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Pancreatic Neoplasms: HELP
Articles by Daniel D. Von Hoff
Based on 72 articles published since 2009
(Why 72 articles?)

Between 2009 and 2019, D. Von Hoff wrote the following 72 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Triptolide and Its Derivatives as Cancer Therapies. 2019

Noel, Pawan / Von Hoff, Daniel D / Saluja, Ashok K / Velagapudi, Mohana / Borazanci, Erkut / Han, Haiyong. ·Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, USA. · Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, USA; HonorHealth Research Institute, Scottsdale, AZ, USA. · Department of Surgery, Miller School of Medicine, Sylvester Pancreatic Cancer Research Institute, University of Miami, Miami, FL, USA. · Minneamrita Therapeutics LLC, Moline, IL, USA. · Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, USA. Electronic address: hhan@tgen.org. ·Trends Pharmacol Sci · Pubmed #30975442.

ABSTRACT: Triptolide, a compound isolated from a Chinese medicinal herb, possesses potent antitumor, immunosuppressive, and anti-inflammatory properties, but is clinically limited due to its poor solubility, bioavailability, and toxicity. Recently, Minnelide, a water-soluble prodrug of triptolide, was shown to have potent antitumor activity in various preclinical cancer models. Minnelide is currently in Phase II clinical trials for treatment of advanced pancreatic cancer, which has fueled increased interest in this promising agent. Here, we review the recent advances in the biological activity of triptolide and its analogs, their mechanisms of actions, and their clinical developments. A special emphasis is given to proteins and pathways within the tumor and stromal compartments that are targeted by triptolide and its analogs as well as the ongoing clinical trials.

2 Review Pancreatic acinar cell carcinoma: A review on molecular profiling of patient tumors. 2017

Al-Hader, Ahmad / Al-Rohil, Rami N / Han, Haiyong / Von Hoff, Daniel. ·Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202-3082, United States. aalhader@iu.edu. · Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. · Molecular Medicine Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, United States. ·World J Gastroenterol · Pubmed #29259370.

ABSTRACT: Pancreatic carcinomas with acinar differentiation are rare, accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma (PACC), pancreatoblastoma, and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as:

3 Review Pancreatic Cancer: "A Riddle Wrapped in a Mystery inside an Enigma". 2017

Borazanci, Erkut / Dang, Chi V / Robey, Robert W / Bates, Susan E / Chabot, John A / Von Hoff, Daniel D. ·HonorHealth, Scottsdale, Arizona and TGen, Phoenix, Arizona. Erkut.Borazanci@HonorHealth.com. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. · National Institutes of Health, Bethesda, Maryland. · Columbia University Medical Center, New York, New York. · James J. Peters Bronx VA Medical Center, Bronx, New York. · HonorHealth, Scottsdale, Arizona and TGen, Phoenix, Arizona. ·Clin Cancer Res · Pubmed #28373361.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology-systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes are

4 Review Microbiome and pancreatic cancer: A comprehensive topic review of literature. 2017

Ertz-Archambault, Natalie / Keim, Paul / Von Hoff, Daniel. ·Natalie Ertz-Archambault, Department of Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic Arizona, Scottsdale, AZ 85259, United States. ·World J Gastroenterol · Pubmed #28348497.

ABSTRACT: AIM: To review microbiome alterations associated with pancreatic cancer, its potential utility in diagnostics, risk assessment, and influence on disease outcomes. METHODS: A comprehensive literature review was conducted by all-inclusive topic review from PubMed, MEDLINE, and Web of Science. The last search was performed in October 2016. RESULTS: Diverse microbiome alterations exist among several body sites including oral, gut, and pancreatic tissue, in patients with pancreatic cancer compared to healthy populations. CONCLUSION: Pilot study successes in non-invasive screening strategies warrant further investigation for future translational application in early diagnostics and to learn modifiable risk factors relevant to disease prevention. Pre-clinical investigations exist in other tumor types that suggest microbiome manipulation provides opportunity to favorably transform cancer response to existing treatment protocols and improve survival.

