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Murviel-lès-Montpellier, France

Bui-nguyen B.,Institute Bergonie | Ray-coquard I.,Center Leon Berard | Chevreau C.,Institute Claudius Regaud | Penel N.,Center Oscar Lambret | And 9 more authors.
Annals of Oncology | Year: 2012

Background: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients. Patients and methods: Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m 2, day 1-5), ifosfamide (2.5 g/m 2, day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m 2, day 1-4) with PBSC reinjection at day 7. Results: From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity. Conclusion: This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Owens C.,Institute Gustave Roussy | Laurence V.,University Pierre and Marie Curie | Benboubker L.,University of Tours | Defachelles A.-S.,Center Oscar Lambret | And 9 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Background: Phase II trials demonstrate the activity of cisplatin in patients with refractory Ewing sarcoma family tumours (ESFT) and also the feasibility of giving cisplatin with oral VP16 in a variety of different cancers. This trial was conducted to evaluate the activity and toxicity profile of this combination delivered as outpatient therapy in patients with refractory/relapsed ESFT. Methods: Cisplatin was administered on days 1, 8 and 15 and days 29, 36 and 43 (70 mg/m2/dose for patients <21 years of age and 50 mg/m2/dose ≥21 years). VP16 was administered at a dose of 50 mg/m2 on days 1-15 and days 29-43 inclusive. A three-stage Fleming statistical design was used for analysis. Results: Between January 2003 and October 2006, 45 patients aged between 5 and 46 years (median 19) were enrolled. Thirty-eight were evaluable for response. Patients had previously received one to three lines of chemotherapy (median = one). Seventy-three per cent of the patients had grade 3/4 neutropenia, 20 % developed fever, 40 % had grade 3/4 anaemia, 68 % grade 3/4 thrombocytopenia and 16 % grade 2/3 ototoxicity. Measured response after 2 cycles: 0 CR, 7 PR (18 %), 13 SD (34 %), 18 PD (48 %). There was excellent concordance between unidimensional and bidimensional criteria in 31 of 33 responses (94 %). PFS at 1 year was 39 %, with a median PFS of 6 months. Overall survival at 1 year was 44 %; median survival was 11 months. Conclusions: Cisplatin combined with oral VP16 is well tolerated and has acceptable side effects, but limited clinical activity in refractory/relapsed ESFT. © 2012 Springer-Verlag Berlin Heidelberg.

Gravis G.,Institute Paoli Calmettes | Fizazi K.,University Paris - Sud | Joly F.,University of Caen Lower Normandy | Oudard S.,University of Paris Descartes | And 29 more authors.
The Lancet Oncology | Year: 2013

Background: Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer. Methods: In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m2 intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00104715. Findings: Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39-63). Median overall survival was 58·9 months (95% CI 50·8-69·1) in the group given ADT plus docetaxel and 54·2 months (42·2-not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75-1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 [21%]), febrile neutropenia (six [3%]), abnormal liver function tests (three [2%]), and neutropenia with infection (two [1%]). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group. Interpretation: Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer. Funding: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen. © 2013 Elsevier Ltd.

Montpellier University and Center Val Daurelle Paul Lamarque | Date: 2012-05-21

The present invention provides for isolated anti-human-HER3 antibodies or fragments thereof. More particularly the present invention provides an isolated monoclonal antibody that specifically binds to the extracellular domain of HER-3 and competes for binding to the extracellular domain of human HER-3 with the antibody produced obtainable from hybridoma deposited as CNCM-I-4486. The antibodies described in the present invention are useful for the treatment of cancer.

Manceau G.,Paris-Sorbonne University | Manceau G.,University Pierre and Marie Curie | Imbeaud S.,French Institute of Health and Medical Research | Thiebaut R.,IntegraGen | And 26 more authors.
Clinical Cancer Research | Year: 2014

Purpose: To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Experimental Design: miRNA profiling was performed in a training set of 87 patients with mCRC refractory to chemotherapy treated with anti-EGFR antibodies. This included 33 fresh-frozen (FF) and 35 formalin-fixed paraffin-embedded (FFPE) samples retrospectively collected and 19 prospectively collected FF samples. An independent validation cohort consisting of 19 FF and 26 FFPE prospectively collected samples from patients with mCRC treated with anti-EGFR antibodies was used to confirm our findings. Results: After screening the expression of 1,145 miRNAs in FF samples from the training set, we identified that hsa-miR-31-3p expression level was significantly associated with progression-free survival (PFS). Statistical models based on miRNA expression discriminated between high and low risk of progression for both FF and FFPE samples. These models were confirmed in the validation cohort for both FF [HR, 4.1; 95% confidence interval (CI), 1.1-15.3; P < 0.04] and FFPE samples (HR, 2.44; 95% CI, 1.1-5.4; P = 0.028). The percentage of variation of RECIST criteria in the validation series was significantly associated with the expression level of hsa-miR-31-3p ( r2 = 0.49; P = 0.0035) and risk status determined by hsa-miR-31-3p expression level (P = 0.02, Kruskal-Wallis rank test). Nomograms were built and validated to predict PFSdepending on hsa-miR-31-3p expression level. Following in vitro studies, we identified 47 genes regulated by hsa-miR-31-3p. Conclusion: Hsa-miR-31-3p seems to be a new mCRC biomarker whose expression level allows for the identification of patients with wild-type KRAS mCRC who are more likely to respond to anti-EGFR therapy. © 2014 AACR. doi: 10.1158/1078-0432.CCR-13-2750.

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