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Trabectedin contribution to the treatment of sarcomas PowerPoint Presentation

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Description : Check out this medical presentation on Desmoid Tumor, which is titled "Trabectedin contribution to the treatment of sarcomas", to know about the treatment of sarcomas.

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Published on : May 13, 2021 | Views : 1137 | Downloads : 0

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Slide 1-

Trabectedin contribution to the treatment of sarcomas Pr JY Blay Centre Leon Berard, Lyon EORTC
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Adipocytic tumours Well deifferentiated / dedifferentiated liposarcoma Myxoid / round cell liposarcoma Pleomorphic liposarcoma ….. Fibroblastic / myofibroblastic tumours Fibromatosis (desmoid) Solitary fibrous tumour / haemangiopericytoma Low grade myofibroblastic tumour Infantile fibrosarcoma Adult fibrosarcoma Mixofibrosarcoma ….. So-called fibrohistiocytic tumours Pleomorphic MFH / Undifferentiated pleomorphic sarcoma ….. Smooth muscle tumours Leiomyosarcoma ….. Skeletal muscle tumours Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma Vascular tumours Epithelioid haemangioendothelioma Angiosarcoma of soft tissue ….. Chondro-osseous tumours Mesenchymal chondrosarcoma Extraskeletal osteosarcoma Tumours of uncertain differentiation Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Extraskeletal Ewing tumour Desmoplastic small round cell tumour Extra-renal rhabdoid tumour Malignant mesenchymoma Neoplasms with perivascular epithelioid cell differentiation (PEComa) Intimal sarcoma Many different histotypes And even more molecular subtypes!
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Connective tissue tumours 5 types of sarcomas Associated with specific translocations generating fusion genes Ewing t(11;22), … Synovialosarcomas t(X;18) Alveolar rhabdomyosarcomas t(1;13), t(2;13) DSRCT t(11;22) etc... Kinase mutations (KIT, PDGFR in GIST) Gene inactivation (INI1 in rhabdoid tumors) Simple genetic alterations: amplifications (mdm2+cdk4 in LPS) Complex genetic alterations (MFH, LMS, ...)
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A simple algorithm? LOCAL DISEASE Surgery + Radiotherapy CURE (~50%) METASTASES (~60%) Doxorubicin Ifosfamide Combination Surgery (~10%) Trabectedin Trabectedin Trabectedin Ifosfamide Doxorubicin
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Metastatic phase Doxorubicin- Ifosfamide Trabectedin Gemzar+/-Docetaxel or DTIC Taxol for angiosarcomas
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Systemic treatment of sarcomas 2000-2012 2000 All sarcomas Doxorubicin Ifosfamide DTIC Selected subtypes Dactinomycin CDDP Vincaalcaloids Cyclophosphamide 2012 All subtypes: Same +Trabectedin GIST: Imatinib, sunitinib, nilotinib? Osteosarcomas: MTPPE LPS: Dox, Trabectedin LMS: Dox, Trabectedin, Gem, G/T EWS: A,I,C,V,Ac, TopoI inh., IGF1R A/E RMS: Topo inh ESS: Aromatase inh. All?: mTOR All but LPS: VEGFR TKI Angio: Dox, Paclitaxel, GemTax DFSP: Imatinib PVNS: Imatinib Desmoid Tumors: imatinib
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Trabectedin (Yondelis®) Marine-derived anticancer agent originally isolated from marine Caribbean tunicate, Ecteinascidia turbinata. Currently obtained by a synthetic process. Approved in more than 70 countries for the treatment of relapsed STS and platinum sensitive ovarian cancer.
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Yondelis binds covalently to the DNA minor groove.1 Interaction with the endonuclease XPG.1 The formation of a large ternary cytotoxic complex (DNA-Yondelis-XPG) results in DNA breaks.1 Yondelis: A Unique Mechanism of Action1 Formation of a ternary complex between DNA (blue), Yondelis (Orange) and XPG (Green) Affecting “the two” cellular processes related to DNA: replication1 and transcription2, and finally inducing an apoptotic cell death.1 1. Herrero AB, et al. Cancer Res. 2006;66(16):8155-62. 2. Fayette J, et al. Curr Opin Oncol. 2006;18:347-53.
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Yondelis is a multitarget agent TF FP DNA binding and distortion Displacement of TF and FP Transcription inhibition ARN pol II Tumour microenvironment Pre-treatment Cycle 3 Pre-treatment Cycle 2 Adapted from M D’Incalci et al, 2010 DNA repair XPF XPG
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Major impact (tumor control, 6-PFS) in: Leiomyosarcoma (LMS) 56% Liposarcoma (LPS) 40% 270 patients randomized (260 treated) Baseline characteristics well balanced between both arms 66% leiomyosarcomas / 34% liposarcomas Prior chemotherapy: PD after anthracyclines and ifosfamide 2/3 of pts received additional agents (Gem, 32%; docetaxel, 24%....) STS-201
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STS-201 Historical Context (EORTC): PFS in Sarcomas Both trabectedin schedules showed longer PFS than “active” drugs in similar setting Le Cesne et al. Drugs of today 2009;45(6):403-21 1 2 3 4 1. Trabectedin q3wk 24-h 2. Trabectedin qwk 3-h 3. Active agents (EORTC STBSG) 4. Inactive agents (EORTC STBSG) 14% 6 months PFS 36% 6 months PFS
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LPS MR (SD) 15 cy Alive at 11+ yrs Objective response vs Survival
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Linking with clinical use of trabectedin Histology Combinations Maintenance treatment Rechallenge
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0 +4 c Trabectedin in MLPS: Induction CT in Localized MLPS? N = 23: 4 to 6 cycles of trabectedin/Surgery/ RT End-point: complete histological rate Analysis of fusion Transcripts/ Response Multicenter Phase II (IGR/Milan/CLB/US) A. Gronchi et al, Ann Oncol 2011
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Before After 6 cycles 41 pts MTD and recommended dose: D60 mg/m² + T1.1 mg/m² ORR + SD (tumor control) = 95% 6-months PFS: 59% (> baseline reference EORTC first line) Currently several studies are ongoing with combination therapy: Phase II randomised multicenter study of Trabectedin plus Doxorubicin vs. Doxorubicin in untreated STS patients (GEIS) Blay JY et al CCR 2008 Trabectedin + Doxorubicin
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Trials ongoing in first line Translocation related sarcomas TRUSTs GEIS-20 (Trabectedin + Doxorubicin) LMS-02 (Doxorubicin + Trabectedin)
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Future of Trabectedin in STS Molecular targeted therapy with trabectedin in TRS Combination with others drugs Personalised treatment with surrogate biological markers. Adjuvant approaches? Marker + Marker -
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Trabectedin Importance of maintenance treatment? N=56, interruption vs continuation after 6 courses Explored in the randomized T-DIS trial p=0,001 p=0,009 Blay JY et al, BMC 2012 (Submitted)
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European Clinical trials in Rare Sarcomas within an integrated translational Grant agreement no.: 278742
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