Old and new drugs in ovarian cancer

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1 Chirurgia del carcinoma ovarico - nuove strategie Bergamo 5 maggio 2011 Old and new drugs in ovarian cancer C.Sessa IOSI, Bellinzona (CH) HSR, Milan (I)

2 TRABECTEDIN, YONDELIS (ET-743) Background TETRAHYDROISOQUINOLINE MARINE COMPOUND WITH ANTITUMOR ACTIVITY ISOLATED BY THE CARIBBEAN TUNICATE ECTEINASCIDIA TURBINATA

3 Trabectedin Mechanism of Action Binds to DNA minor groove bending the helix Interacts with transcription factors and other DNA binding proteins Disturbs cell cycle: S delay and G2 block Interferes with DNA repair pathways

4 OVA 301 study Eligibility criteria Only one prior platinum-based chemotherapy Platinum-resistant (PFI<6months) or platinum-sensitive (PFI>6 months) Measurable disease (RECIST) Study design R A N D O M I Z A T I O N PLD 50 mg/m 2 90 minute infusion q 4 weeks PLD 30 mg/m² 90 minute infusion followed by trabectedin* 1.1 mg/m² 3 hour infusion, q 3 weeks *Premedication with dexamethasone is required Assessment q8wks (RECIST,QoL) Endpoint Primary PFS (RECIST) Endpoint Secondary PFS (IA) *TFI = treatment-free interval

5 OVA 301 study results Patients disposition Median progression free survival Monk B. J. et al. JCO, July 2010

6 OVA 301 study update results Median overall survival All patients Platinum-sensitive patients Poveda A. et al. Annals of Oncol 2010

7 OVA 301 study update results Platinum-sensitive patients Time from randomization to subsequent platinum-based therapy Overall survival from subsequent platinum-based therapy Poveda A. et al. Annals of Oncol 2010

8 INOVATYON (INternational OVArian cancer patients Trial with YONdelis) Study: Phase III international, randomized study of Trabectedin plus Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin plus PLD in patients with relapsed ovarian cancer progressing within 6-12 months of last platinum Sponsor: Mario Negri Institute (MaNGO [Mario Negri Gynecologic Oncology Group]) Principal Investigator: Nicoletta Colombo

9 Study Design (II) Relapsed partially platinum sensitive Ovarian Cancer (Progression-Free interval: 6 12 months) after end of 1 st or 2 nd -line platinum-taxane therapy Stratification factors: Line of chemotherapy 2 nd /3rd Measurable disease (Y/N) Previous anthracyclines (Y/N) Center *Dexamethasone premedication mandatory R (1:1) Group A: PLD 30 mg/m² as a 1-h i.v. infusion + Carboplatin AUC min i.v. on Day 1 q4 wks Up to 6 cycles or PD Group B*: PLD 30 mg/m 2 i.v. infusion followed by YONDELIS 1.1 mg/m 2 3-h i.v. on Day 1 q3wks At PD, subsequent therapy at investigator discretion At PD, subsequent platinum rechallenge is mandatory unless refused by the patient First 2 years: tumor evaluation every 12 weeks

10 Drug Resist Updat Apr;7(2):125-38

11 Tumor vessels and drugs Antiangiogenic agents interfere with new vessels formation Vascular-targeting agents (VTAs) compromise established tumor vasculature

12 Clinical studies with antiangiogenetics in ovarian cancer First line GOG218, ICON 7, AGO OVAR 12 Consolidation AGO OVAR 16 Second line OCEANS, ICON 6

13 13 Phase III Trial of Bevacizumab in the Primary Treatment of Advanced Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer: A Gynecologic Oncology Group (GOG) Study R.A. Burger, 1 M.F. Brady, 2 M.A. Bookman, 3 J.L. Walker, 4 H.D. Homesley, 5 J. Fowler, 6 B.J. Monk, 7 B.E. Greer, 8 M. Boente, 9 S.X. Liang 10 1 Fox Chase Cancer Center, Philadelphia, PA; 2 Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; 3 University of Arizona Cancer Center, Tucson, AZ; 4 University of Oklahoma Health Sciences Center, Oklahoma City, OK; 5 Brody School of Medicine, Greenville, NC; 6 James Cancer Hospital at the Ohio State University, Hilliard, OH; 7 University of California, Irvine Medical Center, Orange, CA; 8 Seattle Cancer Care Alliance, Seattle, WA; 9 Minnesota Oncology and Hematology, Minneapolis, MN; 10 State University of New York at Stony Brook, Stony Brook, NY, USA

