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Center Regional Of Lutte Contre Le Cancer Francois Baclesse, University of Caen Lower Normandy and Institute Of Cancerologie Of Louest Rene Gauducheau | Date: 2015-03-03

The invention relates to compounds of formula (I), and to their therapeutic use in the treatment of cancer:


Martin L.-A.,Institute of Cancer Research | Andre F.,University Paris - Sud | Andre F.,Institute Gustave Roussy | Campone M.,Institute Of Cancerologie Of Louest Rene Gauducheau | And 2 more authors.
Cancer Treatment Reviews | Year: 2013

Current therapeutic approaches for advanced breast cancer frequently target receptors mediating cell survival and proliferation, such as the estrogen receptor and/or progesterone receptor and human epidermal growth factor receptor-2. Although these approaches are effective for many patients, treatment resistance is common. Therefore, new treatment approaches are needed for patients with advanced breast cancer. Mammalian target of rapamycin is a highly conserved serine-threonine kinase that acts as a major signaling hub that integrates and synergizes with cellular proliferation, survival, and/or motility signals mediated by estrogen receptor, human epidermal growth factor receptor-2, and other receptor tyrosine kinases. Dysregulation of mammalian target of rapamycin signaling occurs in various tumor types, including breast cancer, and has been associated with cancer pathogenesis, disease progression, and treatment resistance. Recent clinical trials show that combined inhibition of mammalian target of rapamycin and estrogen receptor represents an effective strategy for treating hormone receptor-positive advanced breast cancer progressing on nonsteroidal aromatase inhibitor therapy, and data from ongoing trials combining mammalian target of rapamycin inhibition with human epidermal growth factor receptor-2-targeted therapy are awaited. This review focuses on the molecular rationale underlying strategies to enhance sensitivity to treatment in hormone receptor-positive and human epidermal growth factor receptor-2-positive advanced breast cancer, the clinical efficacy of such approaches, and future perspectives. © 2013.


Baselga J.,Harvard University | Campone M.,Institute Of Cancerologie Of Louest Rene Gauducheau | Piccart M.,Institute Jules Bordet | Burris III H.A.,Sarah Cannon Research Institute | And 17 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity. METHODS: In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone- receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed. RESULTS: Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). CONCLUSIONS:Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.


Heinemann V.,Comprehensive Cancer Center der Krebszentrum Munich | Douillard J.Y.,Institute Of Cancerologie Of Louest Rene Gauducheau | Douillard J.Y.,Institute Of Cancerologie Louest Rene Gauducheau | Ducreux M.,Institute Gustave Roussy | And 2 more authors.
Cancer Treatment Reviews | Year: 2013

In metastatic colorectal cancer (mCRC), an improved understanding of the underlying pathology and molecular biology has successfully merged with advances in diagnostic techniques and local/systemic therapies as well as improvements in the functioning of multidisciplinary teams, to enable tailored treatment regimens and optimized outcomes. Indeed, as a result of these advancements, median survival for patients with mCRC is now in the range of 20-24. months, having approximately tripled in the last 20. years. The identification of KRAS as a negative predictive marker for activity of epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), such as panitumumab (Amgen, Thousand Oaks, USA) and cetuximab (ImClone, Branchburg, USA), has perhaps had the greatest impact on patient management. This meant that, for the first time, mCRC patients unlikely to respond to a targeted therapy could be defined ahead of treatment. Ongoing controversies such as whether patients with KRAS G13D- (or BRAF V600-) mutated tumours can still respond to EGFR-targeted mAbs and the potential impact of inter- and intra-tumour heterogeneity on tumour sampling show that the usefulness of KRAS as a biomarker has not yet been exhausted, and that other downstream biomarkers should be considered. Conversely, a predictive biomarker for anti-angiogenic agents such as bevacizumab (Genentech, San Francisco, USA) in the mCRC setting is still lacking. In this review we will discuss the discovery and ongoing investigation into predictive biomarkers for mCRC as well as how recent advances have impacted on clinical practice and ultimately the overall cost of treatment for these patients. © 2013 .