5 Review Hypoxia-activated prodrugs in the treatment of advanced pancreatic adenocarcinoma. 2017

Babiker, Hani M / Riaz, Irbaz B / Shah, Syed R / Von Hoff, Daniel D / Borad, Mitesh J. ·aVirginia G Piper Cancer Center Clinical Trials, HonorHealth Research Institute bDepartment of Internal Medicine, Division of Hematology-Oncology, Mayo Clinic Cancer Center, Scottsdale cClinical Translational Research Division, Translational Genomics Research Institute (TGen), Phoenix dDepartment of Internal Medicine, Division of Hematology Oncology, University of Arizona Cancer Center eDepartment of Internal Medicine, University of Arizona, Tucson, Arizona fDepartment of Molecular Medicine, Centre for Individualized Medicine, Rochester, Minnesota, USA gDepartment of Medicine, Dow University of Health Sciences, Karachi, Pakistan. ·Anticancer Drugs · Pubmed #27685167.

ABSTRACT: Pancreatic cancer is an aggressive malignancy with poor survival and high mortality rate with 250 000 deaths per year worldwide. The unique pancreatic cancer microenvironment serves as a major obstacle in the effective treatment of this malignancy. The microenvironment consists not only of pancreatic ductal adenocarcinoma cells but also comprises cells of pancreatic cancer stellate, vascular, and immune origin combined with a dense extracellular matrix containing collagen. The aforementioned pathology leads to an increased intratumor pressure combined with an erratic vascular proliferation within the tumor causing hypoxia and decreased drug delivery. This has led both scientists and clinicians to develop and study drugs with unique mechanisms of action to target the pancreatic cancer microenvironment. Herein, we discuss the pancreatic cancer hypoxic microenvironment, development of hypoxia-activated prodrugs, and results of trials utilizing those drugs to target pancreatic cancer.

6 Review Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer: Normalization, Not Destruction. 2015

Whatcott, Clifford J / Han, Haiyong / Von Hoff, Daniel D. ·From the Clinical Translational Research Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ. ·Cancer J · Pubmed #26222082.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the United States. The microenvironment of pancreatic cancer could be one of the "perfect storms" that support the growth of a cancer. Indeed, pancreatic cancer may be the poster child of a problem with the microenvironment. In this article, we review the rationale and attempts to date on modifying or targeting structural proteins in the microenvironment including hyaluronan (HA) (in primary and metastases), collagen, and SPARC (secreted protein, acidic, and rich in cysteine). Indeed, working in this area has produced a regimen that improves survival for patients with advanced pancreatic cancer (nab-paclitaxel + gemcitabine). In addition, in initial clinical trials, PEGylated hyaluronidase appears promising. We also review a new approach that is different than targeting/destroying the microenvironment and that is orchestrating, reengineering, reprogramming, or normalizing the microenvironment (including normalizing structural proteins, normalizing an immunologically tumor-friendly environment to a less friendly environment, reversing epithelial-to-mesenchymal transition, and so on). We believe this will be most effectively done by agents that have global effects on transcription. There is initial evidence that this can be done by agents such as vitamin D derivatives and other new agents. There is no doubt these opportunities can now be tried in the clinic with hopefully beneficial effects.

7 Review Nab-paclitaxel and gemcitabine for the treatment of patients with metastatic pancreatic cancer. 2014

Borazanci, Erkut / Von Hoff, Daniel D. ·Translational Genomics Research Institute, Phoenix, AZ, USA. ·Expert Rev Gastroenterol Hepatol · Pubmed #24882381.

ABSTRACT: Adenocarcinoma of the pancreas or pancreatic cancer as we will refer to it here, is a cancer of poor prognosis with a high mortality, particularly in the advanced or metastatic setting. Until 2011 and the Phase III results of FOLFIRINOX, standard treatment options were limited to gemcitabine. Combination therapy had shown either a lack of or very limited improvement versus monotherapy with gemcitabine. With the positive results of the MPACT study in 2013 showing improved survival with nab-paclitaxel plus gemcitabine combination therapy, there are now more options for oncologists to treat patients with advanced pancreatic cancer. This paper will highlight the Phase I/II and Phase III trials of nab-paclitaxel plus gemcitabine along with discussing their biology and further possible development in treating patients with pancreatic cancer.

8 Review Taxanes: impact on pancreatic cancer. 2014

Chiorean, E Gabriela / Von Hoff, Daniel D. ·aDepartment of Medicine, University of Washington, Seattle, Washington bTranslational Genomics Research Institute (TGen)/Virginia Piper Cancer Center, Scottsdale, Arizona, USA. ·Anticancer Drugs · Pubmed #24463484.

