Istotipi “frequenti”: Aggiornamento protocolli A
Transcript
Istotipi “frequenti”: Aggiornamento protocolli A
Il problema dei tumori rari è socialmente rilevante, paradossalmente proprio in termini quantitativi, oltre naturalmente a costituire una priorità per motivi etici. Sotto il profilo etico, infatti, non è giusto che i pazienti con tumore raro abbiano a soffrire discriminazioni dovute alla bassa incidenza della loro malattia, come invece può accadere. I tumori rari, come le malattie rare in genere, comportano difficoltà particolari. Le competenze cliniche sui tumori rari non sono reperibili con facilità dalla persona malata, in quanto i centri che ne dispongono sono pochi e dispersi geograficamente. Inoltre, il trattamento dei tumori rari richiede spesso approcci multidisciplinari, e dunque la dispersione geografica delle competenze risulta ancora più frequente. Di fatto, i tumori rari sottendono un elevato grado di migrazione sanitaria, all'interno e verso l'esterno del Paese: i costi sociali sono impressionanti Anche i costi sanitari vengono impattati dai tumori rari. Sono frequenti delle prestazioni improprie al di fuori dei centri di riferimento. Esse possono incidere sfavorevolmente sulla prognosi dei Pazienti, e questo costituisce il principale problema etico. Ma, anche qualora la prognosi possa essere mantenuta invariata attraverso successivi interventi "di salvataggio", rimane una moltiplicazione dei costi. Lo sviluppo dei nuovi farmaci nei tumori rari è tutelato dalle normative sui farmaci "orfani", che prevedono incentivi economici per le aziende che ne ottengano la registrazione. Perché questo avvenga, è però necessario effettuare studi clinici, e dunque raccogliere casistiche di sufficiente numerosità da avviare a studi clinici formalizzati. Per migliorare la qualità di cura nell'ambito dei tumori rari, sono obiettivi primari: • Assimilare la diagnosi e il trattamento secondo criteri comuni • Realizzare la condivisione a distanza di casi clinici fra i centri • Promuovere un razionale accesso alle risorse di diagnosi e cura Attraverso il perseguimento degli obiettivi primari, si intende anche: • contribuire alla ricerca clinica sui tumori rari; • contribuire alla diffusione della conoscenza sui tumori rari; • fungere da modello metodologico e tecnologico per la collaborazione in rete geografica nell'ambito oncologico e delle malattie rare. Un Paziente che venga trattato direttamente presso la Struttura Specializzata può: • Ricevere un trattamento convenzionale, nell’ambito delle linee guida consolidate • Ricevere un trattamento fortemente individualizzato, in rapporto a peculiarità del caso singolo • Ricevere un trattamento all’interno di uno studio clinico (ad esempio su un nuovo farmaco o su una strategia terapeutica innovativa) . TRATTAMENTO MEDICO Relative frequency of soft tissue sarcoma subtypes Leiomyosarcoma 3% Malignant fibrous histiocytoma Liposarcoma 24% Synovial sarcoma 36% Rhabdomyosarcoma 9% Angiosarcoma Kaposi's sarcoma Fibrosarcoma 5% 12% 2% 2% 5% 2% 17 Survival in advanced soft tissue sarcoma The prognosis is usually poor for patients with locally advanced or metastatic STS 5-year survival in patients presenting with distant metastases or after metastatic relapse is ~16% Survival in patients with STS after local or metastatic relapse Patients with local recurrence/metastases after surgery and radiotherapy (n=402) Disease-specific survival (%) 5 years 10 years Overall 25 19 Isolated recurrence 48 46 Metastatic relapse 16 10 Retrospective study of 402 consecutive patients sustaining a first relapse of sarcoma after combined surgery and radiotherapy. Median follow-up after relapse: 6.8 years 18 5-year survival in soft tissue sarcoma varies depending on histological subtype 5-year survival in patients ages ≥20 years presenting with STS (all stages) 100 5-year survival (%) 80 60 40 20 0 Chemioterapia in adiuvante Slide11 Slide12 Slide27 Slide28 trial design, group 1 histology-driven chemo x 3 LMS: GEM + DTIC Mixoyd Liposarcoma: trabectedin Synovial sa: HD-IFX MPNST: IFX + VP16 Pleiomorphic : GEM + TAX R high grade deep seated >5 cm EPI+IFO x 3 Surgery + RT Surgery + RT trial design, group 2 high grade deep seated >5 cm EPI+ IFO x 3 Surgery + RT myxofibrosarcoma pleomorphic liposarcoma unclassified spindle cell sarcoma pleomorphic rabdomyosarcoma trial design, group 1 + RT histology-driven chemo x 3 synovial sa: HD-IFX MPNST: IFX + VP16 Surgery R + RT EPI+IFOx 3 Surgery trial design, group 1 + RT EPI+IFOx 3 LMS MRCLPS UPS Surgery trial design, group 2 + RT epiADM+IFX x 3 Surgery myxofibrosarcoma pleomorphic liposarcoma unclassified spindle cell sarcoma pleomorphic rabdomyosarcoma tumor response MRI (morphologic + functional study) CT (only when MRI is contraindicated) PET scan DCEUS path evaluation timing of radiological assessment: baseline, after one cycle, just before surgery trial status in Italy Site Current status Amendment 1 Enrollment status (n. pts) INT, Milano (001) Open Approved 28 IOR, Bologna (002) Open Approved 30 IRCCS Candiolo (003) Open Approved 3 Gradenigo (004) Open Approved 2 IRST, Meldola (005) Open Approved 2 IOV, Padova (006) Open Approved 6 CRO, Aviano (007) Open Approved 4 IEO, Milano (008) Open Approved 2 Humanitas, Milano (009) Open Approved 13 Brescia (010) Open Waiting for EC 1 IFO, Roma (011) Open Approved 5 Pascale, Napoli (012) Open Waiting for EC - Waiting for EC approval Waiting for EC - Careggi, Firenze trial status in Spain Site Current status Amendment 1 Enrollment status (n. pts) H. SON ESPASES, P. MALLORCA (101) Open Approved 6 H. SANT PAU, BARCELONA (102) Open Approved 11 H. V.HEBRON BARCELONA (103) Open Approved 3 H. VICTORIA; MALAGA (104) Open Approved 1 LA PAZ, MADRID (105) Open Approved 4 TENERIFE (106) Open Approved - IVO, VALENCIA (107) Open Approved - M. SERVET, ZARAGOZA (108) Open Approved 1 MD ANDERSON, MADRID (109) Open Approved - H. ROCIO, SEVILLA (110) Open Approved 1 H. LA FE, VALENCIA (111) Open Approved - NAVARRA, PAMPLONA (112) Open Approved - H. RAMON y CAJAL, MADRID Open Approved - H. ASTURIAS, OVIEDO Open Approved - H. COMPOSTELA Open Approved - H. BASURTO, BILBAO Open Approved - H. VALDECILLA, SANTANDER Open Approved - H. PUERTA HIERRO, MADRID Open Approved - trial status in Poland and France Sites Current Status Enrollment status (n. pts) Open 1 PARIS (2 SITES) Waiting for CA - LYON Waiting for CA - GRENOBLE Waiting for CA - MARSEILLE Waiting for CA - RENNES Waiting for CA - CLERMONT-FERRAND Waiting for CA - SAINT-HERBLAIN Waiting for CA - STRASBOURG Waiting for CA - VILLEJUIF Waiting for CA - PL – WARSAW (301) Ruolo della chemioterapia nella malattia avanzata Slide15 Istotipi “frequenti”: Aggiornamento protocolli Y-IMAGE: a non-interventional multicenter, prospective study to evaluate treatment outcome assessment methods used in routine clinical practice on patients with advanced soft tissue sarcoma treated with trabectedin according to the Summary of Product Characteristics This non-interventional, prospective, observational phase IV study will estimate the PFS at 6 months based on RECIST and/or Choi criteria in real-life clinical practice using trabectedin for the management of advanced soft tissue sarcoma Patients with advanced or metastatic histologically-proven STS with measurable disease with a baseline tumor evaluation by RECIST and/or Choi criteria 47 centres globally, 251pts will be selected Primary endpoint: PFS at 6 months per RECIST and/or Choi criteria Secondary endpoints: PFS at 12 months, OS, ORR, TTP, Duration of response, GMI where information about a previous therapy’s TTP is available Abstract ID: 2331465 Final ID: Poster 120 CTOS 2015 Y-IMAGE STUDY: A NON-INTERVENTIONAL, PROSPECTIVE PHASE IV STUDY OF TRABECTEDIN IN PATIENTS WITH ADVANCED SOFT TISSUE SARCOMA (STS) Penel Nicolas1, Buonadonna Angela2, Benson Charlotte3, Casanova Jose4, Kasper Bernd5, Nadal José Alberto6, López Pousa Antonio7, Mazzeo Filomena8, Brodowicz Thomas9 BACKGROUND RESULTS TREATMENTS Trabectedin (Yondelis®) is the first marine-derived drug approved in Europe for the treatment of adult patients with advanced STS, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. It acts as a DNA-binding agent and it has been proposed to have antiinflammatory properties and unique modulatory effects on the tumor microenvironment, attributed to its effect on tumor-associated macrophages and histiocytes [1-3]. Case-reports or post hoc analysis from clinical trials have suggested that trabectedin can show atypical radiological responses, such as massive central tumor necrosis [4] or tumor calcification [5], associated with clinical improvement. Assessment of tumor response to trabectedin should include tumor shrinkage (Response evaluation criteria in solid tumors; RECIST), but may also include tumor density changes (Choi criteria). Implementation of Choi and RECIST in a standardized manner remains a challenge in real life practice. A retrospective comparison of trabectedin response evaluated by RECIST/Choi criteria showed that Choi criteria may identify some cases of false progression underlining the importance of correct definition of tumor progression in the decision making strategy for treatment discontinuation [6]. In order to evaluate the use of trabectedin in STS and its response evaluation by RECIST /Choi criteria in real-life practice, an international, prospective, noninterventional study was designed. erapy Median n 199 % 91.7 119 54.8 1 (0-6) (range) Female Age (years) Median (range) % 43. 3 56. 123 7 58 (2179) 132 (63.2%) 0.2 0.1 0.0 0 2 4 6 8 10 12 In-patients 60 (28.7%) Trabectedin exposure; n=217 Cycles at Median (range) enrollment Median total trabectedin exposure Cycles per patient (range) (Y-IMAGE) % 39.2 1 68 31.3 2 13 6.0 3 1 0.5 50 23.0 16 18 20 22 24 ≥6 cycles Median (range), months Histology; n=217 27 sarcoma subtypes Leiomyo sarcoma Liposarc oma* Synovial sarcoma Pleomor phic Fibromyx *Including myxoid liposarcomas osarcoma Chondro sarcoma Angiosar coma At the time of the cut off all the patients had at least one evaluation except 8 patients that were imputed as not available and 59 of these evaluations were clinical. 