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Pancreatic Neoplasms: HELP
Articles by Manuel Hidalgo
Based on 81 articles published since 2009
(Why 81 articles?)

Between 2009 and 2019, M. Hidalgo wrote the following 81 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review Management of hyperbilirubinaemia in pancreatic cancer patients. 2018

Álvarez, R / Carrato, A / Adeva, J / Alés, I / Prados, S / Valladares, M / Macarulla, T / Muñoz, A / Hidalgo, M. ·Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain. Electronic address: ralvarezgallego@hmhospitales.com. · Department Medical Oncology, Ramón y Cajal University Hospital, Alcalá University, IRYCIS, CIBERONC, Madrid, Spain. · Department Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. · Department Medical Oncology, Hospital Regional Universitario de Málaga, Málaga, Spain. · Department of Gastroenterology, Hospital Universitario HM Sanchinarro, Madrid, Spain. · Department Medical Oncology, Hospital Universitario Virgen Del Rocío, Sevilla, Spain. · Department Medical Oncology, Hospital Vall D'Hebrón, Barcelona, Spain. · Department Medical Oncology, Hospital Gregorio Marañón, Madrid, Spain. · Department Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA. ·Eur J Cancer · Pubmed #29505968.

ABSTRACT: Development of hyperbilirubinaemia is common in patients with advanced pancreatic adenocarcinoma, both at diagnosis as well throughout disease evolution. For this reason, hyperbilirubinaemia determines chemotherapy treatment selection, and therefore it should be considered one of the most relevant conditions. There is very little evidence for the use of chemotherapy in this setting. This article summarises the main causes of hyperbilirubinaemia, how to treat them as well as their differential diagnosis. The current clinical evidence of the available drugs as well as the recommendations of use different combinations in the context of hyperbilirubinaemia are also reviewed.

2 Review Management of unresectable, locally advanced pancreatic adenocarcinoma. 2018

Salgado, M / Arévalo, S / Hernando, O / Martínez, A / Yaya, R / Hidalgo, M. ·Department of Medical Oncology, Complejo Hospitalario Universitario de Orense, C/Ramon Puga Noguerol, 54, 32005, Orense, Spain. mercedes.salgado.fernandez@sergas.es. · Department of Medical Oncology, Hospital Universitario Donostia, San Sebastián, San Sebastián, Spain. · Department of Radiation Oncology, Hospital Universitario HM Sanchinarro and Hospital Universitario HM Puerta del Sur, Madrid, Spain. · Department of Medical Oncology, Hospital del Mar, Barcelona, Spain. · Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain. · Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA. ·Clin Transl Oncol · Pubmed #28612202.

ABSTRACT: The diagnosis of unresectable locally advanced pancreatic adenocarcinoma (LAPC) requires confirmation, through imaging tests, of the unfeasibility of achieving a complete surgical resection, in the absence of metastatic spread. The increase in overall survival (OS), together with an appropriate symptom management is the therapeutic target in LAPC, maintaining an acceptable quality of life and, if possible, increasing the time until the appearance of metastasis. Chemoradiation (CRT) improves OS compared to best support treatment or radiotherapy (RT) but with greater toxicity. No significant increase in OS has been achieved with CRT when compared to chemotherapy (QT) alone in patients without disease progression after four months of treatment with QT. However, a significantly better local control, that is, a significant increase in the time to disease progression was associated with this approach. The greater effectiveness of the schemes FOLFIRINOX and gemcitabine (Gem) + Nab-paclitaxel compared to gemcitabine alone, has been extrapolated from metastatic disease to LAPC, representing a possible alternative for patients with good performance status (ECOG 0-1). In the absence of randomized clinical trials, Gem is the standard treatment in LAPC. If disease control is achieved after 4-6 cycles of QT, the use of CRT for consolidation can be considered an option vs QT treatment maintenance. Capecitabine has a better toxicity profile and effectiveness compared to gemcitabine as a radiosensitizer. After local progression, and without evidence of metastases, treatment with RT or CRT, in selected patients, can support to maintain the regional disease control.