Andre F.,Institute Gustave Roussy | Andre F.,French Institute of Health and Medical Research | Andre F.,University Paris - Sud | Bachelot T.,University of Lyon | And 20 more authors.
The Lancet Oncology | Year: 2014

Background: Breast cancer is characterised by genomic alterations. We did a multicentre molecular screening study to identify abnormalities in individual patients with the aim of providing targeted therapy matched to individuals' genomic alterations. Methods: From June 16, 2011, to July 30, 2012, we recruited patients who had breast cancer with a metastasis accessible for biopsy in 18 centres in France. Comparative genomic hybridisation (CGH) array and Sanger sequencing on PIK3CA (exon 10 and 21) and AKT1 (exon 4) were used to assess metastatic biopsy samples in five centres. Therapeutic targets were decided on the basis of identified genomic alterations. The primary objective was to include 30% of patients in clinical trials testing a targeted therapy and, therefore, the primary outcome was the proportion of patients to whom a targeted therapy could be offered. For the primary endpoint, the analyses were done on the overall population registered for the trial. This trial is registered with ClinicalTrials.gov, number NCT01414933. Findings: 423 patients were included, and biopsy samples were obtained from 407 (metastatic breast cancer was not found in four). CGH array and Sanger sequencing were feasible in 283 (67%) and 297 (70%) patients, respectively. A targetable genomic alteration was identified in 195 (46%) patients, most frequently in PIK3CA (74 [25%] of 297 identified genomic alterations), CCND1 (53 [19%]), and FGFR1 (36 [13%]). 117 (39%) of 297 patients with genomic tests available presented with rare genomic alterations (defined as occurring in less than 5% of the general population), including AKT1 mutations, and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET high-level amplifications. Therapy could be personalised in 55 (13%) of 423 patients. Of the 43 patients who were assessable and received targeted therapy, four (9%) had an objective response, and nine others (21%) had stable disease for more than 16 weeks. Serious (grade 3 or higher) adverse events related to biopsy were reported in four (1%) of enrolled patients, including pneumothorax (grade 3, one patient), pain (grade 3, one patient), haematoma (grade 3, one patient), and haemorrhagic shock (grade 3, one patient). Interpretation: Personalisation of medicine for metastatic breast cancer is feasible, including for rare genomic alterations. Funding: French National Cancer Institute, Breast Cancer Research Foundation, Odyssea, Operation Parrains Chercheurs. © 2014 Elsevier Ltd.


Plummer R.,Northern Center for Cancer Care | Stephens P.,Northern Center for Cancer Care | Aissat-Daudigny L.,Teva Laboratories France | Cambois A.,Cephalon France | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme important in DNA repair. PARP-1 activation at points of DNA strand break results in poly(ADP-ribose) polymer formation, opening the DNA structure, and allowing access of other repair enzymes. CEP-9722 inhibits PARP-1 and PARP-2 and is designed to potentiate DNA-damaging chemotherapies. Methods: This dose-escalating phase 1 study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics/pharmacodynamics of CEP-9722 plus temozolomide in adults with solid tumors. Tumor response was also assessed. Participants received a 14-day cycle of CEP-9722 (days 1 and 3-5 or days 1-5), followed by 28-day cycles of CEP-9722 plus temozolomide 150 mg/m2 on days 1-5. The initial CEP-9722 dose (cohort 1) was 150 mg/day; dose escalation followed a modified Fibonnaci sequence. Results: Twenty-six patients received CEP-9722 150-1,000 mg/day combined with temozolomide. Dose-limiting toxicities of asthenia and persistent weight loss at 1,000 mg/day resulted in 750 mg/day being defined as the MTD and recommended dose for further study. Overall, 24 (92 %) patients had treatment-related adverse events (TRAEs), mostly grade 1 or 2, with nausea, vomiting, and diarrhea having the strongest relation to CEP-9722. Four patients had grade 3 TRAEs (asthenia, myositis, diarrhea, and fatigue). Systemic exposure generally increased with dosage, with high inter- and intra-patient variability at all doses. Pharmacodynamic assessment confirmed PARP inhibition although no dose response was apparent. One patient with melanoma achieved a partial response (1,000 mg/day). Conclusions: CEP-9722 was adequately tolerated with temozolomide; the MTD was 750 mg/day. Only limited clinical activity was observed. © 2014 The Author(s).


