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Pancreatic Neoplasms: HELP
Articles by Josep Tabernero
Based on 17 articles published since 2009
(Why 17 articles?)
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Between 2009 and 2019, J. Tabernero wrote the following 17 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials). 2014

Bonnetain, Franck / Bonsing, Bert / Conroy, Thierry / Dousseau, Adelaide / Glimelius, Bengt / Haustermans, Karin / Lacaine, François / Van Laethem, Jean Luc / Aparicio, Thomas / Aust, Daniela / Bassi, Claudio / Berger, Virginie / Chamorey, Emmanuel / Chibaudel, Benoist / Dahan, Laeticia / De Gramont, Aimery / Delpero, Jean Robert / Dervenis, Christos / Ducreux, Michel / Gal, Jocelyn / Gerber, Erich / Ghaneh, Paula / Hammel, Pascal / Hendlisz, Alain / Jooste, Valérie / Labianca, Roberto / Latouche, Aurelien / Lutz, Manfred / Macarulla, Teresa / Malka, David / Mauer, Muriel / Mitry, Emmanuel / Neoptolemos, John / Pessaux, Patrick / Sauvanet, Alain / Tabernero, Josep / Taieb, Julien / van Tienhoven, Geertjan / Gourgou-Bourgade, Sophie / Bellera, Carine / Mathoulin-Pélissier, Simone / Collette, Laurence. ·Methodology and Quality of Life Unit in Cancer, EA 3181, University Hospital of Besançon and CTD-INCa Gercor, UNICNCER GERICO, Besançon, France. Electronic address: franck.bonnetain@univ-fcomte.fr. · Leiden University Medical Center, Leiden, Netherlands. · Department of Medical Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France. · Bordeaux Segalen University & CHRU, Bordeaux, France. · Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden. · Department of Radiation Oncology, Leuven, Belgium. · Digestive Surgical Department, Tenon hospital, Paris, France. · Gastro Intestinal Cancer Unit Erasme Hospital Brussels, Belgium. · Gastroenterology Department, Avicenne Hospital, Paris 13, Bobigny, France. · Institute for Pathology, University Hospital Carl-Gustav-Carus, Dresden, Germany. · Surgical and Gastroenterological Department, Endocrine and Pancreatic Unit, Hospital of 'G.B.Rossi', University of Verona, Italy. · Institut de Cancérologie de l'Ouest - Centre Paul Papin Centre de Lutte Contre le Cancer (CLCC), Angers, France. · Biostatistics Unit, Centre Antoine Lacassagne, Nice, France. · Oncology Department, Hôpital Saint-Antoine & CTD-INCa GERCOR, Assistance Publique des Hôpitaux de Paris, UPMC Paris VI, Paris, France. · Gastroenterology Department, Hopital la Timone, Assitance publique des Hopitaux de Marseille, Marseille, France. · Department of Surgery, Institut Paoli Calmettes, Marseille, France. · Department of Surgery, Agia Olga Hospital, Athens, Greece. · Department of Gastroenterology, Institut Gustave Roussy, Villejuif, France. · Biostatistician, Biostatistics Unit, Centre Antoine Lacassagne, Nice, France. · Department of Radiotherapy, Institut fuer Radioonkologie, Vienna, Austria. · Department of Surgical Oncology, Royal Liverpool Hospital, United Kingdom. · Department of Gastroenterology, Beaujon Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France. · Digestive Oncology and Gastro-enterology Department, Jules Bordet Institute, Brussels, Belgium. · Digestive Cancer Registry, INSERM U866, Dijon, France. · Medical Oncology Unit, Ospedali Riuniti di Bergamo, Bergame, Italy. · Inserm, Centre for Research in Epidemiology and Population Health, U1018, Biostatistics Team, Villejuif, France. · Gastroenterology Department, Caritas Hospital, Saarbrücken, Germany. · Department of the Gastrointestinal Tumors and Phase I Unit, Vall d'Hebron University Hospital, Barcelona, Spain. · Statistics Department, EORTC, Brussels, Belgium. · Department of Medical Oncology, Institut Curie, Hôpital René Huguenin, Saint-Cloud, France. · Division of Surgery and Oncology at the University of Liverpool and Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Digestive Surgery, Universitu Hospital Strasbourg, France. · Department of Hepato-pancreatic and Biliary Surgery, Beaujon Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France. · Department of Hepato-gastroenterology and Digestive Oncology, Georges Pompidou European hospital, Paris, France. · Department of Radiation Oncology, Academisch Medisch Centrum, Amsterdam, The Netherlands. · Institut Du Cancer de Montpellier, Comprehensive Cancer Centre, and Data Center for Cancer Clinical Trials, CTD-INCa, Montpellier, France. · Clinical and Epidemiological Research Unit, Institut Bergonie, Comprehensive Cancer Centre, Bordeaux, France; Data Center for Cancer Clinical Trials, CTD-INCa, Bordeaux, France; INSERM, Centre d'Investigation Clinique - Épidémiologie Clinique CIC-EC 7, F-33000 Bordeaux, France. ·Eur J Cancer · Pubmed #25256896.