3 Review Pancreas Cancer Precision Treatment Using Avatar Mice from a Bioinformatics Perspective. 2017

Perales-Patón, Javier / Piñeiro-Yañez, Elena / Tejero, Héctor / López-Casas, Pedro P / Hidalgo, Manuel / Gómez-López, Gonzalo / Al-Shahrour, Fátima. ·Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ·Public Health Genomics · Pubmed #28858862.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death among solid malignancies. Unfortunately, PDAC lethality has not substantially decreased over the past 20 years. This aggressiveness is related to the genomic complexity and heterogeneity of PDAC, but also to the absence of an effective screening for the detection of early-stage tumors and a lack of efficient therapeutic options. Therefore, there is an urgent need to improve the arsenal of anti-PDAC drugs for an effective treatment of these patients. Patient-derived xenograft (PDX) mouse models represent a promising strategy to personalize PDAC treatment, offering a bench testing of candidate treatments and helping to select empirical treatments in PDAC patients with no therapeutic targets. Moreover, bioinformatics-based approaches have the potential to offer systematic insights into PDAC etiology predicting putatively actionable tumor-specific genomic alterations, identifying novel biomarkers and generating disease-associated gene expression signatures. This review focuses on recent efforts to individualize PDAC treatments using PDX models. Additionally, we discuss the current understanding of the PDAC genomic landscape and the putative druggable targets derived from mutational studies. PDAC molecular subclassifications and gene expression profiling studies are reviewed as well. Finally, latest bioinformatics methodologies based on somatic variant detection and prioritization, in silico drug response prediction, and drug repositioning to improve the treatment of advanced PDAC tumors are also covered.

4 Review Adjuvant treatment for pancreatic ductal carcinoma. 2017

Macarulla, T / Fernández, T / Gallardo, M E / Hernando, O / López, A M / Hidalgo, M. ·Department Medical Oncology, Hospital Vall d'Hebrón, Pg Vall d'Hebrón 119, Barcelona, Spain. tmacarulla@vhio.net. · Department Medical Oncology, Hospital Son Llàtzer, Palma De Mallorca, Spain. · Department Medical Oncology, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain. · Department Radiation Oncology, Hospital Universitario HM Sanchinarro, Madrid, Spain. · Department Radiation Oncology, Hospital Universitario HM Puerta del Sur, Madrid, Spain. · Department Medical Oncology, Hospital Universitario de Burgos, Burgos, Spain. · Beth Israel Deaconness Medical Center, Harvard Medical School, Boston, USA. ·Clin Transl Oncol · Pubmed #28639051.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a very poor prognosis. Most of the patients are diagnosed in advanced stages of the disease, and 5-year survival rates in these patients remains <10%. Surgery still remains the only radical treatment option, although only 15-20% of patients are candidates for surgical resection at the time of the diagnosis. Patients who undergo radical surgery still have a limited survival rate, being the average of 23 months. Three clinical trials have shown that adjuvant chemotherapy therapy after surgery may improve survival: CONKO-1, ESPAC-3, and ESPAC-4. Adjuvant therapy is recommended in patients with R0/R1, T1-4/N1-0 tumors and with ECOG 0-1. In patients with ECOG-2, the decision needs to be individualized. Treatment schemes that have demonstrated efficacy include gemcitabine alone, 5-fluorouracil, or the combination of gemcitabine and capecitabine for six months. Prior to adjuvant treatment, the following test are recommended: Complete blood tests, including CA19.9 biomarker; imaging studies to rule out early disease relapse (preferable thorax-abdomen-pelvic CT). Studies that have evaluated the efficacy of radiation therapy in the adjuvant setting have presented conflicting results. Its use should be considered in patients with R1 or R2 tumors or in those with lymph nodes involved.

5 Review Pancreatic ductal adenocarcinoma: metastatic disease. 2017

Muñoz Martín, A J / Adeva, J / Martínez-Galán, J / Reina, J J / Hidalgo, M. ·Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, C/Doctor Esquerdo 46, 28007, Madrid, Spain. andresmunmar@hotmail.com. · Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. · Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, Granada, Spain. · Department of Medical Oncology, Hospital Universitario Virgen de la Macarena, Seville, Spain. · Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard University, Boston, USA. ·Clin Transl Oncol · Pubmed #28623515.

