Claire Cropet

Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial.

BACKGROUNDnGastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib followed by sunitinib and regorafenib is the standard sequence of treatment for advanced disease. Pazopanib is effective in soft tissue sarcomas but has never been assessed in advanced GIST in a randomised trial. We aimed to assess the efficacy and safety of pazopanib in patients with previously treated advanced GIST.nnnMETHODSnIn this randomised, open-label phase 2 study, we enrolled adults (aged ≥18 years) with advanced GIST resistant to imatinib and sunitinib from 12 comprehensive cancer centres or university hospitals in France and randomly assigned them 1:1 using an interactive web-based centralised platform to 800 mg oral pazopanib once daily in 4-week cycles plus best supportive care or best supportive care alone. Randomisation was stratified by the number of previous treatment regimens (2 vs ≥3); no-one was masked to treatment group allocation. Upon disease progression, patients in the best supportive care group were allowed to switch to pazopanib as compassionate treatment. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat. All randomised participants who received at least one dose of pazopanib were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01323400.nnnFINDINGSnBetween April 12, 2011, and Dec 9, 2013, 81 patients were enrolled and randomly assigned to pazopanib plus best supportive care (n=40) or best supportive care alone (n=41). The median follow-up was 26·4 months (IQR 22·0-37·8) in the pazopanib plus best supportive care group and 28·9 months (22·0-35·2) in the best supportive care group. 4-month investigator-assessed progression-free survival was 45·2% (95% CI 29·1-60·0) in the pazopanib plus best supportive care group versus 17·6% (7·8-30·8) in the best supportive care group (hazard ratio [HR] 0·59, 95% CI 0·37-0·96; p=0·029). Median progression-free survival was 3·4 months (95% CI 2·4-5·6) with pazopanib plus best supportive care and 2·3 months (2·1-3·3) with best supportive care alone (HR 0·59 [0·37-0·96], p=0·03). 36 (88%) of the patients originally assigned to the best supportive care group switched to pazopanib following investigator-assessed disease progression; these patients had a median progression-free survival from pazopanib initiation of 3·5 months (95% CI 2·2-5·2). 55 (72%) of the 76 pazopanib-treated patients had pazopanib-related grade 3 or worse adverse events, the most common of which was hypertension (15 [38%] in the pazopanib plus best supportive care group and 13 [36%] in the best supportive care group). 20 (26%) patients had pazopanib-related serious adverse events (14 [35%] in the pazopanib plus best supportive care group and six [17%] in the best supportive care group), including pulmonary embolism in eight (9%) patients (five [13%] in the pazopanib plus best supportive care group and three [7%] in the best supportive care group). Three pazopanib-related deaths occurred (two pulmonary embolisms [one in each group] and one hepatic cytolysis [in the best supportive care group]). Three adverse event-related but not pazopanib-related deaths occurred in the best supportive care group after switch to pazopanib; these deaths were from hyperammonaemic encephalopathy, pneumopathy, and respiratory failure.nnnINTERPRETATIONnPazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GIST resistant to imatinib and sunitinib, with a toxicity profile similar to that reported for other sarcomas. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients.nnnFUNDINGnGlaxoSmithKline, French National Cancer Institute, EuroSARC (FP7-278742), Centre Léon Bérard.

The off-label use of targeted therapies in sarcomas: the OUTC'S program.