1.0 CHOI (N=44 C=18) RECIST (N=44 C=15) Censored Censored 0.9 0.8 0.7 Intra-patient comparison of PFS; Median PFS 0.6 0.5 RECIST: 8.1 months (95% CI: 5.3-10.7) 0.4 Retrospective CHOI: 15.3 months (95% CI: 6.9-21.2) 0.3 n 14 Time (months) Intra-patient comparison of RECIST vs. retrospective Choi evaluation in 44 patients revealed a differential PFS response with median 15.3 months (95% CI: 6.9-21.2) by Choi vs. 8.1 (95% CI: 5,3-10,7) by RECIST. Median number of trabectedin cycles received per patient was 6 with 56% patients receiving ≥6 cycles and up to a maximum of 44 cycles. Median treatment duration was 5.5 months n UN PFS at 6 months: 46.9% (95% CI: 40.4%53.8 %) 0.3 Cumulative probability Out-patients Both 17 (8.1%) NOTE: The in-patient / out-patient information was recorded only starting on cycle 2 and onwards (8 patients that receive only one cycle). 94 K 0.4 n (%) n (%) 0.2 0.1 2 (2-29) 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) 6 (1-44) SAFETY 121 (55.8%) • 5.5 (0.7-44.2) Overall, 217 patients were enrolled from 11/2011-6/2014 (123 female) from 41 Among 27 sarcoma histotypes as defined by investigators main subtypes were European centers. Median age of patients was 58 years (range: 21-79) and 70.5% leiomyosarcoma (41.9%), liposarcoma (23.5%) and synovial sarcoma (10.6%). had ECOG performance status 0/1. Male PFS at 3 months: 69.4% (95% CI: 63.2%75.7%) 0.5 Progression-Free Survival RECIST and Choi Type of treatment; n=209 Time on treatment Gender 0.6 28.7%; both: 8.1%). DEMOGRAPHICS 16.1% received trabectedin for 1 year or more Demographics; n=217 Median PFS: 5.5 months (95% CI: 4.8-7.1 months) 0.7 0 22 10.1 1 87 40.1 2 74 34.1 3 22 10.1 4-6 12 5.6 Most patients were treated on an outpatient basis (outpatient: 63.2%; inpatient: 85 With 166 PFS events recorded, median PFS was 5.5 months (95% CI: 4,8-7,1 months) as assessed by RECIST (n=178), Choi (n=6) or clinically (n=59). At 3 and 6 months, 69.4% and 46.9% of patients were progressionfree and 16.1% received trabectedin for 1 year or more. Yondelis (N=217 C=51) Censored 0.8 Cumulative probability Surgery Radioth Prior chemotherapy lines • The Y-IMAGE study evaluates trabectedin use in real-life clinical practice across Europe, aiming to compare radiological response assessments obtained by RECIST or Choi criteria. • Data from adult patients with STS treated in 41 European centers with trabectedin within the approved schedule (1.5 mg/m2; 24-h i.v. infusion every 3 weeks) have been collected in a non-interventional phase IV study. To be included patients must have received at least 1 cycle of trabectedin and currently be on treatment before their inclusion in the study. Primary objective The primary endpoint is progression-free survival (PFS) as defined by investigator’s assessment (per RECIST and/or Choi criteria), Secondary objectives Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Aim Here we present the interim analysis of the primary endpoint at the cut-off of March 20th 2015. 0 1.0 0.9 n=217 Prior treatments METHODS ECOG PS; n=217 Kaplan-Meier plot of progression-free survival (PFS) by investigator’s assessment Patients had received a median of 1 prior line of chemotherapy (range: 0-6), mostly with anthracyclines ± ifosfamide (83.9%), whereas 22 (10.1%) patients were chemotherapy-naïve at study entry. n % 91 41.9 51 23.5 23 10.6 8 3.7 6 2.8 3 1.4 2 0.9 • • • Most common grade 3/4 adverse reactions were neutropenia and transaminase increase, reported in 17.9% and 7.9% of patients, respectively. Febrile neutropenia was reported in 2.7% of patients. Fatigue (3.7% of patients), nausea (1.4%) and vomiting (1.4%) were the most common trabectedin-related grade 3 adverse reactions. A fatal case of drug-related pulmonary embolism was registered. CONCLUSION Trabectedin demonstrates long-term efficacy when used in real practice to treat adult subtypes of STS with a manageable safety profile. Choi criteria, although not commonly used in clinical practice, may reveal a differential pattern of response assessment to trabectedin compared with RECIST CTOS 2015 Y-IMAGE (elderly patients) TRABECTEDIN IN ELDERLY PATIENTS WITH RECURRENT SOFT TISSUE SARCOMA (STS): AN INTERIM ANALYSIS OF A NON-INTERVENTIONAL, PROSPECTIVE PHASE IV STUDY Buonadonna Angela, Kasper Bernd, Blay Jean Yves, Fernandes Isabel, Eisterer Wolfgang, Lopez Pousa Antonio, Benson Charlotte, Penel Nicolas B Trabectedin (Yondelis®) is an antineoplastic drug of marine origin for the treatment of advanced STS after failure of anthracyclines and ifosfamide or for patients who are not suitable to receive these agents. M Data from adult STS patients treated with trabectedin have been collected in a real-life phase IV Y-IMAGE study. Patients must have received at least one cycle of trabectedin and be on treatment before their inclusion in the study. The primary endpoint is progression-free