Peeters M.,University of Antwerp | Douillard J.Y.,Institute Of Cancerologie Of Louest Rene Gauducheau | Van Cutsem E.,University Hospital Gasthuisberg | Siena S.,Ospedale Niguarda Ca Granda | And 3 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles. Patients and Methods Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis. Results No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS. Conclusion In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC. © 2013 by American Society of Clinical Oncology.


Fumoleau P.,Center Georges Francois Leclerc | Trigo J.M.,Hospital Clinico Universitario Virgen Of La Victoria | Isambert N.,Center Georges Francois Leclerc | Semiond D.,Sanofi S.A. | And 2 more authors.
BMC Cancer | Year: 2013

Background: Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Methods: Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5-12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Results: Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m2, which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in Cmax and AUC0-t were dose proportional for the 6-12 mg/m2 doses. Conclusion: The MTD of weekly cabazitaxel was 12 mg/m2 and the recommended weekly dose was 10 mg/m2. The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens.Trial registration: The study was registered with ClinicalTrials.gov as NCT01755390. © 2013 Fumoleau et al.; licensee BioMed Central Ltd.


Romagnoli M.,Tufts University | Belguise K.,Toulouse 1 University Capitole | Belguise K.,French National Center for Scientific Research | Yu Z.,Tufts University | And 9 more authors.
Cancer Research | Year: 2012

Induction of epithelial-to-mesenchymal transition (EMT) by TGF-β1 requires Ras signaling. We recently identified the transcriptional repressor Blimp-1 (PRDM1) as a downstream effector of the NF-κB, RelB/Bcl-2/Ras-driven pathway that promotes breast cancer cell migration. As the RelB/Blimp-1 pathway similarly required Ras signaling activation, we tested whether Blimp-1 plays a role in TGF-β1-mediated EMT. Here, TGF-β1 treatment of untransformed NMuMG mammary epithelial and MDA-MB-231 breast cancer cells was shown to induce Blimp-1 expression, which promoted an EMT signature and cell migration. TGFB1 and BLIMP1 RNA levels were correlated in patient breast tumors. BLIMP1 gene transcription was activated by TGF-β1 via a c-Raf (RAF1) to AP-1 pathway. Blimp-1 induced expression of the EMT master regulator Snail (SNAI1) via repressing BMP-5, which inhibited Snail expression upon TGF-β1 treatment. Interestingly, a similar cascade was observed during postnatal mouse mammary gland development. RelB expression was detected early in pregnancy followed progressively by Blimp-1 and then Snail; whereas, BMP-5 levels were high in nulliparous and regressing glands. Finally, lower BMP5 RNA levels were detected in patient breast tumors versus normal tissues, and correlated with cancer recurrence. Thus, the Ras effector Blimp-1 plays an essential role in TGF-β1-induced EMT via repression of BMP-5 in breast cancer. ©2012 American Association for Cancer Research.


Pierga J.-Y.,University Pierre and Marie Curie | Pierga J.-Y.,University of Paris Descartes | Petit T.,Center Paul Strauss | Delozier T.,Center Francois Baclesse | And 13 more authors.
The Lancet Oncology | Year: 2012

Background: Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer; however, few data exist for this regimen in inflammatory breast cancer. In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer. Methods: In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged ≥18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, bevacizumab, and trastuzumab (cycles 5-8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological complete response (defined by central review of surgical specimens according to Sataloff classification, counting missing data as failure) and adverse events in all enrolled patients. This study is registered with . ClinicalTrials.gov, number . NCT00717405. Findings: Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had a pathological complete response according to central review (63·5%, 95% CI 49·4-77·5). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3-4 neutropenia, which was the most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure. Interpretation: Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated in patients with previously untreated primary inflammatory breast cancer. Further confirmation of use of bevacizumab in inflammatory breast cancer is needed. Funding: Roche (France). © 2012 Elsevier Ltd.

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