14 GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) R A N D O M I Z E 1:1:1 BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo I 14 Arm (CP) II (CP + BEV) Stratification variables: GOG performance status (PS) Stage/debulking status Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 BEV 15 mg/kg III (CP + BEV BEV) Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months

15 Proportion surviving progression free GOG-0218: Investigator-Assessed PFS Patients with event, n (%) Arm I CP (n=625) 423 (67.7) Median PFS, months 10.3 Arm II CP + BEV (n=625) 418 (66.9) 11.2 Arm III CP + BEV BEV (n=623) 360 (57.8) Stratified analysis HR (95% CI) One-sided p-value (log rank) ( ) a ( ) < a CP (Arm I) + BEV (Arm II) + BEV BEV maintenance (Arm III) Months since randomization a p-value boundary =

16 Schema Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing 1:1 R n=1528* Carboplatin AUC6 Paclitaxel 175 mg/m 2 Carboplatin AUC6 Paclitaxel 175 mg/m 2 Bevacizumab 7.5 mg/kg q3w Stratification variables: Stage & extent of debulking: I III debulked 1cm vs I III debulked >1 cm vs IV and inoperable stage III Timing of intended treatment start 4 vs >4 weeks after surgery GCIG group *Dec 2006 to Feb cycles Year 1 Years 2 3 Years 4 5 CT Baseline; after cycles 3 & 6; at 9 & 12 months Every 6 months As indicated CA-125/clinical assessment Every chemotherapy cycle; every 6 weeks during maintenance phase Every 3 months Every 6 months

17 Proportion alive without progression Progression-free survival Academic analysis Control Research Events, n (%) 392 (51) 367 (48) Median, months Log-rank test p= HR (95% CI) 0.81 ( ) Control Research Time (months) Number at risk Control Research

18 OCEANS: CG +/- Bevacizumab 18 Recurrent epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer Platinum-Free Interval stratified 6-12 vs >12 months Industry-sponsored multicenter phase II amended to phase III Primary Endpoint: PFS with RECIST Secondary Endpoints: OS, GI perforation event rate I Gemcitabine 1000 mg/m 2 d1,8 Carboplatin AUC=4.0 d1 Placebo IV d1 x 6 Placebo q21d (until PD) II Gemcitabine 1000 mg/m 2 d1,8 Carboplatin AUC=4.0 d1 Bevacizumab 15 mg/kg IV d1 x 6 Bevacizumab q21d (until PD) Open: Apr-07 Closed: --- Target Accrual: 450 pts Aghajanian C, et al. Ongoing

19 AVE8062: Preclinical Pharmacology Compound profile Synthetic, water-soluble derivative of Combretastatin A4 (Ajinotomoto license 2001) M e O M e O OMe OMe NHCO CH(NH 2 )CH 2 OH HCl Combretum caffrum AVE8062A Tubulin polymerization inhibitor Colchicine binding site Inhibits microtubule polymerization Cytoskeleton disorganization of EC Cytotoxic to tumor cells Blood flow shutdown in vivo Tumor necrosis in vivo necrosis Viable cells

20 Tumor weight (mg) Benefit from a combinational approach Viable cells remain at tumor periphery First Treatment Critical for Efficacy Rapid tumor regrowth after termination of treatments Days post implantation Use power of necrosis induction of AVE8062 and combine with other treatment modalities

21 Phase II placebo controlled randomized study of Ombrabulin in platinum sensitive recurrent ovarian cancer treated with Carboplatin / Paclitaxel Eligibility < prior platinum containing CT < 6 mos PFI since last platinum measurable disease Treatment O 35 mg/m2 day 1 P 175 mg/m2 day 2 C AUC 5 or 6 day 2 Statistical considerations PFS primary endpoint HR = 0,7 9.4 median PFS expected accrual period 10 mos q 3 wks

22 DNA DAMAGE DNA REPAIR PATHWAYS TLS (translesion DNA synthesis) FA (Fanconi Anemia ) DR O6MeG BER Damaged base GLYCOSYLASE MMR Misparing, insertion,deletion NER GGR/TCR Bulky lesions HR DSBR Double strand breaks NHEJ ATG APE1 MSH2/6,MSH2/3 RPA,XPA,XPC,TFIIH MRN complex ATM/ATR Ku70/80 DNA-PKcs PARP PCNA,XRCC1, RFC, LIGASES,Pold/e DNA polb MLH1-PMS2, MLH1-PMS1 PCNA, EXO, RFC, RPA,Pold/e,ligase XPA,XPB, XPD, XPG,ERCC1-XPF PCNA,Lig1, RFC,Pold/e RAD52epistasis group, XRCC2/3, and others PCNA,Lig1, RFC,Pold/e DNA Polm, XRCC4, Lig4

