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Trabectedin in patients with BRCA mutated and BRCAness phenotype advanced ovarian cancer (AOC): phase II prospective MITO-15 study Lorusso D1, Ferrandina G2, Pignata S3, Sorio R4, Pietragalla A2, Mosconi A5, Pisano C3, Mangili G6, Masini C7, Artioli G8, Narducci F9, Di Napoli M3, Rigamonti C10, Raspagliesi F1, Scambia G2. 1 Fondazione IRCCS National Cancer Institute Milan, 2Catholic University of Rome, 3National Cancer Institte Naples, 4CRO Aviano, 5University of Perugia, 6San Raffaele Hospital Milan, 7University of Modena and Reggio Emilia, 8 Mirano Hospital, 9Santissima Trinita’ Sora hospital. 10Pharmamar Italy. 26-30 September 2014, Madrid, Spain esmo.org BACKGROUND • • In vitro and clinical studies have reported that mutations in BRCA repair system with functional NER machinery induce greater sensitivity to Trabectedin. We hypotize that Trabectedin will be an effective tretament in patients with BRCAness phenotype, and its activity further enhanced in those carring BRCA 1/2 mutations. Efficacy could also be affected by the presence of different NER related germ line polymorphisms. 26-30 September 2014, Madrid, Spain esmo.org Aim and study design prospective phase II study (EudraCT n: 2011-001298-17) evaluate activity of trabectedin in patients with mutated BRCA and BRCAness phenotype advanced ovarian cancer (AOC) Translational sub-study: • Assess germline mutations of BRCA 1 and 2 • Evaluate activity of trabectedin according to BRCA and single nucleotide polymorphisms (SNPs) in esmo.org 26-30DNA Septemberrepair 2014, Madrid,genes Spain (XPD, XPG and ERCC1) mutations Patients and methods Patients AOC patients BRCA mutation or BRCAness phenotype At least 2 previous response to platinum Stratification Platinum resistant (PR) Treatment Trabectidin 1.3 mg/m2 (3 hour iv infusion) Every 3 weeks until progression 26-30 September 2014, Madrid, Spain Platinum sensitive (PS) esmo.org Results 46 PR 100 enrolled pts 6 months follow-up 88 evaluable pts 42 PS N ORR (%) PR (46) 15 (32.6) PS (42) All (88) CR (%) 0 PR (%) SD (%) DCR PD (ORR + (%) SD) (%) PFS (median, months) OS (median, months) 15 (32.6) 12 (26.1) 27 (58.7) 19 (41.3) 2.7 9.7 21 (50) 4 (9.5) 17 (40.5) 10 (23.8) 31 (73.8) 11 (26.2) 6** 18.5*** 36 (41) 4 (9.5) 32 (36.4) 22 (25) 58* (66) 30 (34%) 5.2 14.7 esmo.org 26-30 September 2014, Madrid, Spain ORR, overall response rate; CR, complete response; PR, partial response; DCR, disease control rate; PD, progressive disease; PFS, progression-free survival; OS, overall survivial.. * DCR vs PD:p=0.088; **PFS PRvsPS p=0.012; ***OS PRvsPS p=0.041 Distribution of BRCA mutations in the study population BRCA mutation data available on 66 patients 43 wild type 12 BRCA 1 mut 11 BRCA 2 mut 34.8% BRCA status PR (43) PS (42) P value WT 26 17 0.60 Mutated 12 11 26-30 September 2014, Madrid, Spain esmo.org Response to trabectedin according to BRCA mutational status BRCA 12 N ORR CR+PR (%) DCR (ORR+SD) PD WT 43 17 (39.5) 27 (62.8)* 14 (32.5) 4.5 66.7** MUT 23 12 (52.2) 17 (73.9) 4.5 83.0 5 (21.7) PFS 3- year (Months) OS (%) *P value DCR: 0.51; **P value OS: 0.041 26-30 September 2014, Madrid, Spain esmo.org Response to trabecteding according to mutations of single nucleotide polymorphisms (SNPs) in DNA repair genes (XPD, XPG and ERCC1) 5 SNPs involved in NER machinery (ERCC1 C118T, ERCC1 C8092, XPG ASP1104HIS, XPD ASP312ASN, XPD LYS751GLN) were evaluated in 75 patients. SNPs CR+PR+ SD (%) PD (%) P value ERCC1 C118T WT (26) MUT (49) 16 (61.5) 33 (67.3) 8 (30.7) 14 (28.5) 0.8 ERCC1 C8092 WT (37) MUT (38) 23 (61.3) 26 (69.3) 12 (32.4) 10 (26.3) 0.6 XPG ASP1104HIS WT (47) MUT (28) 30 (63.8) 19 (67.8) 15 (32) 7 (25) 0.6 XPD ASP312ASN WT (26) MUT (49) 15 (57.6) 34 (69.4) 9 (34.6) 13 (26.5) 0.4 16 (55) 33 (72) 11 (38) 11 (24) 0.2 XPD LYS751GLN WT (29)September 2014, Madrid, Spain 26-30 MUT (46) esmo.org CONCLUSIONS This study shows an increased percentage of BRCA 1/2 mutations in