survival (PFS). The aim of this interim analysis is to evaluate the efficacy of trabectedin in elderly patients with recurrent advanced STS. R: From 11/2011 through 6/2014 217 patients from 41 European centers were treated (Table 1). Out of these, 62 patients aged ≥65 years and 13 of these aged ≥75 years. Baseline characteristics of elderly patients were similar to the overall study population, except for a reduced frequency of synovial sarcoma (6.5% vs. 12.3%) and better ECOG PS score of 0/1 (61.3% vs 74.2%) observed in younger patients. Twice as many patients aged ≥65 received trabectedin as first-line treatment that in the younger cohort (16.1% vs 7.7%). Median number of trabectedin cycles per patient was 5 in and 4 in patients aged ≥65 and ≥75, respectively, reaching up a maximum of 44 cycles. Sixty percent (37/62) of patients aged ≥65 were treated on an outpatient basis, similar to the 61% in younger population (95/156). Nearly all patients aged ≥75 (11/13) received trabectedin as an outpatient treatment. Median PFS was 4.1 months in patients aged ≥65 and 3.3 months in patients aged ≥75 years. A comparable number of patients were progression-free at 3 and 6 months regardless of age (Table 1). Trabectedin was generally well tolerated with no evidence of cumulative toxicity or end-organ dysfunction across all age groups. C: This analysis demonstrated that trabectedin is an efficacious and well tolerated treatment in young and elderly patients with STS. CTOS 2015 Y-IMAGE (early lines) EFFICACY AND SAFETY OF TRABECTEDIN AS AN EARLY TREATMENT FOR ADVANCED STS: AN INTERIM ANALYSIS OF A NON-INTERVENTIONAL, PROSPECTIVE PHASE IV STUDY Mazzeo Filomena, Blay Jean Yves, Maud Toulmonde, Kasper Bernd, Paolo Casali, Giacomo Giulio Baldi, Umberto Basso, Guido Biasco, Buonadonna Angela, Giovannella Palmieri, Penel Nicolas Background: Trabectedin (Yondelis®) is a marine antineoplastic drug for the treatment of advanced STS after failure of anthracyclines and ifosfamide or for patients who are not candidates to receive these agents. Methods: Data from adult STS patients treated with trabectedin 1.5 mg/m2 given as 24-h i.v. infusion every 3 weeks have been collected in a real-life phase IV Y-IMAGE study. To be included patients must have received at least 1 cycle of trabectedin and be currently on treatment before their inclusion in the study. The primary endpoint is progression-free survival (PFS). The aim of this interim analysis is to evaluate the efficacy of trabectedin when used in earlier lines of treatment. Results: From 11/2011-6/2014 217 patients from 41 European centers were treated (Table 1). Median number of administered trabectedin cycles at enrolment was 2. Before trabectedin patients were pretreated with a median of 1 prior line of chemotherapy (range: 0-6): 87, 74 and 34 patients received 1, 2, or 2+ lines, respectively, whereas 22 patients were chemotherapy-naïve (Ch-N). Baseline characteristics of patients were well-balanced among the groups, except for EGOG performance status core of 0 among the Ch-N patients that almost doubled that in the pretreated patients. Predominant histological STS subtypes were leiomyosarcoma (41.9%), liposarcoma (23.5%) with similar percentages in Ch-N and patients pretreated with 1 line. The patients in Ch-N group had longer time of response as the median number of cycles they received (12 cycles) doubled those observed in pretreated patients with 1, 2, or 2+ lines (6, 7 and 5 cycles) and with greater percent of patients on treatment for more >1 year (Ch-N 22.7% vs. 5.7%, 16.2%, 2.9%) (Table 1). With 166 PFS events recorded, median PFS was 5.5 months (95% CI: 4.8-7.1 months) as assessed by RECIST (n=178), Choi (n=6) or clinically (n=59). A clear trend towards shorter PFS in patients who received more extensive prior treatment was observed (median PFS: 10.4, 5.9, 5.3, 4.4 months) (Figure 1). Trabectedin was generally well tolerated. Spontaneously reported adverse events were similar across treatment lines and consistent with the known profile of trabectedin. Conclusions: Trabectedin efficacy can be optimized when it is administered earlier allowing patients to benefit from a long-term treatment, hence, to get longer disease control with respect to patients who are treated later in the course of their disease. Angiogenesis inhibitors Role of VEGF-2 and PDGFR signalling in tumour angiogenesis1–4 PDGF VEGF PDGFR Cell membrane VEGFR-2 P P P P P P P P PI3K FAK PLC Erk AKT Paxillin PKC Proliferation Survival Migration Ras Raf Permeability Vascular tone 1. Hamberg P et al. Oncologist 2010;15:539; 2. Faivre S et al. Nat Rev Drug Discov 2007;6:734; 3. Andrae J et al. Genes Dev 2008;22:1276; 4. Sonpavde G et al. Expert Opin Investig Drugs 2008;17:253 59 Expression of VEGF is increased in soft tissue sarcoma VEGF expression is observed in multiple STS subtypes1 Serum VEGF levels are elevated compared with controls2–6 Increased serum VEGF levels associated with STS subtypes2 1. Potti A et al. J Cancer Res Clin