ABSTRACT: BACKGROUND: Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. METHODS: Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). RESULTS: For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. CONCLUSION: The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

2 Editorial Changing the paradigm in conducting randomized clinical studies in advanced pancreatic cancer: an opportunity for better clinical development. 2009

Tabernero, Josep / Macarulla, Teresa. · ·J Clin Oncol · Pubmed #19858387.

ABSTRACT: -- No abstract --

3 Review TTD consensus document on the diagnosis and management of exocrine pancreatic cancer. 2014

Benavides, M / Abad, A / Ales, I / Carrato, A / Díaz Rubio, E / Gallego, J / García-Foncillas, J / Grávalos, C / Laquente, B / Pericay, C / Rivera, F / Tabernero, J / Aranda, E. ·Hospital Regional Universitario Carlos Haya, Málaga, Spain, manuel.benavides.sspa@juntadeandalucia.es. ·Clin Transl Oncol · Pubmed #24728654.

ABSTRACT: Exocrine pancreatic cancer (PC) is a very aggressive and heterogeneous tumor with several cellular signaling pathways implicated in its pathogenesis and maintenance. Several risk factors increase the risk of developing PC. Therapeutic strategies used are dictated by the extent of disease. Supportive treatment is critical because of the high frequency of symptoms. For localized disease, surgery followed by adjuvant gemcitabine is the standard. Neoadjuvant and new adjuvant chemotherapy regimens are being evaluated. Locally advanced disease should respond best guided by a multidisciplinary team. Various treatment options are appropriate such as chemotherapy alone or chemoradiotherapy with integration of rescue surgery if the tumor becomes resectable. In metastatic disease, chemotherapy should be reserved for patients with ECOG 0-1 using Folfirinox or gemcitabine plus nab-paclitaxel as the most recommended options. Several therapeutic strategies targeting unregulated pathways are under evaluation with an unmet need for biomarkers to guide management.

4 Review [Neuroendocrine tumors: the age of targeted therapies]. 2012

Capdevila, Jaume / Argilés, Guillem / Mulet-Margalef, Nuria / Tabernero, Josep. ·Departamento de Oncología Médica, Hospital Universitario Vall d'Hebron, Barcelona, España. jacapdevila@vhebron.net ·Endocrinol Nutr · Pubmed #22565119.

ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the second most prevalent group of advanced gastrointestinal tract tumors. Resources invested in research on this patient population have exponentially increased in recent years, and this has become one of the most attractive fields for oncological research. Several proangiogenic proteins have been found to be overexpressed in GEP-NETs, including vascular endothelial growth factor and its receptors and the more closely related intracellular signaling pathways such as the epidermal growth factor pathway, type I insulin-like growth factor receptor, and the PI3K-(PTEN)-AKT-mTOR pathway. The recent results of the three most important Phase III studies in GEP-NETs have allowed for approval of two targeted agents, sunitinib and everolimus, for the treatment of patients with pancreatic neuroendocrine tumors after decades of minimal advances in this population.

5 Review A shining light in the darkness for the treatment of pancreatic neuroendocrine tumors. 2011

Capdevila, Jaume / Tabernero, Josep. ·Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. ·Cancer Discov · Pubmed #22586573.

ABSTRACT: SUMMARY: Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summarize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies.

6 Review Consensus on the treatment of pancreatic cancer in Spain. 2009

Hidalgo, M / Abad, A / Aranda, E / Díez, L / Feliu, J / Gómez, C / Irigoyen, A / López, R / Rivera, F / Rubio, C / Sastre, J / Tabernero, J / Díaz-Rubio, E. ·Hospital de Madrid Norte Sanchinarro, Madrid, Spain. mhidalg1jhmi.edu ·Clin Transl Oncol · Pubmed #19451062.

ABSTRACT: Pancreatic cancer (PC) represents one of the greatest oncological challenges of our century, due to its high mortality and incidence. A group of Spanish experts in PC treatment reviewed data available on different therapeutic combinations and established consensus on what would be the best strategy in PC management, depending on the stage of the disease. Surgery with complete resection may produce 5-year survival rates of 18-24%, but definitive control is still precarious. In the absence of consensus, the best evidence suggests that adjuvant chemotherapy with gemcitabine for 6 months using the CONKO-001 regime is the treatment of choice after resection of PC for patients with acceptable functional status. This group recommends chemoradiotherapy (CT-RT) in patients with factors for poor loco-regional prognosis. However, chemotherapy is an option for the treatment of locally advanced PC in patients with good general status and in the absence of metastatic disease the recommended treatment is CT-RT followed by gemcitabine-based chemotherapy. A period of chemotherapy followed by consolidation CT-RT may be appropriate, as it allows selection of patients with locally advanced disease who may benefit most from combined treatment. Erlotinib combined with gemcitabine shows significant survival improvement in PC and must be considered an option in the first-line treatment of advanced and metastatic PC. The gemcitabine-erlotinib combination is proposed as the standard treatment for metastatic PC in patients with PS=/>2. In patients with PS<2, gemcitabine-erlotinib is recommended as the first-line treatment option, supported by a maximum degree of evidence, without ruling out other options, such as gemcitabine-oxaliplatin, gemcitabine-capecitabine or gemcitabine alone.

7 Guideline SEOM clinical guidelines for the treatment of pancreatic cancer. 2011

Gómez-Martín, Carlos / Hidalgo, Manuel / Tabernero, Josep / Isla, Dolores. ·Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain. cgomezm.hdoc@salud.madrid.org ·Clin Transl Oncol · Pubmed #21821486.

ABSTRACT: Pancreatic cancer (PC) is one of the main causes of cancer-related death in the United States and Europe. Due to its poor long-term survival, all patients with PC should undergo a comprehensive evaluation by a Multidisciplinary Tumor Committee to establish the best therapeutic strategy. Pathologic PC diagnosis should be made according to the latest WHO classification of malignant tumours and an accurate staging is crucial to assess resectability, determine the extension and, in some cases, reestablish biliary flow. For patients with localised resectable disease the standard treatment option is radical pancreatic resection. The aim of resection is to obtain microscopically negative margins (R0) and also to resect the drainage lymph nodes. In those cases diagnosed with locally advanced unresectable or metastatic PC, palliative bypass of intestinal or biliary obstruction followed by chemotherapy or chemoradiation remains the main palliative treatment option. Since 1997, gemcitabine monotherapy has been considered the standard of care for advanced PC. In recent years new chemotherapy combinations and targeted agents have demonstrated significant antitumoral activity, increasing the armamentarium that can be used against this lethal disease.

8 Clinical Trial Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer. 2016

Chiorean, E Gabriela / Von Hoff, Daniel D / Tabernero, Josep / El-Maraghi, Robert / Ma, Wen Wee / Reni, Michele / Harris, Marion / Whorf, Robert / Liu, Helen / Li, Jack Shiansong / Manax, Victoria / Romano, Alfredo / Lu, Brian / Goldstein, David. ·Division Oncology, Department of Medicine, University of Washington, 825 Eastlake Avenue E, G4-833, Seattle, WA 98109-1023, USA. · Translational Genomics Research Institute and HonorHealth, 445 North Fifth Street, Suite 600, Phoenix, AZ 85004, USA. · Vall d'Hebron Institute of Oncology (VHIO), P Vall d'Hebron 119-129, Barcelona 08035, Spain. · Royal Victoria Hospital Barrie Canada, 201 Georgian Drive, Barrie, Ontario, Canada L4M 6M2. · Roswell Park Cancer Institute, 665 Elm Street, Buffalo, NY 14203, USA. · San Raffaele Scientific Institute, Via Olgetina 60, 20132 Milan, Italy. · Monash Health, 246 Clayton Road, Melbourne VIC 3168, Australia. · Florida Cancer Specialists, 2401 60th Street Ct W, Bradenton, FL 34209-5500, USA. · Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. · Department of Medical Oncology, Prince of Wales Hospital, South Sydney Illawarra, Barker Street, Sydney NSW 2031, Australia. ·Br J Cancer · Pubmed #27351217.

ABSTRACT: BACKGROUND: This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT). METHODS: Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival. RESULTS: The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment. CONCLUSIONS: These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.

9 Clinical Trial CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. 2016

Chiorean, E G / Von Hoff, D D / Reni, M / Arena, F P / Infante, J R / Bathini, V G / Wood, T E / Mainwaring, P N / Muldoon, R T / Clingan, P R / Kunzmann, V / Ramanathan, R K / Tabernero, J / Goldstein, D / McGovern, D / Lu, B / Ko, A. ·Department of Medicine/Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle gchiorea@uw.edu. · HonorHealth and The Translational Genomics Research Institute (TGen), Scottsdale, USA. · Department of Radiation Oncology, San Raffaele Scientific Institute, Milan, Italy. · Department of Oncology, NYU Langone Arena Oncology, Lake Success. · Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville. · Cancer Center of Excellence, University of Massachusetts Medical School, Worcester. · UAB Comprehensive Cancer Center, Birmingham, USA. · Mater Private Centre for Haematology & Oncology, South Brisbane, Australia. · Department of Oncology, Genesis Cancer Center, Hot Springs, USA. · Southern Medical Day Care Centre, Wollongong, Australia. · Medizinische Klinik und Poliklinik II, University of Wuerzburg, Wuerzburg, Germany. · Medical of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. · Department of Oncology, Prince of Wales Hospital, Sydney, Australia. · Celgene Corporation, Summit, USA. ·Ann Oncol · Pubmed #26802160.

ABSTRACT: BACKGROUND: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. PATIENTS AND METHODS: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. RESULTS: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. CONCLUSION: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.

10 Clinical Trial Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas. 2016

Ramanathan, R K / Goldstein, D / Korn, R L / Arena, F / Moore, M / Siena, S / Teixeira, L / Tabernero, J / Van Laethem, J-L / Liu, H / McGovern, D / Lu, B / Von Hoff, D D. ·Division of Hematology/Oncology, Mayo Clinic, Scottsdale, USA ramanathan.ramesh@mayo.edu. · Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia. · Diagnostic Radiology, Scottsdale Medical Imaging, Ltd, Scottsdale. · Hematology/Oncology, NYU Langone Arena Oncology, Lake Success, USA. · Provencial Health Services Authority, BC Cancer Agency, Vancouver, Canada. · Falck Division of Oncology, Department of Oncology and Hematology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda and Università degli Studi di Millano, Milan, Italy. · Department of Medical Oncology, Hôpital Saint-Antoine, Paris, France. · Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. · University Clinic of Brussels, Hôpital Erasme, Brussels, Belgium. · Biostatistics and Research and Design, Celgene Corporation, Summit. · Clinical Research, Translational Genomics Research Institute and Honor Health, Scottsdale, USA. ·Ann Oncol · Pubmed #26802153.

ABSTRACT: BACKGROUND: In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial. PATIENTS AND METHODS: Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity. RESULTS: PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001). CONCLUSION: Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response. CLINICALTRIALSGOV: NCT00844649.