BackgroundFew targeted therapies (TTs) are registered for sarcoma treatment despite numerous phase II studies and yet there are potential treatment options for patients after standard treatment escape. The French Sarcoma Group - Bone Tumor Study Group (GSF-GETO) created a national registry to evaluate the outcome of patients treated with off-label TTs.MethodsEvery consecutive sarcoma-patient receiving an off-label TT outside a clinical trial was included. The objective was to describe this patient efficacy and safety data in routine practice.ResultsFrom October 2008 to October 2011, 249 patients in 24 centers received 278 treatment lines with TTs. Twenty-five histological subtypes were included: most frequent were leiomyosarcoma (n = 48, receiving sorafenib in 63%, and sunitinib in 27%), GIST (n = 39, receiving sorafenib in 79%), and angiosarcoma (n =18, receiving sorafenib in 78%). The overall response rate to TTs was 15% (95% CI [10,6-20,2]), the disease control rate at 2xa0months was 59%. The median progression-free survival was 4,1xa0months (IC 95% [3,2-4,8]). Three complete responses were observed. No toxic death occurred, grade 3 and 4 toxicities were reported in 74 (27%) and 14 patients (5%) respectively.ConclusionOff-label TTs can be used for sarcoma patients in routine practice with an acceptable toxicity profile and efficacy similar to that reported in non-randomized clinical trials.

Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort)

Purpose The outcome of sarcoma has been suggested in retrospective and non-exhaustive studies to be better through management by a multidisciplinary team of experts and adherence to clinical practice guidelines (CPGs). The aim of this prospective and exhaustive population based study was to confirm the impact of adherence to CPGs on survival in patients with localized sarcoma. Experimental design Between 2005 and 2007, all evaluable adult patients with a newly diagnosis of localized sarcoma located in Rhone Alpes region (n = 634), including 472 cases of soft-tissue sarcoma (STS), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed by multivariate Cox model in this cohort. Results The median age was 61 years (range 16–92). The most common subtypes were liposarcoma (n = 133, 28%), unclassified sarcoma (n = 98, 20.7%) and leiomyosarcoma (n = 69, 14.6%). In the initial management phase, from diagnosis to adjuvant treatment, the adherence to CPGs for patients with localized STS was 36% overall, corresponding to 56%, 85%, 96% and 84% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. Adherence to CPGs for surgery was the strongest independent prognostic factor of PFS, along with age, gender, grade, and tumor size. For OS, multivariate analysis adherence to CPGs for surgery was a strong independent prognostic factor, with an important interaction with a management in the regional expert centers. Conclusions This study demonstrates impact of CPGs and treatment within an expert center on survival for STS patients in a whole population-based cohort.

Burden of HIV-associated histoplasmosis compared with tuberculosis in Latin America: a modelling study

BACKGROUNDnFungal infections remain a major contributor to the opportunistic infections that affect people living with HIV. Among them, histoplasmosis is considered neglected, often being misdiagnosed as tuberculosis, and is responsible for numerous deaths in Latin America. The objective of this study was to estimate the burden of HIV-associated histoplasmosis compared with tuberculosis in Latin American countries.nnnMETHODSnFor this modelling study, we estimated prevalence of previous exposure to Histoplasma capsulatum, HIV-associated histoplasmosis annual incidence, and number of deaths in 2012 in Latin American countries based on historical histoplasmin skin test studies in the general population, with an antigen dilution level of more than 1/10. Studies were identified in a literature search. Data on HIV-associated tuberculosis were extracted from the WHO notifications and outcomes tables and data on people living with HIV were extracted from the UNAIDS report for the year 2012. We systematically propagated uncertainty throughout all the steps of the estimation process.nnnFINDINGSnAmong 1310 articles identified as of June 1, 2015, 24 articles were included in the study, representing 129 histoplasmin skin test studies led in the general population of Latin American countries. For the year 2012, we estimated a range of 6710 (95% CI 5680-7867) to 15u2008657 (13u2008254-18u2008357) cases of symptomatic HIV-associated histoplasmosis in Latin America. Hotspot areas for histoplasmosis prevalence (>30%) and incidence (>1·5 cases per 100 people living with HIV) were Central America, the northernmost part of South America, and Argentina. According to realistic scenarios, we estimated a range of 671 (95% CI 568-787) to 9394 (7952-11u2008014) deaths related to histoplasmosis, compared with 5062 (3777-6405) deaths related to tuberculosis reported in Latin America.nnnINTERPRETATIONnOur estimates of histoplasmosis incidence and deaths are high and consistent with published data. For the first time, the burden of histoplasmosis is estimated to be equivalent in incidence and even higher in deaths when compared with tuberculosis among people living with HIV in Latin America.nnnFUNDINGnNone.