the BRCAness phenotype compared to published data in AOC patients. BRCAness profile and, in particular, a history of higher number of previous responses to platinum, is associated with increased responses to trabectedin Clinical response was higher although non statistically significant in patients carrying germline BRCA 1/2 mutations. The fact that BRCA driven HR is not the only repair mechanism available in tumor cells, can explain the limited sensitivity of germline BRCA mutations as predictive factors in this study. In this clinical study NER polymorphisms did not correlate with responses to trabectedin. 26-30 September 2014, Madrid, Spain esmo.org Next step • Paper finalized • Possible journals: JCO, Lancet Oncology, Annals of Oncology • Clinical substudies: Emesis (Dr Di Napoli), Analisys of subsequent treatments (Dr Salutari) • Translational substudy: evaluation of immoreactive signature in MITO 15 specimens (Dr Gourley) 26-30 September 2014, Madrid, Spain esmo.org MITO 15 Emesi AGGIORNAMENTO Marilena Di Napoli Progetto di valutazione del PFS2 dopo Yondelis nei pazienti arruolati in MITO15 CENTRI AGGIORNAMENTI Centro 001-Roma Si Centro 002-Milano Si Centro 011-Perugia Si Centro 014-Milano Si Centro 021-Mirano Si Centro 043-Catanzaro Si Centro 004-Roma No Centro 009-Ferrara No Centro 013-Modena No Centro 022- Rionero in Vulture No Centro 030-Napoli No Centro 039-Aviano No Centro 047-Sora No Centro N° pz arruolate N° pz sottoposte ad ulteriore CT N° (%) Centro 001-Roma 21 16 (76) Centro 002-Milano 18 13 (72) Centro 011-Perugia 7 4 (57) Centro 014-Milano 7 5 (71) Centro 021-Mirano 4 4 (100) Centro 043-Catanzaro 2 1 (50) Patients (N°) 59 N° (%) Next therapy 43 (73) Not other chemotherapy 13 (22) Screening failure 1 (2) Not evaluable 2 (3) Regime di chemioterapia N° (%) Paclitaxel settimanale 9 (20) Cisplatino d1q21 6 (14) Carboplatino d1q21 5 (12) Doxorubicina Liposomiale Peghilata d1q28 4 (9) Ciclofosfamide p.o. 3 (7) Gemcitabina 2 (5) Carboplatino-Paclitaxel d1q21 2 (5) Cisplatino intraperitoneale 1 (2) Adriamicina 1 (2) Cisplatino-Paclitaxel d1q21 1 (2) Carboplatino settimanale 1 (2) Carboplatino-Gemcitabina 1 (2) Vinorelbina 1 (2) Tamoxifene 1 (2) Carboplatino-PLD d1q28 1 (2) NV 3 (7) Next chemotherapy N % No. total patients 43 100 No. of evaluable patients 26 6 Median PFS (month) Range Progression event 4 (1-14) 25 Randomized phase III trial on Trabectedin (ET 743) vs clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal or fallopian tube cancers of BRCA mutated or BRCAness phenotype patients MITO – 23 MITO-23: TRANSLATIONAL STUDIES • DNA sequencing in order to evaluate mutation/genetic aberration profile in selected panels of genes associated to tumor sensitivity to trabectedin. •Evaluating the impact of altered gene and microRNA (miRNA) expression on trabectedin efficacy with the aim of identify which miRNAs/genes are involved in the so called BRCAness phenotype; • Analysis of cellular infiltrate present on tumor specimens of patients treated with trabectedin; MITO - 23 TRANSLATIONAL STUDIES: Specimens Tumor histological blocks (FFPE material): samples will be collected at primary surgery and/or surgery nearest to trabectedin treatment (or before trabectedin treatment by dedicated biopsies). Storage and analysis will be centralized at Fondazione Istituto Nazionale dei Tumori. •Characterization of tumor infiltrate by IHC (2 slides per marker & 1 HE slide & 3 backup slides); •Extraction of RNA from tissue sections for miRNA/gene expression; •Extraction of DNA from tissue sections for targeted sequencing of “Panel cancer related genes”. Blood samples: Blood samples will be collected at baseline (registration), at third cycle of treatment and at progression. Storage and analyses will be centralized at Istituto Mario Negri, Milan. 10 ml blood sample will be taken at each time point, centrifuged in EDTA, processed to obtain 5 ml plasma collected and stored at -20°C or at -80°C when possible. MITO - 23