ABSTRACT: The treatment of choice of metastatic PADC is systemic chemotherapy. In the last decade, there have been significant advances in this area. New combination poli-chemotherapy schemes have shown a significant increase in overall survival and progression-free survival without impairing quality of life. In addition, the value of second-line chemotherapy treatment has consolidated and a new concept called "therapeutic sequencing" has also emerged. The aim of this article is to review the different therapeutic options in metastatic PDAC based on patient's characteristics.

6 Review Neoadjuvant treatment for borderline and resectable pancreatic ductal adenocarcinoma. 2017

Álvarez, R / Alés, I / Díaz, R / de Paredes, B G / Hidalgo, M. ·Department of Medical Oncology, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain. ralvarezgallego@hmhospitales.com. · Department of Medical Oncology, Hospital Regional Universitario de Málaga, Málaga, Spain. · Department of Medical Oncology, Hospital Universitari i Politècnic La Fe, Valencia, Spain. · Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain. · Beth Israel Deaconness Medical Center, Harvard Medical School, Boston, USA. ·Clin Transl Oncol · Pubmed #28612203.

ABSTRACT: Nowadays and given the improvement in response rate with the new schemes of treatment with chemotherapy, the interest in neoadjuvant treatment for pancreatic ductal adenocarcinoma, allowing the early application of systemic therapies, has also increased. However, treatment selection fundamentally depends on decisions taken by multidisciplinary committees due to the absence of randomized trials on this indication and because the available evidence is based primarily on small studies. The present manuscript tries to establish recommendations based on the available evidence and expert opinion to correctly select the indication, the type of treatment, as well as its duration and how to correctly follow-up patients during treatment with chemotherapy.

7 Review Reduced risk of pancreatic cancer associated with asthma and nasal allergies. 2017

Gomez-Rubio, Paulina / Zock, Jan-Paul / Rava, Marta / Marquez, Mirari / Sharp, Linda / Hidalgo, Manuel / Carrato, Alfredo / Ilzarbe, Lucas / Michalski, Christoph / Molero, Xavier / Farré, Antoni / Perea, José / Greenhalf, William / O'Rorke, Michael / Tardón, Adonina / Gress, Thomas / Barberà, Victor / Crnogorac-Jurcevic, Tatjana / Domínguez-Muñoz, Enrique / Muñoz-Bellvís, Luís / Alvarez-Urturi, Cristina / Balcells, Joaquim / Barneo, Luis / Costello, Eithne / Guillén-Ponce, Carmen / Kleeff, Jörg / Kong, Bo / Lawlor, Rita / Löhr, Matthias / Mora, Josefina / Murray, Lim / O'Driscoll, Damian / Peláez, Pablo / Poves, Ignasi / Scarpa, Aldo / Real, Francisco X / Malats, Núria / Anonymous6460850. ·Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. · Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. · National Cancer Registry Ireland, Cork, Ireland, and Institute of Health & Society, Newcastle University, UK. · Hospital Madrid-Norte-Sanchinarro, Madrid, Spain. · Department of Oncology, Hospital Ramón y Cajal, Madrid, Spain. · Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. · Technical University of Munich, Munich, Germany. · Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Department of Surgery, 12 de Octubre University Hospital, Madrid, Spain. · The Royal Liverpool University Hospital, Liverpool, UK. · Centre for Public Health, Queen's University Belfast, Belfast, UK. · Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain. · Department of Gastroenterology, University Hospital Giessen and Marburg, Marburg, Germany. · Laboratorio de Genética Molecular, Hospital General Universitario de Elche, Elche, Spain. · Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. · Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. · Cirugía General y del Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, Spain. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Gastrocentrum, Karolinska Institutet, Stockholm, Sweden. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ·Gut · Pubmed #26628509.

ABSTRACT: OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk. DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model. RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk. CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.

8 Review Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. 2015

Garrido-Laguna, Ignacio / Hidalgo, Manuel. ·Department of Internal Medicine, Division of Oncology, and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah School of Medicine, University of Utah, Suite 2100, 2000 Circle of Hope, Salt Lake City, UT 84112, USA. · Gastrointestinal Cancer Clinical Research Unit, Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro 3, 28029 Madrid, Spain. ·Nat Rev Clin Oncol · Pubmed #25824606.

ABSTRACT: Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting, FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival. Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.