ABSTRACT: Taxanes are core therapeutic components for several advanced malignancies, and have been studied extensively in pancreatic adenocarcinomas with mixed results. Although the triplet combination FOLFIRINOX improves outcomes for patients with metastatic disease, it is compounded by significant toxicity, and novel regimens, rationally designed and based on thorough mechanistic activity on the tumor targets, are clearly needed. Solvent-based taxanes, docetaxel and paclitaxel, have little activity as single agents, but combinations with fluoropyrimidines and gemcitabine show efficacy, albeit they have not undergone testing in phase III trials. Pancreatic cancer is characterized by an abundant desmoplastic, fibroinflammatory and hypoperfused stroma, which has been blamed for its overall chemoresistance. Nanoparticle bound paclitaxel (nab-paclitaxel) has been pharmacologically designed as a novel water-soluble agent, with improved therapeutic index compared with the cremophor-based formulation, capable of achieving higher systemic exposure. In preclinical systems, when combined with gemcitabine, nab-paclitaxel increased intratumoral gemcitabine delivery, possibly due to inducing stromal 'collapse' and through inhibition of the gemcitabine-catabolizing enzyme cytidine deaminase. Most recently, the combination of nab-paclitaxel and gemcitabine demonstrated significant survival benefit with good tolerability in metastatic pancreatic cancer in the phase III trial MPACT, and now represents one of the gold-standard regimens for this disease. Although taxanes are overall potent chemotherapeutics for various cancers, it is clear that for meaningful results in pancreatic adenocarcinomas, rationally designed combinations and novel technologies for drug delivery are likely to be most successful.

9 Review Tumor-stromal interactions in pancreatic cancer. 2013

Whatcott, Clifford / Han, Haiyong / Posner, Richard G / Von Hoff, Daniel D. ·Clinical Translational Research Division, The Translational Genomics Research Institute (TGEN), Phoenix, Arizona 85004, USA. cwhatcott@tgen.org ·Crit Rev Oncog · Pubmed #23237556.

ABSTRACT: The tumor associated stroma has been described in recent years as being complicit in tumor growth in pancreatic cancer. The stroma hosts a variety of components of both cellular and molecular makeup. In normal tissues, the stroma provides nutrients and regulatory signals for proper cellular polarity and function. However, following oncogenic transformation, the stromal compartment is conscripted to provide stimulatory signals and protection to tumor cells. It is these tumor-stromal interactions that are currently of great therapeutic interest. Several key reports have suggested that therapeutic targeting of the tumor-stromal interactions in pancreatic cancer has the potential to offer survival benefit. In this review, we will discuss the tumor-stromal interactions that contribute to tumor growth and progression, and ways in which we might counter these interactions.

10 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.

11 Review Perineural invasion and associated pain in pancreatic cancer. 2011

Bapat, Aditi A / Hostetter, Galen / Von Hoff, Daniel D / Han, Haiyong. ·Clinical Translational Research Division, Translational Genomics Research Institute, 13208 East Shea Boulevard, Scottsdale, Arizona 85259, USA. ·Nat Rev Cancer · Pubmed #21941281.

ABSTRACT: Perineural invasion (PNI) is a prominent characteristic of pancreatic cancer. PNI is a process whereby cancer cells invade the surrounding nerves, thus providing an alternative route for metastatic spread and pain generation. PNI is thought to be an indicator of aggressive tumour behaviour and has been shown to correlate with poor prognosis of patients with pancreatic cancer. Recent studies demonstrated that some signalling molecules and pathways that are involved in PNI are also involved in pain generation. Targeting these signalling pathways has shown some promise in alleviating pain and reducing PNI, which could potentially improve treatment outcomes for patients with pancreatic cancer.

12 Review Multi-institutional tumor banking: lessons learned from a pancreatic cancer biospecimen repository. 2010

Demeure, Michael J / Sielaff, Timothy / Koep, Larry / Prinz, Richard / Moser, A James / Zeh, Herb / Hostetter, Galen / Black, Jodi / Decker, Ardis / Rosewell, Sandra / Bussey, Kimberly J / Von Hoff, Daniel. ·Scottsdale Healthcare Cancer Surgery, Scottsdale, AZ, USA. mdemeure@tgen.org ·Pancreas · Pubmed #20861694.