23 PARP Inhibitor Mechanism of Action 1. Platinum chemotherapy Inflicts DNA damage via adducts and DNA crosslinking PARP1 2. PARP1 upregulations Base-excision repair of DNA damage PARP1 PARP1 PARP inhibitor 3. Inhibition of PARP1 Disables DNA base-excision repair BRCA-1 BRCA-2 4. Replication fork collapse Double-strand DNA break Cell Survival Cell Death O Shaughnessy J, et al. ASCO Abstract 3. Reproduced with permission.

24 Synthetic Lethality 2 (or more) nonallelic and nonessential mutations, not lethal on their own, but deadly when present within the same cell BRCA1/BRCA2 mutations HR deficiency Loss of expression of FANCA, FANCC, FANCD2, FANCF and FANCG Hypermethylation of promoter of BRCA1, MLH1, MGMT

25 PARP poly (ADP-ribose) polymerase super family of 18 enzymes involved in the regulation of cell death and response to DNA damage, assist in the repair of SSB PARP inhibitors as therapeutic agents in cancer through - potentiation of cytotoxics (AA, Topo I inhibitors) or RT - syntethic lethality: single agent in tumors deficient in HR (BRCA1, BRCA2) - combination with drugs known to be active in tumors with HR defects Ashworth, 2008

26 BRCAness Profile of tumor cells that shaires traits with BRCA1 or BRCA2 mutated tumors BRCAness phenotype: dysfunction of HR due to genetic and epigenetic mechanisms 30% BRCA dysfunction in high-grade serous ovarian cancer 15% due to BRCA1 or BRCA2 germline mut. 20% due to acquired BRCA1 promoter methylation, EMSY gene amplification, MRE11 mut. BRCAness profile associated with platinum and PARP inhibitor responsiveness and RAD51 foci formation

27 fffffff 27 Press JZ, et al., BMC Cancer 2008

28 PARP inhibitors Veliparib (ABT-888) ROUTE 80 % bioavailability PO MK-4827 Olaparib (AZD2281) AGO Iniparib (BSI201) bioavailable PO bioavailable PO IV IV T ½ 4-7 hrs 40 hrs 7 hrs hrs 4 min PgP not substrate substrate substrate BBB crosses unknown crosses unknown crosses Studies PBMC PARP inhib. single agent BRCA; with CTX in BRCA and sporadic EOC single agent BRCA and sporadic OC single agent BRCA and sporadic oc multiple combos single agent BRCA and multiple combos > 80 % > 50 % > 50 % by 6 hrs > 90 % by 5 hrs single agent BRCA and with Carbo/GEM sporadic OC > 80 %

29 Issues in clinical development 1. Mechanisms of resistance, modifies BRCA protein 2. Enhancement of toxicity in combination: dose and schedule 3. Combinations (cytotoxics, MTA, RT) 4. Identify BRCAness: gene profiling and predictive tests for HR dysfunction 5. Clinical biomarkers: resistance to PARPi, biological effects 6. Integration with standard of care: clinical benefit and untoward side effects

30 Issues in clinical development 6. Integration with standard of care in ovarian cancer: clinical benefit and untoward side effects Platinum failure BRCA ½ mut patients single arm 2 sequential cohorts randomized 3 arm study with PLD Platinum failure high grade serous 24% ORR in non BRCA1/2 mut patients

31 Efficacy Olaparib Olaparib 400 mg bid 100 mg bid (n=33) (n=24) RECIST response rate, n (%) 11 (33) 3 (13) Responders by RECIST and/or GCIG criteria, n (%) 20 (61) 4 (17) Responders by RECIST Platinum sensitive, n (%) 1/7 (14) 2/8 (25) Platinum resistant, n (%) 10/26 (38) 1/16 (6) Total, n (%) 11/33 (33) 3/24 (13) Median PFS (95% CI) 5.8 (2.4-12) 1.9 ( ) ITT analysis

32 Study 19: Olaparib in platinum responding recurrent serous ovarian cancer Penultimate platinum-containing regimen Progression >6 months Treatment with a platinum containing regimen Objective PR or CR and/or GCIG response Within 8 wks of completion of last platinum dose N= % AZD % placebo Modified RECIST progression Olaparib (AZD2281; KU )