stage FIGO stage Residual disease after primary surgery Residual disease after primary surgery PFI PFI PS ECOG PS ECOG CA125 CA125 Ascites at recurrence Ascites at recurrence

50 Outcomes in Recurrent Ovarian Cancer: PS TrialTreatmentRR (%)PFS (mo)HROS (mo)HR ICON 4 (n = 802) C P < P = 0.02 C + P AGO (n = 366) C P = P = 0.73 GC OVA-301 (n = 417) PLD? P= P = 0.11 PLD + Trab? CALYPSO (n = 976) C + P– P = P = 0.94 C + PLD– OCEANS (n = 484) GC + PL P < * 1.03 * P = 0.84 GC + BV *Data still maturing. Take home messages: PFS appears to be impacted from combination therapy PFS appears to be impacted from combination therapy No OS effect to date No OS effect to date Post progression survival is dramatically increasing Post progression survival is dramatically increasing

51 Bottom Line…  For Platinum-sensitive disease, I like: –Secondary cytoreduction if small volume and remote recurrence »However, I try HARD to get on clinical trial as this is a very biased situation –Platinum-based doublets »PLD, Gemcitabine and Paclitaxel with carboplatin »If I give gemcitabine doublet I give with bevacizumab  Lots of new trials coming online here as well

52 Ovarian Cancer: Novel Targets Matei, Expert Opin Investig Drugs (2007) 16:1227

53 Developmental Therapeutics: Targets Pericyte Tumor Endothelium Tumor Cell Microenvironment

54 Trebananib: Phase III Studies Weekly paclitaxel + Trebananib ClinicalTrials.gov. NCT Weekly paclitaxel + placebo R Recurrent ovarian, FT, PP cancer R Pegylated Liposomal Doxorubicin (PLD) + Trebananib Pegylated Liposomal Doxorubicin (PLD) + placebo N = 900 Primary Objective: PFS Secondary Objectives: OS, RR (RECIST and CA-125), Safety, pK, QOL TRINOVA-1 Phase III Trial TRINOVA-2 Phase III Trial Recurrent ovarian, FT, PP cancer

55 EC145 Phase III Randomized Study Design in Patients with Platinum Resistant Ovarian Cancer  Blinded Randomized study comparing EC145 + PLD vs. PLD alone  Platinum Resistant patients  ~600 Patients randomized 2:1  Study objectives: –Compare PFS between arms –Independent radiology review –OS in EC20 ++ patients

56 PARP Inhibitors in the Clinic Nature 2005 BRCA +/+ BRCA -/- BRCA +/- 1000x1000x

57 Olaparib Development: Lessons Learned  1 Phase I –MTD 400 mg BID –Expansion Phase (N=39 BRCA+) = responses »Platinum-sensitive > resistant  Phase II (BRCA+) –Dose effect (100 mg BID vs 400 mg BID) 2 –PARPi is best measured by PK (AUC ss ) 2 –Is as active as PLD (RP2) 3  Phase II (BRCA-wt) –HRD exists as somatic event (30%) 4 –RR seen in BRCA-wt, high grade serous 5 –Genomic signature may identify these patients 6 1 Fong, NEJM Audeh Lancet Kaye, ASCO TCGA, Gehlmon, Lancet Konstantinopoulos, JCO 2010

58 Study 19: Maintenance Olaparib Olaparib 400 mg po bid Randomized 1:1 Placebo po bid Patient eligibility: Platinum-sensitive high-grade serous ovarian cancer  2 previous platinum regimens Last chemotherapy: platinum-based with a maintained response Stable CA125 at trial entry Randomization stratification factors: – – Time to disease progression on penultimate platinum therapy – – Objective response to last platinum therapy – – Ethnic descent – – Primary ENDPOINT: PFS Treatment until disease progression Ledermann, N Engl J Med 2012

59 Study 19: Secondary Maintenance Ledermann, N Engl J Med 2012

60 PARP Inhibitors in Clinical Trials AgentAdministrationPhaseComments Olaparib (AZD-2281) OralI, II, IIISingle Agent and Combination, BRCA and non-BRCA, Platinum- sensitive and resistant, Primary and Recurrent AZD-2461OralIFIH, Solid Tumors Veliparib ABT-888 OralI, IISingle Agent and Combination, BRCA and non-BRCA, Platinum- sensitive and resistant, Primary and Recurrent (GOG-9923, PIS1004, GOG-280) BMN 673OralI, IIBRCA mutation carriers, Platinum Sensitive CEP-9722OralICombination, Solid Tumors E7016OralICombination, Solid Tumors Niraparib (MK4827) OralI, IISingle Agent and Combination, BRCA and non-BRCA, Platinum- sensitive and resistant Rucaparib (CO-338) OralI, IIBRCA mutation carriers, Platinum Sensitive AG014699IVII Single Agent, BRCA, Platinum-sensitive and resistant Iniparib (BSI-201) IVII, IIICombination (Gem/Cis or Carbo), Platinum-sensitive and resistant Available at:

61 2013:Phase III Studies in Ovarian Cancer* Front-line added to chemotherapy then as Maintenance 1.Bevacizumab (GOG 262 imaging biomarker study) 2.BIBF 1120 (OVAR 12) - closed 3.Trebananib (GOG 3001/TRINOVA-3) Maintenance alone 1.Polyglutamate paclitaxel (GOG 212) 2.Pazopanib (OVAR 16) - closed 3.CVAC (MUC-1) Platinum-resistant recurrent ovarian cancer 1.Karenitecin 2.Trebananib (with Paclitaxel/TRINOVA-1 [closed] or PLD/TRINOVA-2) 3.Vintafolide (with PLD) Platinum-sensitive recurrent ovarian cancer 1.Bevacizumab (with chemotherapy - GOG 213) 2.Trebananib (with PLD or Paclitaxel) 3.Trabectedin with PLD (in 6 – 12 month group/INOVATYON) 4.Water soluble formulation of Paclitaxel *Phase II studies of PARP inhibitors, and Cabozantinib may lead to FDA approval PLD = Pegylated Liposomal Doxorubicin

62 Take Home Messages  Ovarian cancer is a heterogeneous disease  Molecular sub-classification can describe dependency on different driving/survival mechanisms in otherwise morphologically similar tumors –Consistent patterns of chromosomal change suggests interdependency within individual tumors  Target discovery has led to a flood of clinical trial development –Most promising: angiogenesis, PI3K, HRD, EMT  Lagging are strategic solutions for induced and adaptive responses to treatment and study designs  Need for new composite endpoints (FDA discussions underway)

63 Thanks!


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