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Finn R.S.,University of California at Los Angeles | Crown J.P.,Irish Cooperative Oncology Research Group | Lang I.,Orszagos Onkologiai Intezet | Boer K.,Szent Margit Korhaz | And 14 more authors.
The Lancet Oncology | Year: 2015

Background: Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. Methods: In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2·5 mg daily or continuous oral letrozole 2·5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409. Findings: Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29·6 months [95% CI 27·9-36·0] for the palbociclib plus letrozole group and 27·9 months [25·5-31·1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10·2 months (95% CI 5·7-12·6) for the letrozole group and 20·2 months (13·8-27·5) for the palbociclib plus letrozole group (HR 0·488, 95% CI 0·319-0·748; one-sided p=0·0004). In cohort 1 (n=66), median progression-free survival was 5·7 months (2·6-10·5) for the letrozole group and 26·1 months (11·2-not estimable) for the palbociclib plus letrozole group (HR 0·299, 0·156-0·572; one-sided p<0·0001); in cohort 2 (n=99), median progression-free survival was 11·1 months (7·1-16·4) for the letrozole group and 18·1 months (13·1-27·5) for the palbociclib plus letrozole group (HR 0·508, 0·303-0·853; one-sided p=0·0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. Interpretation: The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. © 2015 Elsevier Ltd.


Grant
Agency: European Commission | Branch: FP7 | Program: NoE | Phase: HEALTH.2010.2.4.1-2 | Award Amount: 15.56M | Year: 2011

Europe has a number of advantages as regards developing translational cancer research, yet there is no clear European strategy to meet the increasing burden posed by cancer. The FP6 Eurocan\Plus project analysed the barriers underlying the increasing fragmentation of cancer research and stressed the need to improve collaboration between basic/preclinical and comprehensive cancer centres (CCCs), institutions in which care and prevention is integrated with research and education. Furthermore, it proposed the creation of a platform of interlinked cancer centres with shared infrastructures and collaborative projects to facilitate rapid advances in knowledge, and their translation into better cancer care. In response to these challenges and in line with the call, EurocanPlatform will work towards the goal of decreasing cancer mortality by dealing with three main areas of strategic research: prevention, early detection and improved treatments. It will build the necessary resources and know-how for the entire research continuum: basic research, early and late translational research, clinical research, epidemiological research, implementation in care and population based outcome research. There will be a strong focus on discovery-driven translational cancer research in five selected tumours: breast, head-neck, lung, malignant melanoma and pancreatic cancer. Joint structures and programmes for early detection will contribute to optimal treatment, and novel prevention research programmes will integrate prevention activities in clinical cancer centres as well as public prevention. Collaborations will also include molecular pathway-driven clinical research supported by joint structures for omics, biobanking and biomarker validation to support clinical trials aimed at enhancing patient benefits by individualised treatments. EurocanPlatform is unique in its nature and represents a commitment from cancer centres to join forces and resources in order to fight cancer.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.75M | Year: 2015

Many tumor cells are characterized by the overexpression of certain antigens. Molecules that specifically recognize these structures are suitable as homing devices in tumor therapy. Conjugates of anticancer drugs with such a delivery vector targeting tumors would be a magic bullet according to the Nobel laureate Paul Ehrlich. Three antibody-drug conjugates (ADC) have already been approved for anticancer therapy. However, ADC have e.g. limitations with respect to tumor penetration, high manufacturing costs, and require challenging conjugation chemistry. Peptide-drug conjugates can have a high drug loading, easily penetrate tissue, and can be easily prepared in a homogenous form with straightforward and well-defined conjugation chemistry. The ETN MAGICBULLET will focus on chemistry-driven approaches toward conjugates between peptides (delivery vectors) that recognize tumors and anticancer drugs (payloads or warheads) in order to selectively fight cancer, a topic with a high demand of research activities. The ETN will develop and validate an array of new peptide-drug conjugates combining either known tumor-specific peptides or newly discovered tumor-homing peptides with potent cytotoxic drugs. The tumor-selective peptides are designed for cellular uptake mediated either by endocytosis or by cell-penetrating peptides. The consortium of the ETN MAGICBULLET covers tumor biology, biochemistry, pharmacology, synthetic chemistry, medicinal chemistry, spectroscopy, conformational analysis, and computational chemistry. The training program focuses on multidisciplinary research to explore and validate molecular targets for innovative treatment or investigations on the molecular mechanisms in organ-specific metastatic growth processes. It aims at scientific multilingualism and relies e.g. on concerted learning, a combination of introductory training, hands-on learning on the bench, teaching by peers, and training in additional skills.


Grant
Agency: European Commission | Branch: H2020 | Program: ERA-NET-Cofund | Phase: HCO-08-2014 | Award Amount: 22.57M | Year: 2015