Oncol 2004;130:52; 2. Yoon SS et al. J Surg Res 2006;135:282; 3. Yoon SS et al. Ann Oncol 2004;15:1261; 4. Graeven U et al. J 60 Cancer Res Clin Oncol 1999;125:577; 5. Feldman A et al. Cancer 2001;91:1525; 6. Hayes AJ et al. Br J Surg 2004;91:242 VEGF expression is correlated with higher tumour grade VEGF overexpression by STS cells leads to increased endothelial cell proliferation, migration and chemoresistance in vitro7 1000 500 0 Grade 3 1500 Grade 2 Benign lesions: 233 pg/ml Grade 2: 413 pg/ml; p=0.007 Grade 3: 467 pg/ml; p=0.003 2000 Grade 1 2500 Benign Median pre-treatment serum VEGF concentration significantly elevated in patients with STS:4 3000 Healthy volunteers Serum VEGF levels are correlated with tumour grade4 Increased VEGF expression has been associated with higher tumour grade in a number of studies in STS1–6 Serum VEGF (pg/ml) 1. Graeven U et al. J Cancer Res Clin Oncol 1999;125:577 2. Pakos EE et al. Anticancer Res 2005;25:3591; 3. Yudoh K et al. Br J Cancer 2001;84:1610; 4. Hayes AJ et al. Br J Surg 2004;91:242; 5. Chao C et al. Ann Surg Oncol 2001;8:260; 6. Iyoda A et al. Ann Thorac Surg 61 2001;71:1635; 7. Zhang L et al. Cancer Res 2006;66:8770 VEGF expression is associated with decreased survival in soft tissue sarcoma Increased VEGF expression has been correlated with decreased survival in a number of studies in STS1–5 In one study, however, in patients with STS, VEGF expression was correlated with tumour grade but not survival6 Median survival is significantly decreased in patients with VEGF-positive leiomyosarcoma1 STS type Median survival (months) p-value VEGF+ VEGF– Dermatofibrosarcoma (n=44) 72 50 0.29 Malignant fibrous histiocytoma (n=50) 14 23 0.30 Leiomyosarcoma (n=36) 8 30 0.01 Overall (n=273) 31 45 0.17 Patients diagnosed with STS between 1986 and 2001 (n=273) *VEGF expression assessed by percentage of immunoreactive cells: >10% of the cells staining was graded as positive. No detectable staining or <10% of cells staining was graded as negative 1. Potti A et al. J Cancer Res Clin Oncol 2004;130:52; 2. Yudoh K et al. Br J Cancer 2001;84:1610; 3. Iyoda A et al. Ann Thorac Surg 2001;71:1635; 4. Kilvaer T et al. PLoS One 2010;5:e15368; 5. Potti A et al. Anticancer Res 2004;24:3339; 6. Chao C et 62 al. Ann Surg Oncol 2001;8:260 Role of PDGF/PDGFR in soft tissue sarcoma PDGF-B is expressed in the majority of STS tumours and expression is correlated with higher tumour grade and increased cell proliferation1 PDGFR-β is also expressed in STS1 PDGFR-α expression is upregulated in STS2 PDGF/PDGFR expression has also been correlated with decreased survival3,4 Survival is associated with PDGF-B expression in patients with wide resection margins3 In patients with STS and wide resection margins (n=108), high expression of PDGF-B (p=0.007) and co-expression of PDGF-B and PDGFR-α (p=0.001) were independent prognostic markers for disease-specific survival3 In patients with rhabdomyosarcoma (n=89), high PDGFR expression was associated with decreased survival4 1 Disease-specific survival p=0.007 Low expression, n=32 0.8 High expression, n=74 0.6 0.4 0.2 0 0 20 40 60 80 Survival (months) 100 120 1. Wang J et al. Cancer Res 1994;54:560; 2. Yoon SS et al. J Surg Res 2006;135:282; 3. Kilvaer T et al. Sarcoma 2010; 2010;751304; 4. Blandford MC et al. Pediatr Blood Cancer 2006;46:329 63 Pazopanib Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-Kit Binds to the cytoplasmic kinase domain of VEGFR-1, -2 and -3, PDGFR-α and -β, and c-Kit1 VEGFR regulates angiogenesis2 PDGFR regulates angiogenesis and proliferation of some tumour cells3,4 c-Kit regulates cellular proliferation, survival, and metastasis5 Monohydrochloride salt Pazopanib has exhibited minimal in vitro inhibition of Flt-3 (involved in the development of haematopoietic stem cells)1 1. 2. 3. 4. 5. Kumar et al. Mol Cancer Ther 2007;6:2012–21. Kerbel. N Engl J Med 2008;358:2039–49. Yu et al. J Biochem Mol Biol 2003;36:49–59. Homsi and Daud. Cancer Control 2007;14:285–94. Demetri. Semin Oncol 2001;28(5 Suppl 17):19–26. Phase I trial of pazopanib in patients with advanced solid tumours1 Open-label, non-randomized, dose-finding trial of pazopanib in patients with advanced-stage, refractory solid tumours Sequential dose-escalating cohorts (dose-escalation phase, n=43; dose expansion phase, n=20) receiving pazopanib 50 mg three times weekly to 2000 mg once daily and 300 mg to 400 mg twice daily Three patients had partial response (two confirmed, one unconfirmed) and 14 patients had stable disease ≥6 months Monotherapy dose of 800 mg once daily was selected for further trials Mean trough concentration of ≥15 had μg/ml (34 μmol/l) at 800 mg once daily Four patients withtarget sarcoma treated with pazopanib stable diseaseachieved ≥6 months Subtype Starting dose (mg) Final dose (mg) Duration of stable disease (months) Leiomyosarcoma 50 once daily 800 once daily 9.0 Chondrosarcoma 400 once daily 800 once daily 7.6 GIST 600 once daily 800 once daily 15.8 Chondrosarcoma 2000 