9 Review Addressing the challenges of pancreatic cancer: future directions for improving outcomes. 2015

Hidalgo, Manuel / Cascinu, Stefano / Kleeff, Jörg / Labianca, Roberto / Löhr, J-Matthias / Neoptolemos, John / Real, Francisco X / Van Laethem, Jean-Luc / Heinemann, Volker. ·Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. Electronic address: mhidalgo@cnio.es. · Department of Medical Oncology, University of Ancona, Ancona, Italy. · Department of General Surgery, Technische Universität München, Munich, Germany. · Ospedale Papa Giovanni XXIII, Bergamo, Italy. · Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden. · National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Cancer Research UK Liverpool Clinical Trials Unit Director, University of Liverpool and Royal Liverpool University Hospital, Liverpool, UK. · Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid and Universitat Pompeu Fabra, Barcelona, Spain. · Department of Gastroenterology-GI Cancer Unit, Erasme University Hospital, Brussels, Belgium. · Comprehensive Cancer Centre Munich, Klinikum der Universität München, Munich, Germany. ·Pancreatology · Pubmed #25547205.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease.

10 Review The winning formulation: the development of paclitaxel in pancreatic cancer. 2013

Ma, Wen Wee / Hidalgo, Manuel. ·Authors' Affiliations: Roswell Park Cancer Institute, Buffalo, New York; and Centro Nacional de Investigaciones Oncologicas and Hospital de Madrid, Madrid, Spain. ·Clin Cancer Res · Pubmed #23918602.

ABSTRACT: Paclitaxel has wide application in anticancer therapy but was never considered an efficacious agent in pancreatic cancer. A review of the experience with the Cremaphor formulation hinted at paclitaxel's activity in pancreatic cancer, but the early development was hampered by significant toxicities such as neutropenia and infection at clinically tolerable doses. However, such efficacy was confirmed in the recently completed phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), in which the addition of nab-paclitaxel to gemcitabine significantly improved the survival of patients with metastatic pancreatic cancer. Several other Cremaphor-free formulations of paclitaxel had also been evaluated in pancreatic cancer, and the reasons for the success of the albumin nanoparticulate are examined here. In the era of biologic and molecularly targeted agents, the success of nab-paclitaxel in recalcitrant pancreatic cancer is a timely reminder of the importance and relevance of pharmacology and novel drug delivery technology in the development of anticancer drugs.

11 Review Translational therapeutic opportunities in ductal adenocarcinoma of the pancreas. 2012

Hidalgo, Manuel / Von Hoff, Daniel D. ·Centro Nacional de Investigaciones Oncológicas, Madrid, Spain. mhidalgo@cnio.es ·Clin Cancer Res · Pubmed #22896691.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) remains a devastating disease with nearly equal incidence and mortality rates. Over the past few decades, a litany of randomized clinical trials has failed to improve the outcome of this disease. More recently, the combination chemotherapy regimen FOLFIRINOX has shown improvement in overall survival over the single agent gemcitabine, and nab-paclitaxel (an albumin-coated formulation of paclitaxel) in combination with gemcitabine has shown promising results in phase II studies. Despite limited impact on patient care as of yet, the molecular and biologic understanding of PDA has advanced substantially. This includes understanding the genomic complexity of the disease, the potential importance of the tumor microenvironment, the metabolic adaptation of PDA cells to obtain nutrients in a hypoxic environment, and the role of pancreatic cancer stem cells. These fundamental discoveries are starting to be translated into clinical studies. In this overview, we discuss the implications of biologic understanding of PDA in clinical research and provide insights for future development of novel approaches and agents in this disease.

12 Review Pancreatic cancer. 2010

Hidalgo, Manuel. ·Centro Nacional de Investigaciones Oncológicas and Hospital de Madrid, Madrid. mhidalgo@cnio.es ·N Engl J Med · Pubmed #20427809.

ABSTRACT: -- No abstract --

13 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.

14 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.