Descriptive epidemiology of suicide attempts and suicide in the remote villages of French Guiana

ObjectiveThe overall rate of suicide in French Guiana is estimated at 6 per 100,000, a rate that is lower than in mainland France. Given the frequent reports of suicide in Amerindian communities, our hypothesis was that this figure fails to capture a more contrasted reality. Our objective was to refine estimates and determine suicide rates in remote villages of French Guiana.MethodsWe included patients for whom a suicide attempt or suicide was mentioned in medical records. The Health centers were grouped into two zones according to geographical remoteness.ResultsThe highest suicide rates observed in the remote Amerindian villages of Camopi and Trois Sauts were, respectively, 118 and 78/100,000. The median age at the time of suicide was significantly younger in remote zones [23xa0years (95% CI 21.59–25.06)] than in non-remote zones—[27xa0years (95% CI 24.47–29.31)]. The most frequent methods were hanging (78%) and intoxication (22%).ConclusionsThe suicide rate in remote areas in French Guiana was eight times higher than in France. The suicide of young people in remote areas in French Guiana and specifically in Amerindian villages must be better understood and prevented with contextualized and adapted care.

Factors associated with sexual risk taking behavior by precarious urban migrants in French Guiana

BackgroundFrench Guiana is highly affected by HIV. The migrant population is particularly susceptible. The objective of this study was to evaluate the level of risk of HIV transmission and its perception among migrants in French Guiana and to identify predictive factors.MethodsAn HIV/AIDS Knowledge, Attitudes, Behaviors and Practices study was conducted in 2012 among migrants living in precarious neighborhoods of French Guiana.ResultsOf the 1039 participants surveyed, 893 were analyzed, of which 35.6% had risky sex during the past 12xa0months. Sexual risk taking was higher among the migrant population than in the general population. The predictors of sexual risk taking behavior were: younger age groups, males, having a job, not living with a spouse, having first had sex before age 16, using alcohol or drugs before sex, and having engaged in commercial sex recently. The factors associated with not being aware of one’s risk were: being a woman, being from Guyana or Suriname, non-systematic use of condoms with a regular partner, and never or not recently having been tested for HIV.ConclusionsThe results suggest there is still a need for information on HIV risks in a highly vulnerable population.

Epidemiology of Human Leptospirosis in French Guiana (2007–2014): A Retrospective Study

Leptospirosis is a worldwide zoonotic bacterial infection with a rising incidence. French Guiana is mostly covered by Amazonian rain forest. Despite a potentially favorable environment, leptospirosis has been barely studied in French Guiana. The objective of this study was to describe the current trends of leptospirosis epidemiology in French Guiana. A cross-sectional study was performed in the two main hospitals of French Guiana. Cases of leptospirosis from 2007 to 2014 were retrospectively identified with a systematic screening of serological and polymerase chain reaction results to classify them as confirmed, probable, or excluded cases. Medical files were reviewed to collect epidemiological data. Among the 72 included patients, 55 (76.4%) cases were confirmed and 17 (23.6%) were probable. The median age was 39 years (range: 16-82 years) and the M/F sex ratio 6.2. Sixty-two (86.1%) patients required hospitalization, including 12 (16.7%) in the intensive care unit. Three (4.2%) patients died. The monthly distribution of cases was correlated with rainfall (P = 0.004) and moisture (P = 0.038). Professional exposure was frequently identified (especially gold mining and construction). Among 16 different serogroups identified by microagglutination test, Icterohaemorrhagiae was the most frequent (38.0%). This study revealed an epidemiology close to that observed in Brazilian regions, and professional and climatic risk factors. The high diversity of serogroups may reveal a complex environmental reservoir requiring further investigations. Only 20% of leptospirosis patients were suspected as such on hospital admission, thus emphasizing the need to inform local physicians.