once daily 800 once daily 19.8 GIST, gastrointestinal stromal tumour 1. Hurwitz H et al. Clin Cancer Res 2009;15:4220 65 66 Phase II EORTC study 62043 (VEG20002): study design1 Treatment phase Stage 1 (n=17) C O N SE N T Adipocytic tumours Verify eligibility ≤2 weeks (n=17) Synovial sarcoma (n=17) Other STS (n=17) Stop if ≤3 of 17 subjects in stage I are alive and progression-free at Week 12 Leiomyosarcoma Futility analysis Follow-up Stage 2 Leiomyosarcoma (additional n=~20) Adipocytic tumours (additional n=~20) Synovial sarcoma Follow-up for PD every 12 weeks (additional n=~20) Follow-up for survival every 3 months Other STS (additional n=~20) WD due to AE Treatment discontinued in either stage when patients: Experience PD Death on treatment End of study WD consent • Phase II trial of pazopanib in relapsed or refractory STS – Pazopanib 800 mg was administered orally, once daily – The primary endpoint was progression-free rate at 12 weeks (PFR12) AE, adverse event; EORTC, European Organisation for Research and Treatment of Cancer ; PD, progressive disease; PFS, progression-free survival; STS, soft tissue sarcoma; WD, withdraw 1. Sleijfer S et al. J Clin Oncol 2009;27:3126 67 Phase II EORTC study 62043 (VEG20002): progression-free survival and overall survival1 Overall survival 100 100 90 90 Adipocytic sarcomas Leiomyosarcomas Synovial sarcomas 80 80 Other sarcomas Overall survival (%) Progression-free survival (%) Progression-free survival 70 60 50 40 30 70 60 50 40 30 20 20 10 10 0 0 0 3 6 9 12 15 18 Time (months) 1. Sleijfer S et al. J Clin Oncol 2009;27:3126 21 24 27 0 3 6 9 12 15 18 21 24 27 Time (months) 68 Phase II EORTC study 62043 (VEG20002): tumour responses1 Leiomyosarcoma (n=41) Adipocytic sarcoma (n=19) Synovial sarcoma (n=37) Other sarcoma types (n=41) Partial response, n 1 0 4 1 Stable disease, n 17 5 14 15 Progressive disease, n 21 13 14 23 Early death, n 1 1 3 2 Not evaluable, n 1 Parameter 1 Clinical progressive disease, n PFS rate at 12 weeks, n/N (%) 1 18/41 (43.9) 5/19 (26.3) 18/37 (48.6) 16/41 (39.0) PFS, progression-free survival CT scan of a patient with leiomyosarcoma with partial response Baseline 1.Sleijfer S et al. J Clin Oncol 2009;27:3126 After 3 months of pazopanib treatment 69 The PALETTE study (PAzopanib expLorEd in sofT-Tissue sarcoma A phasE III study) 1 An EORTC STBSG and GlaxoSmithKline global network study (EORTC 62072; VEG110727) 1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com 70 Phase III Study Design N= 369 R A N D O M I S E Pazopanib*(800mg QD) 10 Endpoint 20 Endpoints (N = 246) 2:1 PFS (RECIST v1.0) Matching Placebo (N = 123) Followed for survival * Until disease progression, unacceptable toxicity, withdrawal of consent for any reason, or death Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com OS ORR QoL Safety Stratification factors Performance status (0 vs 1) Number of prior lines of systemic therapy for advanced disease (0/1 vs 2+) Disease assessment at week 4-8-12-20 and at 8 week intervals thereafter Inclusion Criteria Histology Included: • Fibroblastic • MPNST • Fibrohistiocytic • NOS • Leiomyosarcoma • Vascular STS • Synovial sarcoma • Malignant glomus tumors Excluded: • Adipocytic sarcoma • DFSP • Osteosarcoma • Mixed mesodermal uterine tumor • Ewing sarcoma/PNET • GIST • Chondrosarcoma • Mesothelioma • Inflammatory myofibroblastic sarcoma • Non alveolar and non pleiomophic rhabdomyosarcoma Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com Progression Free Survival1 1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com 73 Overall Survival1 1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com 74 PALETTE: SAFETY DATA PALETTE: newly identified serious adverse events1 SAEs with a higher incidence in the pazopanib-treated aSTS population than in the pazopanib-treated aRCC population On-therapy and post-therapy adverse events Myocardial dysfunction* Venous thromboembolic † events Pneumothorax Placebo (n=123) Any grade 6 (5%) Grade 3 Pazopanib (n=240) Any grade 21 (9%) Grade 3 3 (1%) Grade 4 – Grade 4 – 3 (2%) 1 (<1%) 2 (1%) 13 (5%) 5 (2%) 1 (<1%) – – – 8 (3%) – 1 (<1%) 1 (<1%) *Grouping of MedDRA terms, including left ventricular dysfunction, cardiac failure, restrictive cardiomyopathy and pulmonary oedema †Fatal pulmonary embolus occurred in two of 240 patients treated with pazopanib Dati elaborati da testo 1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com 76 Conclusions Pazopanib demonstrated a statically significant increase in PFS compared to placebo1 PFS improved in patients in all age, for most histological subtypes (leiomyosarcoma, synovial and others) 1 Pazopanib is an active drug for pts with non adipocytic soft tissue sarcoma. 1 “....After the breackthroughs of Imatinib and Sunitinib for GIST, Pazopanib is the FIRST active oral agent for pts with NON GIST and NON LIPO aSTS and is a eaningful addition to the treatment armamentarium for pts with the rare group of tumors.” 