ABSTRACT: Clinically annotated pancreatic cancer samples are needed for progress to be made toward developing more effective treatments for this deadly cancer. As part of a National Cancer Institute-funded program project, we established a biospecimen core to support the research efforts. This article summarizes the key hurdles encountered and solutions we found in the process of developing a successful multi-institution biospecimen repository.

13 Review Skeletal metastases in pancreatic cancer: a retrospective study and review of the literature. 2009

Borad, Mitesh J / Saadati, Hamid / Lakshmipathy, Arun / Campbell, Elizabeth / Hopper, Patricia / Jameson, Gayle / Von Hoff, Daniel D / Saif, M Wasif. ·Translational Genomics Research Institute, Scottsdale Clinical Research Institute, AZ, USA. ·Yale J Biol Med · Pubmed #19325940.

ABSTRACT: BACKGROUND: Skeletal metastases represent an underappreciated site of metastasis in patients with pancreatic cancer. Previous reports have estimated the prevalence to range from 5 percent to 20 percent. With the use of gemcitabine and novel targeted agents such as erlotinib, there has been a modest increase in survival in patients with advanced pancreatic cancer. As such, it is anticipated that previously uncommon occurrences such as skeletal metastases will become more frequent. PATIENTS AND METHODS: Retrospective chart review was conducted at two academic institutions to identify pancreatic cancer patients with skeletal metastases over a two-year period. RESULTS: Seven patients were identified from a database of 323 patients (2.2 percent). All patients had advanced disease and had received prior systemic therapy (range: 1-4 lines, median: 2 lines). Approximately half (57.1 percent) of the patients were symptomatic from their skeletal metastases. The most common sites of skeletal metastases were vertebrae (100 percent), hips (57.1 percent), and ribs (57.1 percent). Both blastic and lytic lesions were noted, with a predominance of blastic lesions (71.4 percent). A majority of patients (71.4 percent) received bisphosphonates as part of their care. DISCUSSION: Skeletal metastases are an uncommon but clinically important occurrence in patients with pancreatic cancer. Clinicians caring for patients with pancreatic cancer should be alert regarding skeletal metastases, due to the morbidity it can cause for these patients (e.g., back pain, fractures, etc.).

14 Clinical Trial Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors. 2018

Lam, Elaine T / Eckhardt, S Gail / Messersmith, Wells / Jimeno, Antonio / O'Bryant, Cindy L / Ramanathan, Ramesh K / Weiss, Glen J / Chadha, Manpreet / Oey, Abbie / Ding, Han Ting / Culp, Patricia A / Keller, Stephan F / Zhao, Vivian Y / Tsao, L Claire / Singhal, Anil / Holen, Kyle D / Von Hoff, Daniel. ·University of Colorado at Denver, Anschutz Medical Campus, Aurora, Colorado. elaine.lam@ucdenver.edu. · University of Colorado at Denver, Anschutz Medical Campus, Aurora, Colorado. · Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, Scottsdale, Arizona. · AbbVie Biotherapeutics Inc., Redwood City, California. · AbbVie Laboratories, Abbott Park, Illinois. ·Mol Cancer Ther · Pubmed #29054986.

ABSTRACT: This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies.

15 Clinical Trial None 2017

Korn, Ronald L / Von Hoff, Daniel D / Borad, Mitesh J / Renschler, Markus F / McGovern, Desmond / Curtis Bay, R / Ramanathan, Ramesh K. ·Imaging Endpoints Core Lab, 9700 N 91st St, B-200, Scottsdale, AZ, 85258, USA. rkorn@imagingendpoints.com. · Translational Genomics Research Institute and HonorHealth, 445 North Fifth St, Suite 600, Phoenix, AZ, 85004, USA. · Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA. · Celgene Corporation, 86 Morris Ave, Summit, NJ, 07901, USA. · Department of Interdisciplinary Health Sciences, A. T. Still University, 5850 E Still Circle, Mesa, AZ 85206, USA. ·Cancer Imaging · Pubmed #28774338.

ABSTRACT: BACKGROUND: Positron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine. METHODS: Tumors were measured by [ RESULTS: Fifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m CONCLUSIONS: The majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m TRIAL REGISTRATION: NCT00398086.

16 Clinical Trial Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis. 2017

Pelzer, Uwe / Blanc, Jean-Frédéric / Melisi, Davide / Cubillo, Antonio / Von Hoff, Daniel D / Wang-Gillam, Andrea / Chen, Li-Tzong / Siveke, Jens T / Wan, Yin / Solem, Caitlyn T / Botteman, Marc F / Yang, Yoojung / de Jong, Floris A / Hubner, Richard A. ·Department of Hematology/Oncology/Tumorimmunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. · Service d'Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Inserm UMR 1053, Université de Bordeaux, Bordeaux, France. · Digestive Molecular Clinical Oncology Unit, University of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy. · Servicio de Oncologia Médica, Centro Integral Oncológico Clara Campal (CIOCC), Hospital Universitario Madrid Sanchinarro, Calle Oña, 10, 28050 Madrid, Spain. · Virginia G. Piper Cancer Center at HonorHealth/TGen, 10460N 92nd St #206, Scottsdale, AZ 85258, USA. · Division of Oncology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, MO 63110, USA. · National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan 70456, Taiwan. · Division of Solid Tumor Translational Oncology, DKTK Partner Site Essen, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Pharmerit International, 4350 East-West Hwy #430, Bethesda, MD 20814, USA. · Shire, Plc, 650 East Kendal St, Cambridge, MA 02142, USA. · Department of Global Medical Affairs Oncology, Shire GmbH, Zählerweg 10, 6300 Zug, Switzerland. · Department of Medical Oncology, Christie Hospital NHS Foundation Trust, 550 Wilmslow Rd, Manchester M20 4BX, UK. ·Br J Cancer · Pubmed #28350787.

ABSTRACT: BACKGROUND: In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). METHODS: Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. RESULTS: Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). CONCLUSIONS: Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

17 Clinical Trial A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. 2017

Laquente, Berta / Lopez-Martin, Jose / Richards, Donald / Illerhaus, Gerald / Chang, David Z / Kim, George / Stella, Philip / Richel, Dirk / Szcylik, Cezary / Cascinu, Stefano / Frassineti, G L / Ciuleanu, Tudor / Hurt, Karla / Hynes, Scott / Lin, Ji / Lin, Aimee Bence / Von Hoff, Daniel / Calvo, Emiliano. ·Institut Català d'Oncologia-IDIBELL (Institut d'Investigació Biomèdica de Bellvitge), Barcelona, Spain. · University Hospital and Research Institute, Madrid, Spain. · US Oncology Research, Tyler, USA. · Hematology, Onkology, and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany. · Virginia Oncology Associates, Eastern Virginia Medical School, US Oncology Research, Hampton, VA, USA. · 21st Century Oncology, University of Florida Health Oncology, Jacksonville, USA. · St. Joseph Mercy Hospital, Ypsilanti, MI, USA. · Academic Medical Center, Amsterdam, Netherlands. · Department of Oncology, Military Institute of Medicine, Warsaw, Poland. · Department of Oncology and Hematology, Universitá di Modena e Reggio Emilia, Policlinico di Modena, Modena, Italy. · Department of Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Institute of Oncology Ion Chiricuta, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj Napoca, Romania. · Eli Lilly and Company, Indianapolis, IN, USA. · Translational Genomics Research Institute (TGen) and HonorHealth Research Institute, Phoenix, AZ, USA. · START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Medical Oncology Division, Hospital Universitario Madrid Norte Sanchinarro, Calle Oña, 10, 28050, Madrid, Spain. emiliano.calvo@start.stoh.com. ·BMC Cancer · Pubmed #28202004.

ABSTRACT: BACKGROUND: The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer. METHODS: Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m RESULTS: Ninety-nine patients (n = 65, LY2603618/gemcitabine; n = 34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3-18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC CONCLUSIONS: LY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer. TRIAL REGISTRATION: NCT00839332 . Clinicaltrials.gov. Date of registration: 6 February 2009.

18 Clinical Trial Tumor Reduction in Primary and Metastatic Pancreatic Cancer Lesions With nab-Paclitaxel and Gemcitabine: An Exploratory Analysis From a Phase 3 Study. 2017

Kunzmann, Volker / Ramanathan, Ramesh K / Goldstein, David / Liu, Helen / Ferrara, Stefano / Lu, Brian / Renschler, Markus F / Von Hoff, Daniel D. ·From the *Medizinische Klinik und Poliklinik II, University of Würzburg, Würzburg, Germany; †Mayo Clinic, Scottsdale, AZ; ‡Prince of Wales Hospital, Sydney, New South Wales, Australia; §Celgene Corporation, Summit, NJ; and ∥Translational German Research Institute and Honor Health Research Institute, Scottsdale, AZ. ·Pancreas · Pubmed #27841795.

ABSTRACT: OBJECTIVES: Results from the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) led to approval of nab-paclitaxel plus gemcitabine for first-line treatment of metastatic pancreatic cancer. The current analysis evaluated the effects of nab-paclitaxel plus gemcitabine versus gemcitabine on primary pancreatic and metastatic lesions. METHODS: In this analysis of the previously described MPACT trial, changes in pancreatic and metastatic tumor burden were assessed using independently measured diameters of lesions on computed tomography or magnetic resonance imaging scans. Changes in the sums of longest tumor diameters were summarized using descriptive statistics and were included in a multivariate analysis of overall survival. RESULTS: Primary pancreatic lesion measurement was feasible. Reductions in primary pancreatic tumor burden and metastatic burden from baseline to nadir were significantly greater with nab-paclitaxel plus gemcitabine versus gemcitabine. Baseline pancreatic tumor burden was independently predictive of survival. Both regimens elicited linear reductions in primary pancreatic and metastatic tumor burden through time. There was a high within-patient concordance of tumor changes between primary pancreatic lesions and metastatic lesions. CONCLUSIONS: This analysis of MPACT demonstrated significant tumor shrinkage benefit for nab-paclitaxel plus gemcitabine in both primary pancreatic and metastatic lesions, supporting ongoing evaluation of this regimen in locally advanced disease.

19 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.

20 Clinical Trial A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers. 2016

Coveler, Andrew L / Ko, Andrew H / Catenacci, Daniel V T / Von Hoff, Daniel / Becerra, Carlos / Whiting, Nancy C / Yang, Jing / Wolpin, Brian. ·Seattle Cancer Care Alliance, University of Washington, 825 Eastlake Ave E, Seattle, WA, 98109, USA. acoveler@u.washington.edu. · Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA. · University of Chicago, Chicago, IL, USA. · TGen Clinical Research Service at Scottsdale Healthcare, Scottsdale, AZ, USA. · Texas Oncology, Baylor Sammons Cancer Center, Dallas, TX, USA. · Seattle Genetics, Inc., Bothell, WA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. ·Invest New Drugs · Pubmed #26994014.

ABSTRACT: Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.

21 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.

22 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.

23 Clinical Trial Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT). 2016

Goldstein, David / Von Hoff, Daniel D / Moore, Malcolm / Greeno, Edward / Tortora, Giampaolo / Ramanathan, Ramesh K / Macarulla, Teresa / Liu, Helen / Pilot, Richard / Ferrara, Stefano / Lu, Brian. ·Prince of Wales Hospital, Department of Oncology, South Eastern Sydney Illawarra, NSW Health, Barker Street, Randwick, NSW 2031, Australia; University of New South Wales, Australia. Electronic address: david.goldstein@sesiahs.health.nsw.gov.au. · Scottsdale Healthcare/TGen, Bisgrove Research Pavilion, 10510 North 92nd Street, Suite 200, Scottsdale, AZ 85258, USA. · Princess Margaret Hospital, 5th Floor 708, 610 University Avenue, Toronto, Ontario M5G2M9, Canada. · University of Minnesota, Division of Hematology, Oncology and Transplantation, 420 Delaware Street SE, MMC 480, Minneapolis, MN 55455, USA. · Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico Borgo Roma, Piazzale L. Scuro, 10, 37134 Verona, Italy. · Mayo Clinic, 13400 E Shea Blvd FL 3, Scottsdale, AZ 85259, USA. · Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), P. Vall d'Hebron 119-129, Barcelona, Spain. · Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. ·Eur J Cancer · Pubmed #26655559.

ABSTRACT: BACKGROUND: In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. PATIENTS AND METHODS: Patients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). RESULTS: In the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤ I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). CONCLUSIONS: nab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤ I in many patients (median ≈ 1 month) NCT00844649.

24 Clinical Trial Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. 2016

Wang-Gillam, Andrea / Li, Chung-Pin / Bodoky, György / Dean, Andrew / Shan, Yan-Shen / Jameson, Gayle / Macarulla, Teresa / Lee, Kyung-Hun / Cunningham, David / Blanc, Jean F / Hubner, Richard A / Chiu, Chang-Fang / Schwartsmann, Gilberto / Siveke, Jens T / Braiteh, Fadi / Moyo, Victor / Belanger, Bruce / Dhindsa, Navreet / Bayever, Eliel / Von Hoff, Daniel D / Chen, Li-Tzong / Anonymous3111266. ·Washington University School of Medicine, St Louis, MO, USA. · Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan. · St László Teaching Hospital, Budapest, Hungary. · St John of God Hospital, Subiaco, WA, Australia. · National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan. · TGen, Phoenix, and HonorHealth, Scottsdale, AZ, USA. · Vall d'Hebron University Hospital (HUVH) and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Seoul National University Hospital, Seoul, South Korea. · The Royal Marsden Hospital, London, UK. · Hôpital Saint-André, Bordeaux, France. · The Christie NHS Foundation Trust, Manchester, UK. · China Medical University Hospital, Taichung, Taiwan. · Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. · Klinikum rechts der Isar der T U München, Munich, Germany. · Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA. · Merrimack Pharmaceuticals, Cambridge, MA, USA. · National Institute of Cancer Research, National Health Research Institutes, Tainan, and Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan. Electronic address: leochen@nhri.org.tw. ·Lancet · Pubmed #26615328.

ABSTRACT: BACKGROUND: Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. METHODS: We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. FINDINGS: Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). INTERPRETATION: Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. FUNDING: Merrimack Pharmaceuticals.

25 Clinical Trial (90)Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies. 2015

Picozzi, Vincent J / Ramanathan, Ramesh K / Lowery, Maeve A / Ocean, Allyson J / Mitchel, Edith P / O'Neil, Bert H / Guarino, Michael J / Conkling, Paul R / Cohen, Steven J / Bahary, Nathan / Frank, Richard C / Dragovich, Tomislav / Bridges, Benjamin B / Braiteh, Fadi S / Starodub, Alexander N / Lee, Fa-Chyi / Gribbin, Thomas E / Richards, Donald A / Lee, Marie / Korn, Ronald L / Pandit-Taskar, Neeta / Goldsmith, Stanley J / Intenzo, Charles M / Sheikh, Arif / Manzone, Timothy C / Horne, Heather / Sharkey, Robert M / Wegener, William A / O'Reilly, Eileen M / Goldenberg, David M / Von Hoff, Daniel D. ·Virginia Mason Medical Center, Seattle, WA, United States. · Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ, United States. · Memorial Sloan-Kettering Cancer Center, New York, NY, United States. · Weill Cornell Medical College, New York, NY, United States. · Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, United States. · UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, United States. · Helen F. Graham Cancer Center at Christiana Care Health System, Newark, DE, United States. · US Oncology Phase II Group, Virginia Oncology Associates, Norfolk, VA, United States. · Fox Chase Cancer Center, Philadelphia, PA, United States. · University of Pittsburgh Medical Center, Pittsburgh, PA, United States. · Whittingham Cancer Center at Norwalk Hospital, Norwalk, CT, United States. · Banner MD Anderson Cancer Center, Gilbert, AZ, United States. · St Luke's Mountain States Tumor Institute, Meridian, ID, United States. · Comprehensive Cancer Centers of Nevada, Las Vegas, NV, United States. · Indiana University Health Center for Cancer Care, Goshen, IN, United States. · University of New Mexico Health Science Center, Albuquerque, NM, United States. · Lacks Cancer Center, Saint Mary's Health Care, Grand Rapids, MI, United States. · Tyler Cancer Center, US Oncology Research, Tyler, TX, United States. · Immunomedics, Inc., Morris Plains, NJ, United States. · Immunomedics, Inc., Morris Plains, NJ, United States; Center for Molecular Medicine and Immunology/Garden State Cancer Center, Morris Plains, NJ, United States. Electronic address: dmg.gscancer@att.net. ·Eur J Cancer · Pubmed #26187510.

ABSTRACT: BACKGROUND: For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine. METHODS: Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m(2)doses×3, plus gemcitabine, weekly 200 mg/m(2) doses×4 starting 1 week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated. RESULTS: Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1 year. CONCLUSIONS: Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.