Abstract CT333: Elypse-7: A randomized, placebo-controlled, Phase 2a evaluating the impact of IL-7 immunotherapy on CD4 count, risks of severe haematological toxicity and tumor progression in metastatic breast cancer patients

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnBackground: Total and CD4 lymphopenia is observed in 25% of advanced cancers patients and is a predictive factor of chemotherapy (CT)-induced death, febrile neutropenia, thrombocytopenia, anemia, as well as an independent prognostic factor for survival and tumor progression. CYT107 is a glycosylated recombinant human IL-7 (CYTHERIS, France) emerging as a promising immuno-restorative agent well tolerated in Phase 1 trials. To date, it is unknown whether IL-7 can correct lymphopenia during CT and whether this could translate into clinical benefit in advanced cancer patients.nnMethods: A placebo-controlled, monocentric, Phase 2a ([NCT01368107][1]) was conducted in lymphopenic metastatic breast cancer (MBC) patients to be treated by capecitabine (2500mg/m2/d, pers os, 21-day cycle from D21 after randomization). Using a 2x2 factorial design, patients were randomly allocated to 4 arms to receive 1) before the 1st cycle of CT : r-hIL-7 (CYT107:10µg/kg, subcutaneously, weekly at D0, D7, D14, groups 2 & 4) or placebo (groups 1 & 3), then 2) during the 3rd cycle of CT: r-hIL-7 (weekly at D57, D64, D71, groups 3 & 4) or placebo (groups 1 & 2). The primary endpoint, CD4 count evolution, was evaluated before (D0 to D21) and during CT (D57 to D78). Secondary endpoints include risks of severe hematological AE, safety and progression free survival (PFS). An ancillary study has evaluated the quantitative and functional changes in circulating immune cells (see abstract Menetrier-Caux).nnResults: From Nov. 2011 to Jun. 2013, 20 patients (median age [range]: 60 [39-76 y.]; median CD4 count on D0: 242 [22-522 cells/µL]) with MBC (mainly with bone and liver metastasis) were enrolled. Before CT (n=20), r-hIL-7 treatment induced a significant increase of CD4 count (median relative evolution: +148.1% [41.8-763.9 cells/µL] in r-hIL-7 groups vs +9.9% [-50.3-102.2 cells/µL] in placebo [Wilcoxon, p=0.002]). During CT (n=11), r-hIL-7 treatment also increased CD4 count (+58.6%[-15.2-281.5 cells/µL] in r-hIL-7 groups vs -2.4% [-27.6-112.5 cells/µL] in placebo [p=0.121]). Overall, r-hIL-7 was well tolerated with reactions related to injection as the main specific AE, no binding or neutralizing antibodies, and no r-hIL-7-related ≥ Grade 3 AE except 1 fatal SAE for which one a relationship to r-hIL-7 cannot be ruled out. Interestingly, r-hIL-7 treatment during CT reduced the incidence of Grade 3 hematological AE compared to placebo (0 vs 5 events, respectively). PFS data will be available by Feb. 2014.nnConclusion: In this exploratory trial, r-hIL-7 treatment was safe at biologically active dose, able to correct CD4 lymphopenia and associated with lower incidence of severe hematological toxicity during CT. These early results are encouraging and warrant further investigations of IL-7 clinical applications in the oncology field.nnCitation Format: Ray-Coquard Isabelle, Olivier Tredan, Gwenaele Garin, Christine Menetrier-Caux, Sylvie Chabaud, Thomas Bachelot, Claire Cropet, Pierre-Etienne Heudel, Paul Rebattu, Patricia Dupont, Estelle Verronese, Anne-claire Cadore, Valerie Fouillat, Olfa Derbel, Nathalie Bonnin, Therese Croughs, Michel Morre, Nicolas Pasqual, Manuari Manuel, Gilles Clapisson, Christophe Caux, David Perol, Jean-Yves Blay. Elypse-7: A randomized, placebo-controlled, Phase 2a evaluating the impact of IL-7 immunotherapy on CD4 count, risks of severe haematological toxicity and tumor progression in metastatic breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT333. doi:10.1158/1538-7445.AM2014-CT333nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01368107&atom=%2Fcanres%2F74%2F19_Supplement%2FCT333.atom