15 Clinical Trial Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. 2018

Van Cutsem, Eric / Hidalgo, Manuel / Canon, Jean-Luc / Macarulla, Teresa / Bazin, Igor / Poddubskaya, Elena / Manojlovic, Nebojsa / Radenkovic, Dejan / Verslype, Chris / Raymond, Eric / Cubillo, Antonio / Schueler, Armin / Zhao, Charles / Hammel, Pascal. ·Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg/Leuven & KULeuven, Leuven, Belgium. · Centro Nacional Investigaciones Oncologicas, Madrid, Spain and START Madrid, Madrid, Spain. · Service d'Oncologie-Hématologie, Grand Hopital de Charleroi, Charleroi, Belgium. · Gastrointestinal Cancer Unit, Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Barcelona, Spain. · Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer Research Center, and I.M. Sechenov First Moscow State Medical University, Moscow, Russia. · Clinic for Gastroenterology and Hepatology, Military Medical Academy of Serbia, Belgrade, Serbia. · First Surgical Clinic, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. · Medical Oncology Département, Saint Joseph Hospital, Paris, France. · HM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal (HM-CIOCC), and Departamento de Ciencias Médicas Clínicas, Universidad CEU San Pablo, Madrid, Spain. · Biostatistics, Merck KGaA, Darmstadt, Germany. · Clinical Oncology Early Development, EMD Serono, Billerica, MA. · Digestive Oncology Unit, Hôpital Beaujon, Clichy, France. ·Int J Cancer · Pubmed #29756206.

ABSTRACT: The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m

16 Clinical Trial Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. 2018

Hurwitz, Herbert / Van Cutsem, Eric / Bendell, Johanna / Hidalgo, Manuel / Li, Chung-Pin / Salvo, Marcelo Garrido / Macarulla, Teresa / Sahai, Vaibhav / Sama, Ashwin / Greeno, Edward / Yu, Kenneth H / Verslype, Chris / Dawkins, Fitzroy / Walker, Chris / Clark, Jason / O'Reilly, Eileen M. ·Duke University Medical Center, Campus mail 439 Seeley-mudd Bldg, 10 Bryan Searle Drive, Duke University M, Durham, NC, 27710, USA. · Clinical Digestive Oncology, University Hospitals Leuven and KU Leuven, UZ Herestraat 49, 3000, Leuven, Belgium. · Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Ave N, Nashville, TN, 37203, USA. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. · Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 11217, Taiwan. · School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Beitou District, Taipei, 112, Taiwan. · Pontificia Universidad Católica de Chile, Av Libertador Bernardo O'Higgins, 340, Santiago, Región Metropolitana, Chile. · Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital (HUVH), Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain. · Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Cancer Center Floor B1 Reception E, 1500 E Medical Center Dr SPC 5912, Ann Arbor, MI, 48109-5912, USA. · Thomas Jefferson University Hospital, 925 Chestnut Street, Suite 320A, Philadelphia, PA, 19107, USA. · Division of Hematology, Oncology and Transplantation, University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN, 55455, USA. · Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. · Incyte Corporation, 1801 Augustine Cut-off, Wilmington, DE, 19803, USA. · Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. oreillye@mskcc.org. · Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. oreillye@mskcc.org. ·Invest New Drugs · Pubmed #29508247.

ABSTRACT: Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m

17 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.

18 Clinical Trial Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). 2014

Dragovich, T / Laheru, D / Dayyani, F / Bolejack, V / Smith, L / Seng, J / Burris, H / Rosen, P / Hidalgo, M / Ritch, P / Baker, A F / Raghunand, N / Crowley, J / Von Hoff, D D. ·Banner MD Anderson Cancer Center, 1900 N. Higley Road, Gilbert, AZ, 85234, USA, Tomislav.dragovich@bannerhealth.com. ·Cancer Chemother Pharmacol · Pubmed #24939212.

ABSTRACT: PURPOSE: Vatalanib (PTK 787/ZK22584) is an oral poly-tyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy. METHODS: Vatalanib treatment consisted of a twice daily oral dosing using a "ramp-up schedule," beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. The primary objective of this study was to evaluate the 6-month survival rate. RESULTS: Sixty-seven patients were enrolled. The median age was 64, and 66% (N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20%; N = 13), fatigue (17%; N = 11), abdominal pain (17%; N = 11), and elevated alkaline phosphatase (15%; N = 10). Among the 65 evaluable patients, the 6-month survival rate was 29% (95% CI 18-41%) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. Two patients had objective partial responses, and 28% of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug. CONCLUSION: Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls.

19 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.).

