03083nas a2200493 4500008004100000022001400041245014600055210006900201260001200270300001400282490000700296520140800303100002001711700002401731700002901755700002801784700002501812700002501837700001801862700002401880700002901904700003101933700003501964700002101999700003102020700002102051700001902072700002802091700001802119700003102137700002802168700001702196700003902213700001702252700002502269700002202294700002002316700002302336700001802359700002202377700002902399700002502428856013602453 2021 eng d a1878-026100aA DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.0 aDNA damage repair geneassociated signature predicts responses of c2021 12 a3691-37050 v153 a
Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.
1 aMoura, David, S1 aPeña-Chilet, Maria1 aVarela, Juan, Antonio Co1 aAlvarez-Alegret, Ramiro1 aAgra-Pujol, Carolina1 aIzquierdo, Francisco1 aRamos, Rafael1 aOrtega-Medina, Luis1 aMartin-Davila, Francisco1 aCastilla-Ramirez, Carolina1 aHernandez-Leon, Carmen, Nieves1 aRomagosa, Cleofe1 aSalgado, Maria, Angeles Va1 aLavernia, Javier1 aBagué, Silvia1 aMayodormo-Aranda, Empar1 aVicioso, Luis1 aBarceló, Jose, Emilio Her1 aRubio-Casadevall, Jordi1 ade Juan, Ana1 aFiaño-Valverde, Maria, Concepcion1 aHindi, Nadia1 aLopez-Alvarez, Maria1 aLacerenza, Serena1 aDopazo, Joaquin1 aGutierrez, Antonio1 aAlvarez, Rosa1 aValverde, Claudia1 aMartinez-Trufero, Javier1 aMartin-Broto, Javier uhttps://www.clinbioinfosspa.es/content/dna-damage-repair-gene-associated-signature-predicts-responses-patients-advanced-soft-tissue03275nas a2200493 4500008004100000022001400041245012000055210006900175260001200244490000600256520175600262653001002018653000902028653004102037653001102078653001102089653000902100653001602109653001402125653001202139653001402151653001602165100002502181700001702206700002302223700002902246700002002275700002202295700002402317700002502341700002402366700002302390700002502413700002802438700002202466700001902488700002402507700002002531700002702551700002502578700002002603700002602623856013202649 2020 eng d a2051-142600aNivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.0 aNivolumab and sunitinib combination in advanced soft tissue sarc c2020 110 v83 aBACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).
METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).
RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).
CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.
10aAdult10aAged10aAntineoplastic Agents, Immunological10aFemale10aHumans10aMale10aMiddle Aged10aNivolumab10aSarcoma10aSunitinib10aYoung Adult1 aMartin-Broto, Javier1 aHindi, Nadia1 aGrignani, Giovanni1 aMartinez-Trufero, Javier1 aRedondo, Andres1 aValverde, Claudia1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aD'Ambrosio, Lorenzo1 aGutierrez, Antonio1 aPerez-Vega, Herminia1 aEncinas-Tobajas, Victor1 ade Alava, Enrique1 aCollini, Paola1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aCarrasco-Garcia, Irene1 aLopez-Alvarez, Maria1 aMoura, David, S1 aLopez-Martin, Jose, A uhttps://www.clinbioinfosspa.es/content/nivolumab-and-sunitinib-combination-advanced-soft-tissue-sarcomas-multicenter-single-arm04661nas a2200625 4500008004100000022001400041245010700055210006900162260001200231300001200243490000700255520277400262653000903036653001103045653002203056653001103078653001403089653000903103653001603112653002403128653001403152653002403166653003003190653001603220653004903236653002803285653001703313653001803330100002503348700001903373700001903392700001903411700001703430700001603447700002003463700002103483700002203504700003403526700002003560700002403580700002303604700001903627700002003646700002003666700002503686700002303711700002203734700002003756700002903776700003203805700002103837700002003858700002403878856013303902 2020 eng d a1474-548800aPazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of typical solitary fibrous tumours a mu c2020 03 a456-4660 v213 aBACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.
METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.
FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).
INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.
FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
10aAged10aFemale10aFollow-Up Studies10aHumans10aIndazoles10aMale10aMiddle Aged10aNeoplasm Metastasis10aPrognosis10aProspective Studies10aProtein Kinase Inhibitors10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Rate1 aMartin-Broto, Javier1 aCruz, Josefina1 aPenel, Nicolas1 aLe Cesne, Axel1 aHindi, Nadia1 aLuna, Pablo1 aMoura, David, S1 aBernabeu, Daniel1 ade Alava, Enrique1 aLopez-Guerrero, Jose, Antonio1 aDopazo, Joaquin1 aPeña-Chilet, Maria1 aGutierrez, Antonio1 aCollini, Paola1 aKaranian, Marie1 aRedondo, Andres1 aLopez-Pousa, Antonio1 aGrignani, Giovanni1 aDiaz-Martin, Juan1 aMarcilla, David1 aFernandez-Serra, Antonio1 aGonzalez-Aguilera, Cristina1 aCasali, Paolo, G1 aBlay, Jean-Yves1 aStacchiotti, Silvia uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-typical-solitary-fibrous-tumours-multicentre-single-arm-phase-2-trial05186nas a2200661 4500008004100000022001400041245013800055210006900193260001200262300001200274490000700286520316900293653001003462653000903472653002803481653002603509653001103535653001103546653001403557653000903571653001603580653002603596653001603622653004903638653002603687653002803713653001703741653002203758100002503780700002403805700002503829700002003854700002103874700002203895700002103917700002203938700002303960700002003983700002404003700002204027700002204049700001804071700001904089700003004108700002904138700002304167700001804190700002904208700002404237700001704261700001504278700002004293700002704313700001804340700002004358700001904378856012704397 2019 eng d a1474-548800aPazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of advanced malignant and dedifferentiat c2019 01 a134-1440 v203 aBACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.
METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.
FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).
INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.
FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
10aAdult10aAged10aAngiogenesis Inhibitors10aAntineoplastic Agents10aFemale10aHumans10aIndazoles10aMale10aMiddle Aged10aMultivariate Analysis10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSoft Tissue Neoplasms10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Analysis1 aMartin-Broto, Javier1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aRedondo, Andres1 aBernabeu, Daniel1 ade Alava, Enrique1 aCasali, Paolo, G1 aItaliano, Antoine1 aGutierrez, Antonio1 aMoura, David, S1 aPeña-Chilet, Maria1 aDiaz-Martin, Juan1 aBiscuola, Michele1 aTaron, Miguel1 aCollini, Paola1 aRanchere-Vince, Dominique1 aDel Muro, Xavier, Garcia1 aGrignani, Giovanni1 aDumont, Sarah1 aMartinez-Trufero, Javier1 aPalmerini, Emanuela1 aHindi, Nadia1 aSebio, Ana1 aDopazo, Joaquin1 aTos, Angelo, Paolo Dei1 aLeCesne, Axel1 aBlay, Jean-Yves1 aCruz, Josefina uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-advanced-malignant-and-dedifferentiated-solitary-fibrous-tumour