1 1. Van Der Graaf W et al. Published on line May 16 2012. www.thelancet.com 77 Angiogenesis inhibitors Istotipi “frequenti”: Aggiornamento protocolli A Phase II study (TRAVELL) on trabectedin in advanced retroperitoneal leiomyosarcoma and well differentiated/dedifferentiated liposarcoma Patients with previously treated retroperitoneal leiomyosarcoma and well differentiated/dedifferientiated liposarcoma unamenable to surgery or amenable but the addition of a medical treatment is clinically felt advisable Istotipi “frequenti”: Aggiornamento protocolli A Phase II study (TRAVELL) on trabectedin in advanced retroperitoneal leiomyosarcoma and well differentiated/dedifferentiated liposarcoma Main inclusion criteria Persistent or locally relapsed and/or metastatic disease (in case of local disease, surgery may be technically feasible or not, but the clinical judgment must be that a medical therapy is indicated) Pathology specimens available for centralized review (Department of Pathology of Treviso-Dr. Dei Tos) ECOG PS <=2 One or more previous systemic treatments employing anthracyclines and ifosfamide (unless one or both are clinically contraindicated) Main exclusion criteria Prior exposure to trabectedin Istotipi “frequenti”: Aggiornamento protocolli A Phase II study (TRAVELL) on trabectedin in advanced retroperitoneal leiomyosarcoma and well differentiated/dedifferentiated liposarcoma Phase II, multicenter, single arm Enrolling centres: about 20 centres ISG of 3-4 years Primary end-point: Growth modulation rate = 80 patients over a period PFS to T ---------------------TTP to previous CT Secondary end-points: Objective response, progression free survival, and objective response in the two eligible histological types, PFS in pts who undergo surgery and those who do not, pathological tumor response in pts undergoing surgery, safety profile Istotipi “frequenti”: Aggiornamento protocolli A Phase II study (TRAVELL) on trabectedin in advanced retroperitoneal leiomyosarcoma and well differentiated/dedifferentiated liposarcoma Trabectedin 1,5 mg/mq or 1,3 mg/mq according to Investigator’s choice (with a top-dose of 2,6 total mg per cycle) CT scan will be performed every 3 cycles Translational Study About 15-20 patient to asses tumor biological features associated to different response patterns to trabectedin All patients who undergone surgery after trabectedin treatment Istotipi “frequenti”: Aggiornamento protocolli STRASS Study: A phase III randomized study of preoperative radiotherapy plus surgery versus surgery alone for patients with Retroperitoneal sarcoma (RPS) Primary soft tissue sarcoma of retroperitoneal or infra-peritoneal spaces of pelvis, unifocal disease and not previously treated 259 pts will be randomized over a period of 39 months Primary endpoint: abdominal recurrence free survival (local relapse, R2 surgery, PD or non-resectable disease during RT, peritoneal sarcomatosis) Istotipi “frequenti”: Aggiornamento protocolli Investigational arm : preoperative RT 50.4 Gy (28 daily fractions) + Large en-bloc curative-intent surgery Control arm: Large en-bloc curative-intent surgery alone GIST Chemotherapy, Radiation, and Surgery in GIST Surgery1,2 Principal treatment for resectable primary GIST Chemotherapy1,3-5 Ineffective in sarcomas Response limited: ~5% Survival: no impact 1. DeMatteo RP et al. Hum Pathol. 2002;33:466-477. 2. Pierie JP et al. Arch Surg. 2001;136:383-389. 3. Hatch KF et al. World J Surg. 2000;24:437-443. Radiation1,2 Results in injury to adjacent organs Tumors exhibit radioresistance Possible therapeutic role in rectal tumors 4. Rossi CR et al. Int J Cancer. 2003;107:171-176. 5. Demetri G et al. J Natl Compr Canc Netw. 2004;2 (suppl 1):S1-S26. GIST: Current Treatment Options Surgery Treatment of choice for localized primary resectable GIST1,2 1. Demetri G et al. J Natl Compr Canc Netw. 2004;2(suppl 1):S1-S26. 2. Blay JY et al. Ann Oncol. 2005;16:566-578. Imatinib First-line treatment of malignant unresectable or metastatic GIST1,2 Treatment Algorithm for Patients With Primary Metastatic or Recurrent GIST Primary disease No Metastasis Recurrent disease Surgery feasible or unresectable (Neoadjuvant) Imatinib Surgery Nilotinib Postoperative imatinib (adjuvant) Response or stable disease Surgery ?? Adapted from Sanne M et al Cancer 2005;104:1781-8. Progression Sunitinib or surgery ?? Clinical trials: Imatinib + nilotinib Imatinib + other Risk of Aggressive Tumor Behavior All GISTs should be considered to have potential for malignant behavior1,2 Size (cm) Mitotic Count (HPF) Very low risk <2 <5/50 Low risk 2-5 <5/50 Intermediate risk <5 5-10 6-10/50 <5/50 >5 >10 Any size >5/50 Any mitotic rate >10/50 High risk HPF, high-power fields. 1. Fletcher CD et al. Hum Pathol. 2002;33:459-465. 2. Miettinen M et al. Hum Pathol. 2002;33:478-483. Classificazione del rischio cm M/50HPF gastric jejunal/ ileal duodenal rectal 1 <2 <5 0 none 0 none 0 none 0 none 2 >2<5 <5 1.9% very low 4.3% low 8.3% low 8.5% low 3a >5<10 <5 3.6% low 24% moderate 3b >10 <5 12% moderate 52% high 34% high 57% high 4 <2 >5 0 50% 5 >2<5 >5 16% moderate 73% high 6a >5<10 >5 55%, high 85%, high 6b >10 >5 86% high 90% high 54% high 50% high 52% high 86% high 71% high Regorafenib nella terapia per i GIST: ora disponibile tramite il SSN Siamo lieti di comunicare che è stata pubblicata la DETERMINA 24 luglio 2015 con la quale l’Agenzia Italiana del Farmaco AIFA ha autorizzato la classificazione e la rimborsabilità di Regorafenib (Stivarga) nell’uso dei GIST e dei Carcinomi del Colon Retto. Con Determina n. 1016 AIFA ha autorizzato il nuovo medicinale per il trattamento dei pazienti adulti affetti da tumori stromali gastrointestinali (gastrointestinal stromal tumors, GIST) non resecabili, dopo progressione di malattia o intolleranti al trattamento precedente con imatinib e sunitinib. STUDI APPROVATI NON ANCORA APERTI PER IL RECLUTAMENTO Masitinib Studio prospettico di Fase III , multicentrico, randomizzato, controllato con placebo per confrontare l'efficacia e la sicurezza di masitinib vs placebo in pazienti con GIST primario localizzato dopo completa chirurgia e con alto rischio di recidiva. Sponsor AB Science Numero ID AB 12004 Arruolamento stimato n. 330 Inizio Gennaio 2014 Compimento Dicembre 2016 https://clinicaltrials.gov/ct2/show/NCT02009423?term=NCT02009423&rank=1 SARC 029 Trametinib e Pazopanib in pazienti con GIST. Studio di Fase II di Trametinib in combinazione con Pazopanib in pazienti con GIST avanzato refrattari o intolleranti ad almeno imatinib e sunitinib. Studio non randomizzato, in aperto per valutare efficacia e sicurezza. Sponsor: Sarcoma Alliance for Research through Collaboration. Collaboratori GlaxoSmithKline Arruolamento stimato n. 45 Inizio Marzo 2015. Compimento Marzo 2018 Contatti: SARC OFFICE 734-930-7600 [email protected] https://clinicaltrials.gov/ct2/show/NCT02342600?term=gastrointestinal+stromal+tumor&rank=54 Studio di fase II di BB1503 in pazienti adulti con tumore stromale gastrointestinale avanzato. E' uno studio in aperto, multicentrico, per pazienti che hanno esaurito le opzioni terapeutiche standard attualmente approvate. Il farmaco è' somministrato per via orale, ogni giorno alla dose di 300 mg una volta al giorno. ID N. BB1503-205c Sponsor Boston Biomedical Inc Arruolamento stimato n. 30 Inizio Gennaio 2015 Compimento Gennaio 2016 https://clinicaltrials.gov/ct2/show/NCT02232620?term=gastrointestinal+stromal+tumor&recr=Open&no_unk=Y&rank=10 CABOGIST Studio di fase II multicentrico, muultinazionale a braccio singolo per valutare la sicurezza e l'attività di cabozantinib in pazienti con GIST metastatico che hanno avuto progressione durante terapia neoadiuvante, adiuvante o terapia palliativa con imatinib e sunitinib. Sponsor EORTC European Organisation for Research and Treatment of Cancer N. ID dello studio EORTC-1317, 2014-000501-13 N. stimato dei pazienti arruolati 50 Inizio Luglio 2015 Completamento stimato Gennaio 2017 https://clinicaltrials.gov/ct2/show/NCT02216578?term=CABOGIST&rank=1 Studio di Fase I di BLU-285 in pazienti con tumore stromale gastrointestinale ed altri tumori solidi recidivati o refrattari. Sponsor: Blueprint Medicines Corporatio. E' uno studio di fase I open label, studio di aumento della dose, per valutare la sicurezza, la tollerabilità, l'efficacia, la farmacodinamica, la farmacocinetica e la preliminare attività antitumorale di BLU 285 somministrata oralmente in pazienti con GIST inoperabile o altri tumori solidi recidivati o refrattari. Lo studio consiste di due parti, una parte di aumento della dose ed una parte di espansione. Nella parte 1 saranno arruolati pazienti con GIST inoperabile, con malattia che ha avuto progressione dopo imatinib e almeno uno dei seguenti agenti: sunitinib, regorafenib, sorafenib, dasatinib,pazopanib o altro farmaco sperimentale inibitore di KIT, o malattia con mutazione D842 nel gene PDGFRA. Arruolamento stimato, n.60 Inizio Agosto 2015; completamento maggio 2019 Centri di sperimentazione 3 USA (Boston, Portland, Philadelphia) https://www.clinicaltrials.gov/ct2/show/NCT02508532?term=gastrointestinal+stromal+tumor&rank=75 Therapeutic Drug Monitoring “process of assessing concentration of the drug in biological fluids such that it is maintained within the therapeutic range” Drugs Requiring TDM - Narrow therapeutic range - Significant pharmacokinetic variability (ADME) - Drugs which show therapeutic as well as ADR based on their concentrations - Well established relationship between PK exposure and clinical response - Drugs which follow saturation metabolism - Availability of cost effective drug assay IMATINIB PHARMACOKIENTICS INTERPATIENTS VARIABILITY - Dosage regimen and Duration of therapy - Patient characteristics - Alteration in elimination of drugs - Alteration in Protein binding - Pathological characteristics - Drug interactions - Diet, smoking and alcohol consumption DISTRIBUTION OF IMATINIB CMIN Cmin is associated to clinical benefit Cmin cutoff 1100 ng/mL OUR RESULTS titolo Most of the patients present C trough within the optimal range however some patients are under dosed