11 Clinical Trial SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial. 2015

Hidalgo, Manuel / Plaza, Carlos / Musteanu, Monica / Illei, Peter / Brachmann, Carrie B / Heise, Carla / Pierce, Daniel / Lopez-Casas, Pedro P / Menendez, Camino / Tabernero, Josep / Romano, Alfredo / Wei, Xinyu / Lopez-Rios, Fernando / Von Hoff, Daniel D. ·Centro Nacional de Investigaciones Oncologicas, Madrid, Spain. mhidalgo@cnio.es mmusteanu@cnio.es. · Laboratorio de Dianas Terapeuticas, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain. · Johns Hopkins Medical Institutions, Baltimore, Maryland. · Celgene Corporation, Summit, New Jersey. · Centro Nacional de Investigaciones Oncologicas, Madrid, Spain. · Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. · Celgene Corporation, Boudry, Switzerland. · Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona. ·Clin Cancer Res · Pubmed #26169969.

ABSTRACT: PURPOSE: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint. EXPERIMENTAL DESIGN: Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted. RESULTS: SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n = 71) vs. low (n = 185)] was not associated with overall survival (OS; HR, 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy. CONCLUSIONS: SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression.

12 Clinical Trial nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. 2015

Goldstein, David / El-Maraghi, Robert Hassan / Hammel, Pascal / Heinemann, Volker / Kunzmann, Volker / Sastre, Javier / Scheithauer, Werner / Siena, Salvatore / Tabernero, Josep / Teixeira, Luis / Tortora, Giampaolo / Van Laethem, Jean-Luc / Young, Rosemary / Penenberg, Darryl Neil / Lu, Brian / Romano, Alfredo / Von Hoff, Daniel D. ·Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia (DG) · Royal Victoria Regional Health Centre, Barrie, ON, Canada (RHEM) · Hôpital Beaujon, Clichy, France (PH) · Klinikum Grosshadern, University of Munich, Munich, Germany (VH) · Universitätsklinikum Würzburg, Würzburg, Germany (VK) · Hospital Clinico San Carlos, Madrid, Spain (JS) · Medizinische Universität Wien, Wien, Austria (WS) · Ospedale Niguarda Ca' Granda, Milan, Italy (SS) · Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain (JT) · Hôpital Saint Antoine, Paris, France (LT) · Azienda Ospedaliera Universitaria Integrata and University of Verona, Verona, Italy (GT) · Hôpital Erasme, Brussels, Belgium (JLVL) · Royal Hobart Hospital, Hobart, Australia (RY) · Celgene Corporation, Summit, NJ (DNP) · Celgene Corporation, Summit, NJ (BL) · Celgene Corporation, Boudry, Switzerland (AR) · Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ (DDVH). ·J Natl Cancer Inst · Pubmed #25638248.

ABSTRACT: BACKGROUND: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. METHODS: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P < .001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P < .001 for CA19-9 level ≥ median and HR = 0.81, P = .079 for NLR > 5). CONCLUSIONS: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer.

13 Clinical Trial Prognostic factors of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. 2015

Tabernero, Josep / Chiorean, E Gabriela / Infante, Jeffrey R / Hingorani, Sunil R / Ganju, Vinod / Weekes, Colin / Scheithauer, Werner / Ramanathan, Ramesh K / Goldstein, David / Penenberg, Darryl N / Romano, Alfredo / Ferrara, Stefano / Von Hoff, Daniel D. ·Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; Division of Oncology, University of Washington, Seattle, Washington, USA; Department of Oncology/Hematology, Sarah Cannon Research Institute, Nashville, Tennessee, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Oncology, Peninsula Oncology Centre, Monash University, Frankston, Victoria, Australia; Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado, USA; Division of Clinical Oncology, Medizinische Universität Wien, Vienna, Austria; Mayo Clinic, Scottsdale, Arizona, USA; Department of Oncology, Prince of Wales Hospital, Randwick, New South Wales, Sydney, Australia; Celgene Corporation, Summit, New Jersey, USA; Department of Oncology, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona, USA jtabernero@vhio.net. · Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; Division of Oncology, University of Washington, Seattle, Washington, USA; Department of Oncology/Hematology, Sarah Cannon Research Institute, Nashville, Tennessee, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Oncology, Peninsula Oncology Centre, Monash University, Frankston, Victoria, Australia; Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado, USA; Division of Clinical Oncology, Medizinische Universität Wien, Vienna, Austria; Mayo Clinic, Scottsdale, Arizona, USA; Department of Oncology, Prince of Wales Hospital, Randwick, New South Wales, Sydney, Australia; Celgene Corporation, Summit, New Jersey, USA; Department of Oncology, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona, USA. ·Oncologist · Pubmed #25582141.

ABSTRACT: BACKGROUND: nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. MATERIALS AND METHODS: Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. RESULTS: Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. CONCLUSION: The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.

14 Clinical Trial Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. 2013

Von Hoff, Daniel D / Ervin, Thomas / Arena, Francis P / Chiorean, E Gabriela / Infante, Jeffrey / Moore, Malcolm / Seay, Thomas / Tjulandin, Sergei A / Ma, Wen Wee / Saleh, Mansoor N / Harris, Marion / Reni, Michele / Dowden, Scot / Laheru, Daniel / Bahary, Nathan / Ramanathan, Ramesh K / Tabernero, Josep / Hidalgo, Manuel / Goldstein, David / Van Cutsem, Eric / Wei, Xinyu / Iglesias, Jose / Renschler, Markus F. ·From the Translational Genomics Research Institute, Phoenix, and Virginia G. Piper Cancer Center, Scottsdale - both in Arizona (D.D.V.H., R.K.R.) · Cancer Specialists, Fort Myers, FL (T.E.) · Arena Oncology Associates, Lake Success (F.P.A.), and Roswell Park Cancer Institute, Buffalo (W.W.M.) - both in New York · University of Washington, Seattle (E.G.C.) · Sarah Cannon Research Institute-Tennessee Oncology, Nashville (J. Infante) · Princess Margaret Hospital, Toronto (M.M.) · Atlanta Cancer Care (T.S.) and Georgia Cancer Specialists (M.N.S.) - both in Atlanta · Blokhin Cancer Research Center, Moscow (S.A.T.) · Southern Health, East Bentleigh, VIC (M.H.), Prince of Wales Hospital, Sydney (D.G.), and Bionomics, Thebarton, SA (J. Iglesias) - all in Australia · San Raffaele Scientific Institute, Milan (M.R.) · Tom Baker Cancer Centre, Calgary, AB, Canada (S.D.) · Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (D.L.) · University of Pittsburgh Medical Center, Pittsburgh (N.B.) · Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona (J.T.) · Centro Integral Oncológico Clara Campal, Madrid (M.H.) · University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium (E.V.C.) · and Celgene, Summit, NJ (X.W., M.F.R.). ·N Engl J Med · Pubmed #24131140.

ABSTRACT: BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

15 Article CanStem111P trial: a Phase III study of napabucasin plus nab-paclitaxel with gemcitabine. 2019

Sonbol, Mohamad Bassam / Ahn, Daniel H / Goldstein, David / Okusaka, Takuji / Tabernero, Josep / Macarulla, Teresa / Reni, Michele / Li, Chung-Pin / O'Neil, Bert / Van Cutsem, Eric / Bekaii-Saab, Tanios. ·Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ 85054, USA. · Department of Medical Oncology, Prince of Wales Hospital, Sydney, NSW, Australia. · Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Vall d'Hebron University Hospital & Institute of Oncology (VHIO), CIBERONC, Universitat Autònoma de Barcelona, Barcelona, Spain. · Vall d'Hebron University Hospital & Institute of Oncology (VHIO), Barcelona, Spain. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Division of Gastroenterology & Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. · National Yang-Ming University School of Medicine, Taipei, Taiwan. · Department of Medicine, IU Health University Hospital, Indianapolis, IN, 46202, USA. · University Hospital Gasthuisberg, Leuven & KU Leuven, Leuven, Belgium. ·Future Oncol · Pubmed #30768369.

ABSTRACT: Napabucasin (also known as BBI-608 or BBI608) is an investigational, oral agent hypothesized to inhibit multiple oncogenic pathways. In this article, we describe the design and rationale for the CanStem111P clinical trial, a multicenter, randomized, open-label, Phase III study designed to determine the efficacy and safety of combining napabucasin with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma (NCT02993731). Patients were randomized in a 1:1 fashion to receive weekly gemcitabine and nab-paclitaxel with or without napabucasin. The results of this study will help define the role of this novel agent in the management of advanced pancreatic cancer.

16 Article Overexpression of Yes Associated Protein 1, an Independent Prognostic Marker in Patients With Pancreatic Ductal Adenocarcinoma, Correlated With Liver Metastasis and Poor Prognosis. 2017

Salcedo Allende, Maria Teresa / Zeron-Medina, Jorge / Hernandez, Javier / Macarulla, Teresa / Balsells, Joaquim / Merino, Xavier / Allende, Helena / Tabernero, Josep / Ramon Y Cajal, Santiago. ·From the *Pathology, †Oncology, ‡Surgery, and §Radiology Departments, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. ·Pancreas · Pubmed #28697132.

ABSTRACT: OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Overexpression of Yes associated protein 1 (YAP1), a downstream target of Hippo pathway, implicated in regulation of cell growth and apoptosis, has been reported in several human tumor types. The objective of this study was to investigate YAP1 expression in patients with PDAC and its prognostic values. METHODS: We evaluated YAP1 expression in 64 PDAC and 15 chronic pancreatitis (CP) cases and its related pancreatic intraepithelial neoplasia (PanIN) lesions and in 5 control subjects. Yes associated protein 1 expression was determined by immunohistochemistry. Association of YAP1 with clinicopathologic features in PDAC, disease-free survival, and overall survival was analyzed. RESULTS: We found a higher positive rate of nuclear expression of YAP1 in PDAC than in CP (P = 0.000) and lower expression of YAP1 in PanIN lesions in CP in contrast with expression in PanIN lesions in PDAC. Nuclear overexpression of YAP1 in PDAC is associated with hepatic metastasis (P = 0.0280) and is a prognostic factor (P = 0.0320), as well as surgical margin involvement (P = 0.0013) and tumoral stage (P = 0.0109). CONCLUSIONS: Overexpression of YAP1 may occur as a part of tumorigenesis of PDAC. Yes associated protein 1 is an independent prognostic marker for overall survival of PDAC and associated with liver metastasis, being a potential therapeutic target.

17 Article Pancreatic cancer heterogeneity and response to Mek inhibition. 2017

Pedersen, K / Bilal, F / Bernadó Morales, C / Salcedo, M T / Macarulla, T / Massó-Vallés, D / Mohan, V / Vivancos, A / Carreras, M-J / Serres, X / Abu-Suboh, M / Balsells, J / Allende, E / Sagi, I / Soucek, L / Tabernero, J / Arribas, J. ·Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · CIBER-ONC, Barcelona, Spain. · Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Campus de la UAB, Bellaterra, Spain. · Vall d'Hebron University Hospital (HUVH), Barcelona, Spain. · Universitat Autónoma de Barcelona, Barcelona, Spain. · Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. · Clinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. ·Oncogene · Pubmed #28581516.

ABSTRACT: Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes. Although the drug targeting inactivation of tumor suppressors by DNA methylation had little effect, the inhibition of Mek, a K-Ras effector, in combination with the standard of care (chemotherapy consisting of gemcitabine/Nab-paclitaxel), reduced the growth of three out of five PC-PDXs and impaired metastasis. The two least responding PC-PDXs were composed of genetically diverse cells, which displayed sensitivities to the Mek inhibitor differing by >10-fold. Unexpectedly, our analysis of this genetic diversity unveiled different KRAS mutations. As mutation in KRAS occurs early during progression, this heterogeneity may reflect the simultaneous appearance of different malignant cellular clones or, alternatively, that cells containing two mutations of KRAS are selected during tumor evolution. In vitro and in vivo analyses indicated that the intratumoral heterogeneity, along with the selective pressure imposed by the Mek inhibitor, resulted in rapid selection of resistant cells. Together with the gemcitabine/Nab-paclitaxel backbone, Mek inhibition could be effective in treatment of PC. However, resistance because of intratumoral heterogeneity is likely to develop frequently, pointing to the necessity of identifying the factors and mechanisms of resistance to further develop this therapy.