Cancer is a worldwide health burden and represents a major public health challenge in Europe. It is responsible for 25% of all deaths, being the second most common cause of death after cardio-vascular diseases and the main cause of mortality among people aged 4564. Today, an estimated 9 million individuals in Europe live with cancer (Globocan 2008, http://globocan.iarc.fr/). Cancer became a chronic disease which contributed substantially to the growth of medical expenditures and constitutes a major socio-economic challenge for Europe as well as globally. A rapid and effective bidirectional transfer of relevant cancer research findings between bench and bedside would play a pivotal role in addressing top-priority needs at the EU level to reduce incidence and mortality of malignancies and to improve the quality of life of cancer patients. The proposed ERA-NET Cofund TRANSCAN-2, in continuity with the preceding and ongoing TRANSCAN ERA-NET, aims at linking translational cancer research funding programmes in 15 Member States, 3 Associated Countries, and a third country. By concentrating transnational resources, TRANSCAN-2 will provide a critical financial and scientific mass for tackling large-scale problems, relevant for improving translational cancer research globally. A co-funded joint transnational call (JTC) will be launched focusing on the topic Intratumour heterogeneity in resistance to therapy and recurrence followed by three additional JTCs that will be implemented in a frame of multinational translational cancer research programmes. In addition, strategies will be developed for the enlargement of the network, for improvement of coordination and for an efficient communication and dissemination of the results of the consortium as well as of the research projects funded through the JTCs. The monitoring of the projects funded through the JTCs and the critical assessment of the performance of TRANSCAN-2, based on key indicators, will be also realised.


Grant
Agency: European Commission | Branch: FP7 | Program: CSA-CA | Phase: HEALTH.2010.2.4.1-1 | Award Amount: 2.42M | Year: 2011

Cancer is a worldwide health burden and a major public health challenge in Europe, responsible for 25% of all deaths; a situation expected to worsen with population ageing. The strengthening of translational cancer research is an urgent need in European cancer research, i.e. the integration of basic, epidemiological, preclinical and clinical research with the implementation and evaluation of interventions in prevention, diagnosis, prognosis, treatment and care. The proposed ERA-NET TRANSCAN aims at linking translational cancer research funding programmes in 19 Member States and Associated Countries. By concentrating transnational resources TRANSCAN will provide a critical financial and scientific mass for tackling large scale problems, relevant for improving translational cancer research in each Member State or Associated Country as well as overall in Europe. The objectives of TRANSCAN will be achieved through interconnected activities, structured into six work packages (WP) and facilitated by the project coordination and management (WP1). A survey and analysis of national cancer research funding (WP2) will provide a comprehensive picture of the nature and extent of translational cancer research funding in the EU. Based on this knowledge, TRANSCAN will identify gaps in and opportunities for coordinated translational research, and will thus contribute to the development of a coordinated funding research policy shared by European countries. Based also on the outcome of these activities, three joint transnational calls for multinational translational cancer research programmes will be designed (WP3) and implemented (WP4). In this context, training programmes/activities of multi-disciplinary translational cancer research teams will be supported (WP5). The TRANSCAN performance will be monitored and confronted with the partners expectations, and a sustainability plan for the network beyond TRANSCAN will be elaborated (WP6), contributing to the building of a pan-European platform for translational cancer research.


Robert C.,CNRS Gustave Roussy Institute | Dummer R.,UniversitatsSpital Zurich | Gutzmer R.,Medizinische Hochschule Hanover | Lorigan P.,Christie NHS Foundation Trust | And 8 more authors.
The Lancet Oncology | Year: 2013

Background: Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. Methods: This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m2 on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. Findings: Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2-15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6-14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67-1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47-0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9-5·9) versus 3·0 months (2·8-4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). Interpretation: Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. Funding: AstraZeneca. © 2013 Elsevier Ltd.


Ajani J.A.,University of Texas M. D. Anderson Cancer Center | Rodriguez W.,Institute Oncologia y Radioterapia Clinica Ricardo Palma | Bodoky G.,Sumy Regional Oncology Center | Moiseyenko V.,Hospital Nacional Edgardo Rebagliati Martins | And 3 more authors.
Journal of Clinical Oncology | Year: 2010

Purpose: Patients with advanced gastric or gastroesophageal adenocarcinoma need more efficacious and safer treatments than established today. S-1, a contemporary oral fluoropyrimidine, can provide that advantage. Patients and Methods: This study was conducted in 24 countries and 146 centers. One thousand fifty-three patients were stratified (center, number of metastatic sites, prior adjuvant therapy, and measurable cancer) and randomly assigned. Patients received either S-1 at 50 mg/m2divided in two daily doses for 21 days and cisplatin at 75 mg/m2intravenously on day 1, repeated every 28 days (527 patients) or infusional fluorouracil at 1,000 mg/m2/24 hours for 120 hours and cisplatin at 100 mg/m2intravenously on day 1, repeated every 28 days (526 patients). The primary end point was superiority in overall survival (OS) from cisplatin/S-1 compared with cisplatin/infusional fluorouracil in patients with advanced, untreated gastric, or gastroesophageal adenocarcinoma. The secondary end points were response rate, progression-free survival, time to treatment failure, and safety. Results: The median OS was 8.6 months in the cisplatin/S-1 arm and 7.9 months in the cisplatin/infusional fluorouracil arm (HR, 0.92; 95% CI, 0.80 to 1.05; P = .20). Significant safety advantages were observed in the cisplatin/S-1 arm compared with the cisplatin/infusional fluorouracil arm for the rates of grade 3/4 neutropenia (32.3% v 63.6%), complicated neutropenia (5.0% v 14.4%), stomatitis (1.3% v 13.6%), hypokalemia (3.6% v 10.8%), and treatment-related deaths (2.5% v 4.9%; P < .05). Conclusion: Cisplatin/S-1 did not prolong OS of patients with advanced gastric or gastroesophageal adenocarcinoma compared with cisplatin/infusional fluorouracil, but it did result in a significantly improved safety profile. © 2010 by American Society of Clinical Oncology.

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