20 Clinical Trial Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer. 2013

Herman, Joseph M / Fan, Katherine Y / Wild, Aaron T / Hacker-Prietz, Amy / Wood, Laura D / Blackford, Amanda L / Ellsworth, Susannah / Zheng, Lei / Le, Dung T / De Jesus-Acosta, Ana / Hidalgo, Manuel / Donehower, Ross C / Schulick, Richard D / Edil, Barish H / Choti, Michael A / Hruban, Ralph H / Pawlik, Timothy M / Cameron, John L / Laheru, Daniel A / Wolfgang, Christopher L. ·Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA. jherma15@jhmi.edu ·Int J Radiat Oncol Biol Phys · Pubmed #23773391.

ABSTRACT: PURPOSE: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. METHODS AND MATERIALS: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m(2) twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). RESULTS: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. CONCLUSION: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

21 Clinical Trial Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer. 2013

Wolpin, B M / O'Reilly, E M / Ko, Y J / Blaszkowsky, L S / Rarick, M / Rocha-Lima, C M / Ritch, P / Chan, E / Spratlin, J / Macarulla, T / McWhirter, E / Pezet, D / Lichinitser, M / Roman, L / Hartford, A / Morrison, K / Jackson, L / Vincent, M / Reyno, L / Hidalgo, M. ·Dana-Farber Cancer Institute, Boston, MA 02215, USA. bwolpin@partners.org ·Ann Oncol · Pubmed #23448807.

ABSTRACT: BACKGROUND: We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m(2) weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression. RESULTS: Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9-57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1-69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup. CONCLUSIONS: This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma. ClinicalTrials.gov identifier: NCT00902291.

22 Clinical Trial Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer. 2012

Arcaroli, John / Quackenbush, Kevin / Dasari, Arvind / Powell, Rebecca / McManus, Martine / Tan, Aik-Choon / Foster, Nathan R / Picus, Joel / Wright, John / Nallapareddy, Sujatha / Erlichman, Charles / Hidalgo, Manuel / Messersmith, Wells A. ·University of Colorado Cancer Center, Denver, Colorado 80045, USA. ·Cancer Med · Pubmed #23342270.

ABSTRACT: Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.

23 Clinical Trial Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer. 2012

Laheru, Daniel / Shah, Preeti / Rajeshkumar, N V / McAllister, Florencia / Taylor, Gretchen / Goldsweig, Howard / Le, Dung T / Donehower, Ross / Jimeno, Antonio / Linden, Sheila / Zhao, Ming / Song, Dongweon / Rudek, Michelle A / Hidalgo, Manuel. ·Department of Medical Oncology, Skip Viragh Center for Pancreatic Cancer Research and Patient Care, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting- Blaustein Cancer Research Building, Room 4M09, Baltimore, MD 21231, USA. laherda@jhmi.edu ·Invest New Drugs · Pubmed #22547163.

ABSTRACT: PURPOSE: S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). PATIENTS AND METHODS: In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. RESULTS: Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. CONCLUSION: The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

24 Clinical Trial Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. 2011

Von Hoff, Daniel D / Ramanathan, Ramesh K / Borad, Mitesh J / Laheru, Daniel A / Smith, Lon S / Wood, Tina E / Korn, Ronald L / Desai, Neil / Trieu, Vuong / Iglesias, Jose L / Zhang, Hui / Soon-Shiong, Patrick / Shi, Tao / Rajeshkumar, N V / Maitra, Anirban / Hidalgo, Manuel. ·TGen/Virginia G Piper Cancer Ctr, 445 N Fifth St, Suite 600, Phoenix, AZ 85004, USA. dvh@tgen.org ·J Clin Oncol · Pubmed #21969517.

ABSTRACT: PURPOSE: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. PATIENTS AND METHODS: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. RESULTS: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. CONCLUSION: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

25 Clinical Trial Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. 2011

Villarroel, Maria C / Rajeshkumar, N V / Garrido-Laguna, Ignacio / De Jesus-Acosta, Ana / Jones, Siân / Maitra, Anirban / Hruban, Ralph H / Eshleman, James R / Klein, Alison / Laheru, Daniel / Donehower, Ross / Hidalgo, Manuel. ·Corresponding Author: Manuel Hidalgo, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro, 3, 28029, Madrid, Spain. ·Mol Cancer Ther · Pubmed #21135251.

ABSTRACT: Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer.