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Pancreatic Neoplasms: HELP
Articles by Malcolm J. Moore
Based on 37 articles published since 2008

Between 2008 and 2019, M. J. Moore wrote the following 37 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
Pages: 1 · 2
1 Review Changing the way we do business: recommendations to accelerate biomarker development in pancreatic cancer. 2013

Tempero, Margaret A / Klimstra, David / Berlin, Jordan / Hollingsworth, Tony / Kim, Paula / Merchant, Nipun / Moore, Malcolm / Pleskow, Doug / Wang-Gillam, Andrea / Lowy, Andrew M. ·Pancreas Center, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA. mtempero@medicine.ucsf.edu ·Clin Cancer Res · Pubmed #23344262.

ABSTRACT: Pancreatic ductal adenocarcinoma is the most aggressive of all epithelial malignancies. In contrast to the favorable trends seen in most other common malignancies, the five-year survival of patients with this disease remains only 6%, a statistic that has changed minimally for decades. Only two drugs have been approved by the U.S. Food and Drug Administration (FDA) for use in pancreatic cancer in the last 15 years, and there are no established strategies for early detection.

2 Review Evolution of systemic therapy for advanced pancreatic cancer. 2010

Renouf, Daniel / Moore, Malcolm. ·Department of Medical Oncology, Princess Margaret Hospital, 5-708, 610 University Avenue, Toronto, ON M5G 2M9, Canada. daniel.renouf@uhn.on.ca ·Expert Rev Anticancer Ther · Pubmed #20397918.

ABSTRACT: The prognosis for advanced pancreatic cancer remains poor and successful drug development in this disease continues to be a major challenge. In the last decade the approach to drug development in pancreatic cancer has included a focus on combinations of cytotoxic agents. While some promising results were seen in Phase II studies, none of the Phase III trials of cytotoxic combinations were able to demonstrate an improvement in overall survival over that seen with the single-agent gemcitabine. Newer studies have assessed the efficacy of 'targeted' agents that inhibit pathways thought to be important in the development, growth, invasion and metastasis of pancreatic cancer. Although some agents had promising activity in preclinical studies, none has made a major impact in the clinic. There has been some success with the addition of the EGF receptor tyrosine kinase inhibitor erlotinib to gemcitabine, which was the first combination to achieve an overall survival benefit compared with gemcitabine alone in a Phase III trial. Future directions for drug development in pancreatic cancer will mainly involve testing new targeted agents, although some cytotoxic combinations are currently in Phase III testing. There is a need to better understand the biology of the disease and incorporate this into trials in an attempt to search for predictive and prognostic markers that will aid in drug development. Control of pancreatic cancer will require combinations of targeted agents, probably individualized based on tumor genetics. We are just beginning to explore the efficacy of combining targeted agents in the clinic.

3 Review Advanced pancreatic carcinoma: current treatment and future challenges. 2010

Stathis, Anastasios / Moore, Malcolm J. ·Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, University of Toronto, Toronto, ON M5G 2M9, Canada. ·Nat Rev Clin Oncol · Pubmed #20101258.

ABSTRACT: Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth leading cause of cancer-related death in North America. Most patients present with locally advanced or metastatic disease that precludes curative resection. These patients have an extremely poor prognosis. In the absence of effective screening methods, considerable efforts have been made during the past decade to identify better systemic treatments. Unfortunately most trials have not shown a survival advantage for most therapies. In tandem with this increased clinical research, there has also been an expansion of preclinical laboratory investigation. These preclinical studies revealed many of the molecular mechanisms involved in pancreatic cancer development, which has provided insights into why current therapies are ineffective. These new discoveries provide some optimism that new agents inhibiting specific targets will improve outcome and overcome the resistance of pancreatic cancer to most standard treatments. We review the current standards of care for patients with locally advanced and metastatic pancreatic carcinoma and outline some future directions for the development of new treatment strategies.

4 Review Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. 2009

Philip, Philip A / Mooney, Margaret / Jaffe, Deborah / Eckhardt, Gail / Moore, Malcolm / Meropol, Neal / Emens, Leisha / O'Reilly, Eileen / Korc, Murray / Ellis, Lee / Benedetti, Jacqueline / Rothenberg, Mace / Willett, Christopher / Tempero, Margaret / Lowy, Andrew / Abbruzzese, James / Simeone, Diane / Hingorani, Sunil / Berlin, Jordan / Tepper, Joel. ·Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA. philipp@karmanos.org ·J Clin Oncol · Pubmed #19858397.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

5 Clinical Trial Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. 2018

Lowery, Maeve A / Kelsen, David P / Capanu, Marinela / Smith, Sloane C / Lee, Jonathan W / Stadler, Zsofia K / Moore, Malcolm J / Kindler, Hedy L / Golan, Talia / Segal, Amiel / Maynard, Hannah / Hollywood, Ellen / Moynahan, MaryEllen / Salo-Mullen, Erin E / Do, Richard Kinh Gian / Chen, Alice P / Yu, Kenneth H / Tang, Laura H / O'Reilly, Eileen M. ·Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Princess Margaret Cancer Center- University Health Network, Toronto, Canada. · University of Chicago Medical Center, Chicago, IL, USA. · Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Share Zedek Medical Center, Jerusalem, Israel. · National Cancer Institute, Bethesda, MD, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: oreillye@mskcc.org. ·Eur J Cancer · Pubmed #29223478.

ABSTRACT: PURPOSE: BRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC). METHODS: Patients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1-2 lines of treatment, Eastern Cooperative Oncology Group 0-2, were enrolled. Veliparib was dosed at a volume of 300 mg twice-daily (N = 3), then 400 mg twice-daily (N = 15) days 1-28. The primary end-point was to determine the response rate of veliparib; secondary end-points included progression-free survival (PFS), duration of response, overall survival (OS) and safety. RESULTS: Sixteen patients were enrolled; male N = 8 (50%). Median age was 52 years (range 43-77). Five (31%) had a BRCA1 and 11 (69%) had a BRCA2 mutation. Fourteen (88%) patients had received prior platinum-based therapy. No confirmed partial responses (PRs) were seen: one (6%) unconfirmed PR was observed at 4 months with disease progression (PD) at 6 months; four (25%) had stable disease (SD), whereas 11 (69%) had PD as best response including one with clinical PD. Median PFS was 1.7 months (95% confidence interval [CI] 1.57-1.83) and median OS was 3.1 months (95% CI 1.9-4.1). Six (38%) patients had grade III toxicity, including fatigue (N = 3), haematology (N = 2) and nausea (N = 1). CONCLUSIONS: Veliparib was well tolerated, but no confirmed response was observed although four (25%) patients remained on study with SD for ≥ 4 months. Additional strategies in this population are needed, and ongoing trials are evaluating PARPis combined with chemotherapy (NCT01585805) and as a maintenance strategy (NCT02184195).

6 Clinical Trial Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer. 2017

Evans, T R J / Van Cutsem, E / Moore, M J / Bazin, I S / Rosemurgy, A / Bodoky, G / Deplanque, G / Harrison, M / Melichar, B / Pezet, D / Elekes, A / Rock, E / Lin, C / Strauss, L / O'Dwyer, P J. ·Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK. · Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. · Princess Margaret Cancer, Toronto, Canada. · Federal State Budgetary Institution, Dubna, Russia. · Surgery, Florida Hospital, Tampa, Tampa, USA. · Oncology, St.László Teaching Hospital, Budapest, Hungary. · Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · East and North Hertfordshire NHS Trust, Northwood, Middlesex, UK. · Department of Oncology, Lekarska Fakulta Univerzity Palackeho a Fakultni Nemocnice, Olomouc, Czech Republic. · CHU Estaing, Clermont-Ferrand, France. · Otsuka Pharmaceutical Development and Commercialization, Princeton. · Bristol-Myers Squibb Company, Princeton. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA. ·Ann Oncol · Pubmed #27998964.

ABSTRACT: Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

7 Clinical Trial PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. 2016

Gill, Sharlene / Ko, Yoo-Joung / Cripps, Christine / Beaudoin, Annie / Dhesy-Thind, Sukhbinder / Zulfiqar, Muhammad / Zalewski, Pawel / Do, Thuan / Cano, Pablo / Lam, Wendy Yin Han / Dowden, Scot / Grassin, Helene / Stewart, John / Moore, Malcolm. ·Sharlene Gill and Malcolm Moore, BC Cancer Agency, Vancouver · Muhammad Zulfiqar, BC Cancer Agency, Abbotsford · Thuan Do, BC Cancer Agency, Surrey · Wendy Yin Han Lam, Burnaby Hospital Cancer Centre, Burnaby, British Columbia · Yoo-Joung Ko, Sunnybrook Health Sciences Centre · Malcolm Moore, Princess Margaret Hospital, Toronto · Christine Cripps, Ottawa Hospital Cancer Centre, Ottawa · Sukhbinder Dhesy-Thind, Juravinski Cancer Centre, Hamilton · Pawel Zalewski, RSM Durham Regional Cancer Centre, Oshawa · Pablo Cano, Sudbury Regional Hospital, Sudbury, Ontario · Annie Beaudoin, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke · Helene Grassin and John Stewart, Sanofi Canada, Laval, Quebec · and Scot Dowden, Alberta Health Service, Calgary, Alberta, Canada. ·J Clin Oncol · Pubmed #27621395.

ABSTRACT: Purpose The standard of care for second-line therapy in patients with advanced pancreatic cancer after gemcitabine-based therapy is not clearly defined. The CONKO-003 phase III study reported a survival benefit with second-line fluorouracil (FU) and oxaliplatin using the oxaliplatin, folinic acid, and FU (OFF) regimen.

8 Clinical Trial Significance of baseline and change in quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3. 2016

Vickers, M M / Lee, C / Tu, D / Wheatley-Price, P / Parulekar, W / Brundage, M D / Moore, M J / Au, H / O'Callaghan, C J / Jonker, D J / Ringash, J / Goldstein, D. ·The Ottawa Hospital Cancer Center, Ottawa, ON, Canada. Electronic address: mvickers@toh.ca. · NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW, Australia. · NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada. · The Ottawa Hospital Cancer Center, Ottawa, ON, Canada. · Kingston Cancer Centre, Kingston, ON, Canada. · BC Cancer Agency, Vancouver, BC, Canada. · Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada. · Prince of Wales Hospital, Randwick, NSW, Australia. ·Pancreatology · Pubmed #27600995.

ABSTRACT: BACKGROUND: There is insufficient information regarding the prognostic significance of baseline and change in quality of life (QoL) scores on overall survival (OS) in advanced pancreatic cancer. METHODS: QoL was assessed prospectively using the EORTC QLQ-C30 as part of the PA.3 trial of gemcitabine + erlotinib (G + E) vs. gemcitabine + placebo (G + P). Relevant variables and QoL scores at baseline and change at 8 weeks were analyzed by Cox stepwise regression to determine predictors of OS. RESULTS: 222 of 285 patients (pts) treated with G + E and 220 of 284 pts treated with G + P completed baseline QoL assessments. In a multivariable Cox analysis combining all pts, better QoL physical functioning (PF) score independently predicted longer OS (HR 0.86; CI: 0.80-0.93), as did non-white race (HR 0.64; CI: 0.44-0.95), PS 0-1 (HR 0.65; CI: 0.50-0.85), locally advanced disease (HR 0.55; CI: 0.43-0.71) and G + E (HR 0.78; CI: 0.64-0.96). Improvement in physical function at week 8 also predicted for improved survival (HR 0.89; CI: 0.81-0.97 for 10 point increase in score, p = 0.02). CONCLUSION: In addition to clinical variables, patient reported QoL scores at baseline and change from baseline to week 8 added incremental predictive information regarding survival for advanced pancreatic cancer patients.

9 Clinical Trial A phase II study of the HSP90 inhibitor AUY922 in chemotherapy refractory advanced pancreatic cancer. 2016

Renouf, D J / Hedley, D / Krzyzanowska, M K / Schmuck, M / Wang, L / Moore, M J. ·British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z4E6, Canada. drenouf@bccancer.bc.ca. · University Health Network-Princess Margaret Cancer Centre, Toronto, ON, Canada. · British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z4E6, Canada. ·Cancer Chemother Pharmacol · Pubmed #27422303.

ABSTRACT: OBJECTIVES: AUY922 is a novel heat shock protein inhibitor with preclinical activity in pancreatic cancer. This phase II study evaluated the efficacy of AUY922 in patients with advanced pancreatic cancer previously treated with chemotherapy. METHODS: In this single-arm, Simon two-stage phase II trial, patients with metastatic or locally advanced pancreatic ductal adenocarcinoma who had progressed on at least one line of chemotherapy and were of good performances status (ECOG 0 or 1) were treated with AUY922 at a dose of 70 mg/m(2) IV weekly. The primary endpoint was disease control rate (objective response and stable disease ≥16 weeks). RESULTS: Twelve patients were accrued, all of whom received treatment. At least possibly related ≥grade 3 adverse events included fatigue (8 %) and AST elevation (8 %). Ten patients were evaluable for response with 1 (10 %) having stable disease and 9 (90 %) progressive disease. The median progression-free survival was 1.6 months, and the median overall survival was 2.9 months. CONCLUSIONS: AUY922 was not associated with significant efficacy in previously treated patients with advanced pancreatic cancer.

10 Clinical Trial Prognostic nomogram and score to predict overall survival in locally advanced untreated pancreatic cancer (PROLAP). 2016

Vernerey, Dewi / Huguet, Florence / Vienot, Angélique / Goldstein, David / Paget-Bailly, Sophie / Van Laethem, Jean-Luc / Glimelius, Bengt / Artru, Pascal / Moore, Malcolm J / André, Thierry / Mineur, Laurent / Chibaudel, Benoist / Benetkiewicz, Magdalena / Louvet, Christophe / Hammel, Pascal / Bonnetain, Franck. ·Methodological and Quality of Life in Oncology Unit, EA 3181, University Hospital of Besançon, 3 Boulevard Alexandre Fleming, Besançon 25030, France. · Oncology Multidisciplinary Research Group (GERCOR), 151 rue du Faubourg Saint Antoine, Paris 75011, France. · Department of Radiotherapy, Tenon Hospital (AP-HP), 4 rue de la Chine, Paris 75020, France. · Department of Gastroenterology, University Hospital of Besançon, 3 Boulevard Alexandre Fleming, Besançon 25030, France. · Department of Medical Oncology, Prince of Wales hospital and Prince of Wales Clinical school, UNSW, Sydney, New South Wales 2031, Australia. · AGITG (Australasian Gastrointestinal Trials Group), 119-143 Missenden Rd, Camperdown, New South Wales 2050, Australia. · Department of Gastroenterology, Erasme University Hospital, Route de Lennik 808, Brussels 1070, Belgium. · Department of Radiology, Oncology and Radiation Science, University of Uppsala, Uppsala 75105, Sweden. · Department of Gastroenterology, Jean Mermoz Hospital, 55 avenue Mermoz, Lyon 69008, France. · Department of Medical Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. · Department of Medical Oncology, Saint-Antoine Hospital (AP-HP), 184 rue du Faubourg Saint Antoine, Paris 75011, France. · Department of Radiotherapy and Medical Oncology, Sainte-Catherine Institute, 250 Chemin de Baigne Pieds, Avignon 84918, France. · Department of Medical Oncology, Franco-British Hospital Institute, 3 Rue Barbès, Levallois-Perret 92300, France. · Department of Medical Oncology, Institute Mutualiste Montsouris, 42 Boulevard Jourdan, Paris 75014, France. · Department of Digestive Oncology, Beaujon Hospital (AP-HP), 100 boulevard du General Leclerc, Clichy 92110, France. ·Br J Cancer · Pubmed #27404456.

ABSTRACT: BACKGROUND: The management of locally advanced pancreatic cancer (LAPC) patients remains controversial. Better discrimination for overall survival (OS) at diagnosis is needed. We address this issue by developing and validating a prognostic nomogram and a score for OS in LAPC (PROLAP). METHODS: Analyses were derived from 442 LAPC patients enrolled in the LAP07 trial. The prognostic ability of 30 baseline parameters was evaluated using univariate and multivariate Cox regression analyses. Performance assessment and internal validation of the final model were done with Harrell's C-index, calibration plot and bootstrap sample procedures. On the basis of the final model, a prognostic nomogram and a score were developed, and externally validated in 106 consecutive LAPC patients treated in Besançon Hospital, France. RESULTS: Age, pain, tumour size, albumin and CA 19-9 were independent prognostic factors for OS. The final model had good calibration, acceptable discrimination (C-index=0.60) and robust internal validity. The PROLAP score has the potential to delineate three different prognosis groups with median OS of 15.4, 11.7 and 8.5 months (log-rank P<0.0001). The score ability to discriminate OS was externally confirmed in 63 (59%) patients with complete clinical data derived from a data set of 106 consecutive LAPC patients; median OS of 18.3, 14.1 and 7.6 months for the three groups (log-rank P<0.0001). CONCLUSIONS: The PROLAP nomogram and score can accurately predict OS before initiation of induction chemotherapy in LAPC-untreated patients. They may help to optimise clinical trials design and might offer the opportunity to define risk-adapted strategies for LAPC management in the future.

11 Clinical Trial A Novel Biomarker Panel Examining Response to Gemcitabine with or without Erlotinib for Pancreatic Cancer Therapy in NCIC Clinical Trials Group PA.3. 2016

Shultz, David B / Pai, Jonathan / Chiu, Wayland / Ng, Kendall / Hellendag, Madeline G / Heestand, Gregory / Chang, Daniel T / Tu, Dongsheng / Moore, Malcolm J / Parulekar, Wendy R / Koong, Albert C. ·Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · School of Medicine, University of California San Francisco, San Francisco, United States of America. · Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States of America. · Kaiser Permanente Medical Center, San Francisco, United States of America. · Moores Cancer Center, University of California San Diego, La Jolla, CA, United States of America. · NCIC Clinical Trials Group, Queen's University, Kingston, Canada. · British Columbia Cancer Agency, Vancouver, British Columbia, CA, United States of America. ·PLoS One · Pubmed #26808546.

ABSTRACT: PURPOSE: NCIC Clinical Trials Group PA.3 was a randomized control trial that demonstrated improved overall survival (OS) in patients receiving erlotinib in addition to gemcitabine for locally advanced or metastatic pancreatic cancer. Prior to therapy, patients had plasma samples drawn for future study. We sought to identify biomarkers within these samples. EXPERIMENTAL DESIGN: Using the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies for 35 key proteins selected from a global genetic analysis of pancreatic cancers, and used to quantify protein levels in 20 uL of patient plasma. To determine if any of these proteins levels independently associated with OS, univariate and mulitbaraible Cox models were used. In addition, we examined the associations between biomarker expression and disease stage at diagnosis using Fisher's exact test. The correlation between Erlotinib sensitivity and each biomarkers was assessed using a test of interaction between treatment and biomarker. RESULTS AND CONCLUSION: Of the 569 eligible patients, 480 had samples available for study. Samples were randomly allocated into training (251) and validation sets (229). Among all patients, elevated levels of interleukin-8 (IL-8), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1-alpha (HIF-1 alpha), and interleukin-6 were independently associated with lower OS, while IL-8, CEA, platelet-derived growth factor receptor alpha and mucin-1 were associated with metastatic disease. Patients with elevated levels of receptor tyrosine-protein kinase erbB-2 (HER2) expression had improved OS when treated with erlotinib compared to placebo. In conclusion, PLA is a powerful tool for identifying biomarkers from archived, small volume serum samples. These data may be useful to stratify patient outcomes regardless of therapeutic intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00040183.

12 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.

13 Clinical Trial A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. 2015

Fuchs, C S / Azevedo, S / Okusaka, T / Van Laethem, J-L / Lipton, L R / Riess, H / Szczylik, C / Moore, M J / Peeters, M / Bodoky, G / Ikeda, M / Melichar, B / Nemecek, R / Ohkawa, S / Świeboda-Sadlej, A / Tjulandin, S A / Van Cutsem, E / Loberg, R / Haddad, V / Gansert, J L / Bach, B A / Carrato, A. ·Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA charles_fuchs@dfci.harvard.edu. · Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. · Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia. · Department of Hematology, Oncology, and Tumor Immunology, Charité University, Berlin, Germany. · Department of Oncology, Military Institute of Health Services, Warsaw, Poland. · Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Oncology, Antwerp University Hospital, Edegum, Belgium. · Department of Oncology, St László Hospital, Budapest, Hungary. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc. · Department of Oncology, Masaryk University Medical School and Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. · Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Center, Moscow, Russia. · Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Medical Sciences, Amgen Inc., Thousand Oaks, USA. · Global Biostatistical Science, Amgen Ltd, Cambridge, UK. · Global Development, Thousand Oaks. · Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, USA. · Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain. ·Ann Oncol · Pubmed #25609246.

ABSTRACT: BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

14 Clinical Trial Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors. 2015

Hobday, Timothy J / Qin, Rui / Reidy-Lagunes, Diane / Moore, Malcolm J / Strosberg, Jonathan / Kaubisch, Andreas / Shah, Manisha / Kindler, Hedy Lee / Lenz, Heinz-Josef / Chen, Helen / Erlichman, Charles. ·Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN · Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York · Andreas Kaubisch, Montefiore Medical Center, Bronx, NY · Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada · Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL · Manisha Shah, Ohio State University, Columbus, OH · Hedy Lee Kindler, University of Chicago, Chicago, IL · Heinz-Josef Lenz, University of Southern California, Los Angeles, CA · and Helen Chen, National Cancer Institute, Rockville, MD. ·J Clin Oncol · Pubmed #25488966.

ABSTRACT: PURPOSE: There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. PATIENTS AND METHODS: We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. RESULTS: A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). CONCLUSION: The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

15 Clinical Trial A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. 2014

Aglietta, M / Barone, C / Sawyer, M B / Moore, M J / Miller, W H / Bagalà, C / Colombi, F / Cagnazzo, C / Gioeni, L / Wang, E / Huang, B / Fly, K D / Leone, F. ·Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin massimo.aglietta@ircc.it. · Department of Medical Oncology, Catholic University of the Sacred Heart, Rome, Italy. · Department of Oncology, University of Alberta, Edmonton. · Division of Medical Oncology, Princess Margaret Hospital and University of Toronto, Toronto. · Department of Oncology, McGill University, Montreal, Canada. · Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin. · Pfizer Oncology Global Research and Development, Groton, USA. ·Ann Oncol · Pubmed #24907635.

ABSTRACT: BACKGROUND: Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. RESULTS: From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). CONCLUSION: Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer. CLINICALTRIALSGOV ID: NCT00556023.

16 Clinical Trial A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. 2014

Renouf, D J / Tang, P A / Hedley, D / Chen, E / Kamel-Reid, S / Tsao, M S / Tran-Thanh, D / Gill, S / Dhani, N / Au, H J / Wang, L / Moore, M J. ·British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. Electronic address: drenouf@bccancer.bc.ca. · Tom Baker Cancer Centre, Calgary, AB, Canada. · University Health Network-Princess Margaret Cancer Centre, Toronto, ON, Canada. · British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. · Cross Cancer Institute, Edmonton, AB, Canada. ·Eur J Cancer · Pubmed #24857345.

ABSTRACT: BACKGROUND: Erlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine. METHODS: Erlotinib was given at an initial dose of 150 mg/day, and the dose was escalated by 50mg every 2 weeks (to a maximum of 300 mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8 weeks). RESULTS: Fifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200-300 mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾ grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17-47%)). Disease control was observed in nine patients (24% (95% CI: 10-38%)). Median survival was 3.8 months, and 6 month overall survival rate was 32% (95% CI 19-47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival. CONCLUSIONS: Erlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.

17 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.).

18 Clinical Trial A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer. 2013

Kim, Edward J / Ben-Josef, Edgar / Herman, Joseph M / Bekaii-Saab, Tanios / Dawson, Laura A / Griffith, Kent A / Francis, Isaac R / Greenson, Joel K / Simeone, Diane M / Lawrence, Theodore S / Laheru, Daniel / Wolfgang, Christopher L / Williams, Terence / Bloomston, Mark / Moore, Malcolm J / Wei, Alice / Zalupski, Mark M. ·Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. ·Cancer · Pubmed #23720019.

ABSTRACT: BACKGROUND: The purpose of this study was to evaluate preoperative treatment with full-dose gemcitabine, oxaliplatin, and radiation therapy (RT) in patients with localized pancreatic cancer. METHODS: Eligibility included confirmation of adenocarcinoma, resectable or borderline resectable disease, a performance status ≤2, and adequate organ function. Treatment consisted of two 28-day cycles of gemcitabine (1 g/m(2) over 30 minutes on days 1, 8, and 15) and oxaliplatin (85 mg/m(2) on days 1 and 15) with RT during cycle 1 (30 Gray [Gy] in 2-Gy fractions). Patients were evaluated for surgery after cycle 2. Patients who underwent resection received 2 cycles of adjuvant chemotherapy. RESULTS: Sixty-eight evaluable patients received treatment at 4 centers. By central radiology review, 23 patients had resectable disease, 39 patients had borderline resectable disease, and 6 patients had unresectable disease. Sixty-six patients (97%) completed cycle 1 with RT, and 61 patients (90%) completed cycle 2. Grade ≥3 adverse events during preoperative therapy included neutropenia (32%), thrombocytopenia (25%), and biliary obstruction/cholangitis (14%). Forty-three patients underwent resection (63%), and complete (R0) resection was achieved in 36 of those 43 patients (84%). The median overall survival was 18.2 months (95% confidence interval, 13-26.9 months) for all patients, 27.1 months (95% confidence interval, 21.2-47.1 months) for those who underwent resection, and 10.9 months (95% confidence interval, 6.1-12.6 months) for those who did not undergo resection. A decrease in CA 19-9 level after neoadjuvant therapy was associated with R0 resection (P = .02), which resulted in a median survival of 34.6 months (95% confidence interval, 20.3-47.1 months). Fourteen patients (21%) are alive and disease free at a median follow-up of 31.4 months (range, 24-47.6 months). CONCLUSIONS: Preoperative therapy with full-dose gemcitabine, oxaliplatin, and RT was feasible and resulted in a high percentage of R0 resections. The current results are particularly encouraging, because the majority of patients had borderline resectable disease.