Abstract 2574: Interleukin-7 (CYT107) treatment in lymphopenic 1st line metastatic breast carcinoma patients treated with chemotherapy regimen (Capecitabine) favors the restoration of T-cell subsets number

Introduction: We previously showed that T ( Methods: Lymphocytes, NK, monocytes and DC subpopulations quantification and functional competence after reactivation (PMA/ionomycin, TLR7/8-Ligand) were assessed by multiparametric flow-cytometry (surface markers/ intracytoplasmic cytokines) on fresh whole blood (D0, D21, D57, D78, EOS). Impact of CYT107 treatment before (D0-D21) or during (D57-D78) chemotherapy on immune parameters was assessed. Results: At inclusion, 20 patients presented strong quantitative alteration of all lymphocytes subsets compared to a healthy donor women cohort (n=30). Inflammatory monocytes (infl-Mo) and DC subsets were quantitatively reduced. CD4 CD45R0 + T (IFNγ/IL-2), Tγδ cells and NK (IFNγ) cytokine productions were altered independently of quantitative alterations highlighting the importance to assess both. Pre-chemotherapy, CYT107 significantly increased CD3 T cell absolute number (median relative evolution: CYT107+128.5%[39;606cells/µL] vs placebo +1.6%[-34;85cells/µL], p=0.002) involving both CD4 (p=0.002) or CD8 (p=0.006) T cells and naive (CD4:p=0.005 and CD8:p -3 ) and memory subsets (CD4:p -3 and CD8:p=0.008). CYT107 pre-chemotherapy induced a Treg number increase (p=0.017) remaining however in the normal range. In contrast, B cells, infl-Mo, DC and NK absolute numbers were not significantly modified. During chemotherapy (D57-D78, n=11), T cell absolute number increases in CYT107 group vs placebo (median relative evolution: CYT107 +61.5%[-11.1;229.7cells/µL] vs placebo -0.5%[-30.7;73.5cells/µL], p=0.083), CD4 and CD8 subsets being affected and in particular CD8 naive(median relative evolution: CYT107 +75.8%[39.0;314.6cells/µL] vs placebo -0.6%[-18.7;48.4cells/µL], p=0.022) and memory subsets (median relative evolution: CYT107 +72.1%[-21.9;282.7cells/µL] vs placebo -8.6%[-43.3;32.8cells/µL], p=0.055). Of importance, no significant modulation of immune cells functional competence was observed upon CYT107 treatment. Conclusion: CYT107 administered before chemotherapy, increases all T cell subsets absolute number but no other compartments without affecting their functional responses. Interestingly, during chemotherapy, CYT107 induces an increase of CD8 memory cells, known to play a role in long lasting defense against tumors. Citation Format: Christine Menetrier-Caux, Isabelle Ray-Coquard, Claire Cropet, Estelle Verronese, Thomas Bachelot, Olivier Tredan, Gwenaelle Garin, Pierre Heudel, Axelle N9Kodia, Ana Delgado, Christine Bardin-Dit-Courageot, Chantal Rigal, Gilles Clapisson, Sylvie Chabaud, David Perol, Paul Rebattu, Therese Croughs, Nicolas Pasqual, Manuarii Manuel, Michel Morre, Jean-Yves Blay, Christophe Caux. Interleukin-7 (CYT107) treatment in lymphopenic 1 st line metastatic breast carcinoma patients treated with chemotherapy regimen (Capecitabine) favors the restoration of T-cell subsets number. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2574. doi:10.1158/1538-7445.AM2014-2574