19 Clinical Trial Comorbidity, age and overall survival in patients with advanced pancreatic cancer - results from NCIC CTG PA.3: a phase III trial of gemcitabine plus erlotinib or placebo. 2012

Vickers, M M / Powell, E D / Asmis, T R / Jonker, D J / Hilton, J F / O'Callaghan, C J / Tu, D / Parulekar, W / Moore, M J. ·Department of Oncology, Tom Baker Cancer Centre, Alberta, Canada. michael.vickers@albertahealthservices.ca ·Eur J Cancer · Pubmed #22119354.

ABSTRACT: BACKGROUND: The effect of comorbidity, age and performance status (PS) on treatment of advanced pancreatic cancer is poorly understood. We examined these factors as predictors of outcome in advanced pancreatic cancer patients treated with gemcitabine +/- erlotinib. PATIENTS AND METHODS: Comorbidity was evaluated by two physicians using the Charlson Comorbidity Index (CCI) and correlated with clinical outcome data from the NCIC Clinical Trials Group (NCIC CTG) PA.3 clinical trial. RESULTS: Five hundred and sixty-nine patients were included; 47% were aged ≥ 65 years old, 36% had comorbidity (CCI>0). In multivariate analysis, neither age (p=0.22) nor comorbidity (p=0.21) was associated with overall survival. The baseline presence of better PS and lower pain intensity scores was associated with better overall survival (p < 0.0001 and p=0.01, respectively). An improvement in survival with the addition of erlotinib therapy was seen in patients age < 65 (adjusted hazard ratio (HR) 0.73, p=0.01) or in the presence of comorbidity (adjusted HR 0.72, p=0.03). However, neither age nor CCI score was predictive of erlotinib benefit after test for interaction. Patients treated with gemcitabine plus erlotinib who were ≥ 65 years of age or those with comorbidity had a higher rate of infections ≥ grade 3. CONCLUSION: Low baseline pain intensity and better PS were associated with improved overall survival, while age and comorbidity were not independent prognostic factors for patients treated with gemcitabine-based therapy.

20 Clinical Trial Phase I study of axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer. 2012

Spano, Jean-Philippe / Moore, Malcolm J / Pithavala, Yazdi K / Ricart, Alejandro D / Kim, Sinil / Rixe, Olivier. ·Groupe Hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. jean-philippe.spano@psl.aphp.fr ·Invest New Drugs · Pubmed #21670972.

ABSTRACT: PURPOSE: Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. PATIENTS AND METHODS: Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m(2)), C1D14 (steady state, axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state axitinib). Adverse events were monitored weekly at the clinic. RESULTS: Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. CONCLUSIONS: Axitinib (5 mg BID) and gemcitabine (1,000 mg/m(2)) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity.

21 Clinical Trial A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer. 2012

Renouf, Daniel J / Tang, Patricia A / Major, Pierre / Krzyzanowska, Monika K / Dhesy-Thind, Bindi / Goffin, John R / Hedley, David / Wang, Lisa / Doyle, L / Moore, Malcolm J. ·University Health Network-Princess Margaret Hospital, Toronto, ON, Canada. ·Invest New Drugs · Pubmed #21526355.

ABSTRACT: BACKGROUND: Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. RESULTS: Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. CONCLUSION: Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.

22 Clinical Trial A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer. 2012

Renouf, Daniel J / Moore, Malcolm J / Hedley, David / Gill, Sharlene / Jonker, Derek / Chen, Eric / Walde, David / Goel, Rakesh / Southwood, Bernadette / Gauthier, Isabelle / Walsh, Wendy / McIntosh, Lynn / Seymour, Lesley. ·Division of Medical Oncology and Hematology, Rm 5-708, Princess Margaret Hospital, 610 University Avenue, Toronto M5G2M9, Canada. ·Invest New Drugs · Pubmed #21170669.

ABSTRACT: AIM: This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m(2)) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥ 4 months (SD4) rate; if ≥ 8 patients had OR+SD4, the study would proceed to stage 2. RESULTS: Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients. CONCLUSION: Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.

23 Clinical Trial Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. 2010

da Cunha Santos, Gilda / Dhani, Neesha / Tu, Dongsheng / Chin, Kayu / Ludkovski, Olga / Kamel-Reid, Suzanne / Squire, Jeremy / Parulekar, Wendy / Moore, Malcolm J / Tsao, Ming Sound. ·Department of Pathology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada. ·Cancer · Pubmed #20824720.

ABSTRACT: BACKGROUND: National Cancer Institute of Canada Clinical Trials Group PA.3 (NCIC CTG PA.3) was a phase 3 study (n = 569) that demonstrated benefits for overall survival and progression-free survival with the addition of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to gemcitabine in patients with advanced pancreatic carcinoma (APC). Mutation status of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR gene copy number (GCN) were evaluated as predictive markers in 26% of patients who had tumor samples available for analysis. METHODS: KRAS mutation status was evaluated by direct sequencing of exon 2, and EGFR GCN was determined by fluorescence in situ hybridization (FISH) analysis. The results were correlated with survival, which was the primary endpoint of the trial. RESULTS: KRAS analysis was successful in 117 patients, and EGFR FISH analysis was successful in 107 patients. KRAS mutations were identified in 92 patients (78.6%), and EGFR amplification or high polysomy (FISH-positive results) was identified in 50 patients (46.7%). The hazard ratio of death between gemcitabine/erlotinib and gemcitabine/placebo was 0.66 (95% confidence interval [CI], 0.28-1.57) for patients with wild-type KRAS and 1.07 (95% CI, 0.68-1.66) for patients with mutant KRAS (P value for interaction = .38), and the hazard ratio was 0.6 (95% CI, 0.34-1.07) for FISH-negative patients and 0.90 (95% CI, 0.49-1.65) for FISH-positive patients (P value for interaction = .32). CONCLUSIONS: In a molecular subset analysis of patients from NCIC CTG PA.3, EGFR GCN and KRAS mutation status were not identified as markers predictive of a survival benefit from the combination of erlotinib with gemcitabine for the first-line treatment of APC.

24 Clinical Trial Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. 2010

Neoptolemos, John P / Stocken, Deborah D / Bassi, Claudio / Ghaneh, Paula / Cunningham, David / Goldstein, David / Padbury, Robert / Moore, Malcolm J / Gallinger, Steven / Mariette, Christophe / Wente, Moritz N / Izbicki, Jakob R / Friess, Helmut / Lerch, Markus M / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Doi, Ryuichiro / Lind, Pehr A / Smith, David / Valle, Juan W / Palmer, Daniel H / Buckels, John A / Thompson, Joyce / McKay, Colin J / Rawcliffe, Charlotte L / Büchler, Markus W / Anonymous9620671. ·Liverpool Cancer Research UK Cancer Trials Unit, Cancer Research UK Centre, University of Liverpool, Fifth Floor, UCD Bldg, Daulby Street, Liverpool, L69 3GA, United Kingdom. j.p.neoptolemos@liverpool.ac.uk ·JAMA · Pubmed #20823433.

ABSTRACT: CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

25 Clinical Trial Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. 2009

Van Cutsem, Eric / Vervenne, Walter L / Bennouna, Jaafar / Humblet, Yves / Gill, Sharlene / Van Laethem, Jean-Luc / Verslype, Chris / Scheithauer, Werner / Shang, Aijing / Cosaert, Jan / Moore, Malcolm J. ·University Hospital Gasthuisberg/Leuven, Digestive Oncology Unit, Herestraat 49, B-3000 Leuven, Belgium. eric.vancutsem@uz.kuleuven.ac.be ·J Clin Oncol · Pubmed #19307500.

ABSTRACT: PURPOSE: Treatment with gemcitabine provides modest benefits in patients with metastatic pancreatic cancer. The addition of erlotinib to gemcitabine shows a small but significant improvement in overall survival (OS) versus gemcitabine alone. Phase II results for bevacizumab plus gemcitabine provided the rationale for a phase III trial of gemcitabine-erlotinib plus bevacizumab or placebo. PATIENTS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine (1,000 mg/m(2)/week), erlotinib (100 mg/day), and bevacizumab (5 mg/kg every 2 weeks) or gemcitabine, erlotinib, and placebo in this double-blind, phase III trial. Primary end point was OS; secondary end points included progression-free survival (PFS), disease control rate, and safety. RESULTS: A total of 301 patients were randomly assigned to the placebo group and 306 to the bevacizumab group. Median OS was 7.1 and 6.0 months in the bevacizumab and placebo arms, respectively (hazard ratio [HR], 0.89; 95% CI, 0.74 to 1.07; P = .2087); this difference was not statistically significant. Adding bevacizumab to gemcitabine-erlotinib significantly improved PFS (HR, 0.73; 95% CI, 0.61 to 0.86; P = .0002). Treatment with bevacizumab plus gemcitabine-erlotinib was well tolerated: safety data did not differ from previously described safety profiles for individual drugs. CONCLUSION: The primary objective was not met. The addition of bevacizumab to gemcitabine-erlotinib did not lead to a statistically significant improvement in OS in patients with metastatic pancreatic cancer. PFS, however, was significantly longer in the bevacizumab group compared with placebo. No unexpected safety events were observed from adding bevacizumab to gemcitabine-erlotinib.