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Pancreatic Neoplasms: HELP
Articles by Hedy Lee Kindler
Based on 28 articles published since 2009
(Why 28 articles?)
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Between 2009 and 2019, H. Kindler wrote the following 28 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial A Glimmer of Hope for Pancreatic Cancer. 2018

Kindler, Hedy L. ·From the Section of Hematology-Oncology, University of Chicago Medicine, Chicago. ·N Engl J Med · Pubmed #30575492.

ABSTRACT: -- No abstract --

2 Review Current controversies in the stage-specific multidisciplinary management of pancreatic cancer. 2014

Katz, Matthew H G / Landry, Jerome / Kindler, Hedy Lee. ·From The University of Texas MD Anderson Cancer Center, Houston, TX; Winship Cancer Institute, Emory University, Atlanta, GA; Section of Hematology/Oncology, University of Chicago, Chicago, IL. ·Am Soc Clin Oncol Educ Book · Pubmed #24857097.

ABSTRACT: Encouraging therapeutic approaches and treatment regimens for patients with both localized and metastatic pancreatic cancer have emerged over the last 5 years. However, these new strategies have brought important challenges and controversy. Clinical staging criteria are constantly evolving. No system has been uniformly adopted, limiting our understanding of the role of both pancreatectomy and neoadjuvant therapies for localized disease. The role of radiation therapy for the treatment of both resectable and unresectable pancreatic cancer remains unclear despite multiple prospective studies. Although two new systemic chemotherapy regimens have essentially transformed the care of many patients with metastatic cancer, criteria to guide their use in the general population have yet to be clearly established. Herein we provide an overview of these important controversies in the context of a broad update on the stage-specific management of patients with newly diagnosed pancreatic cancer.

3 Review Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. 2013

Katz, Matthew H G / Marsh, Robert / Herman, Joseph M / Shi, Qian / Collison, Eric / Venook, Alan P / Kindler, Hedy L / Alberts, Steven R / Philip, Philip / Lowy, Andrew M / Pisters, Peter W T / Posner, Mitchell C / Berlin, Jordan D / Ahmad, Syed A. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhgkatz@mdanderson.org ·Ann Surg Oncol · Pubmed #23435609.

ABSTRACT: BACKGROUND: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy. METHODS: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed. RESULTS: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed. CONCLUSIONS: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.

4 Clinical Trial Maintenance Olaparib for Germline 2019

Golan, Talia / Hammel, Pascal / Reni, Michele / Van Cutsem, Eric / Macarulla, Teresa / Hall, Michael J / Park, Joon-Oh / Hochhauser, Daniel / Arnold, Dirk / Oh, Do-Youn / Reinacher-Schick, Anke / Tortora, Giampaolo / Algül, Hana / O'Reilly, Eileen M / McGuinness, David / Cui, Karen Y / Schlienger, Katia / Locker, Gershon Y / Kindler, Hedy L. ·From the Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (T.G.) · Hôpital Beaujon (Assistance Publique-Hôpitaux de Paris), Clichy, and University Paris VII, Paris (P.H.) · IRCCS Ospedale San Raffaele Scientific Institute, Milan (M.R.), Azienda Ospedaliera Universitaria Integrata Verona, Verona (G.T.), and Fondazione Policlinico Universitario Gemelli IRCCS, Rome (G.T.) - all in Italy · University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.) · Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (T.M.) · Fox Chase Cancer Center, Philadelphia (M.J.H.) · Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-O.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (D.-Y.O.) - both in Seoul, South Korea · University College London Cancer Institute, London (D.H.), and AstraZeneca, Cambridge (D.M.) - both in the United Kingdom · Asklepios Tumorzentrum Hamburg Asklepios Klinik Altona, Hamburg (D.A.), St. Josef-Hospital, Ruhr University Bochum, Bochum (A.R.-S.), and Klinikum rechts der Isar, Department of Internal Medicine II, Technische Universität München, Munich (H.A.) - all in Germany · Memorial Sloan Kettering Cancer Center, New York (E.M.O.) · AstraZeneca, Gaithersburg, MD (K.Y.C., G.Y.L.) · Merck, Kenilworth, NJ (K.S.) · and the University of Chicago, Chicago (H.L.K.). ·N Engl J Med · Pubmed #31157963.

ABSTRACT: BACKGROUND: Patients with a germline METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline

5 Clinical Trial The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. 2018

Innocenti, Federico / Owzar, Kouros / Jiang, Chen / Etheridge, Amy S / Gordân, Raluca / Sibley, Alexander B / Mulkey, Flora / Niedzwiecki, Donna / Glubb, Dylan / Neel, Nicole / Talamonti, Mark S / Bentrem, David J / Seiser, Eric / Yeh, Jen Jen / Van Loon, Katherine / McLeod, Howard / Ratain, Mark J / Kindler, Hedy L / Venook, Alan P / Nakamura, Yusuke / Kubo, Michiaki / Petersen, Gloria M / Bamlet, William R / McWilliams, Robert R. ·UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, United States of America. · Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America. · Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America. · North Shore University Health System, Evanston, IL, United States of America. · Northwestern University, Chicago, IL, United States of America. · University of California at San Francisco, San Francisco, CA, United States of America. · Moffitt Cancer Center, Tampa, FL, United States of America. · University of Chicago, Chicago, IL, United States of America. · Center for Genomic Medicine, RIKEN, Yokohama, Japan. · Mayo Clinic, Rochester, MN, United States of America. ·PLoS One · Pubmed #30107003.

ABSTRACT: PURPOSE: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. PATIENTS AND METHODS: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. RESULTS: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63-0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. CONCLUSION: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.

6 Clinical Trial Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. 2018

O'Reilly, Eileen M / Lee, Jonathan W / Lowery, Maeve A / Capanu, Marinela / Stadler, Zsofia K / Moore, Malcolm J / Dhani, Neesha / Kindler, Hedy L / Estrella, Hayley / Maynard, Hannah / Golan, Talia / Segal, Amiel / Salo-Mullen, Erin E / Yu, Kenneth H / Epstein, Andrew S / Segal, Michal / Brenner, Robin / Do, Richard K / Chen, Alice P / Tang, Laura H / Kelsen, David P. ·Memorial Sloan Kettering Cancer Center, New York, New York. · Weill Cornell Medicine, New York, New York. · Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. · University of Chicago Medical Center, Chicago, Illinois. · 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, Maryland. ·Cancer · Pubmed #29338080.

ABSTRACT: BACKGROUND: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. METHODS: Gemcitabine and cisplatin were dosed at 600 and 25 mg/m RESULTS: Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). CONCLUSIONS: The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society.

7 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).

8 Clinical Trial Primary systemic therapy in resectable pancreatic ductal adenocarcinoma using mFOLFIRINOX: A pilot study. 2018

de W Marsh, Robert / Talamonti, Mark S / Baker, Marshall S / Posner, Mitchell / Roggin, Kevin / Matthews, Jeffrey / Catenacci, Daniel / Kozloff, Mark / Polite, Blase / Britto, Michele / Wang, Chi / Kindler, Hedy. ·Department of Medicine, Kellogg Cancer Center, NorthShore University HealthSystem, Evanston, Illinois. · Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois. · Department of Surgery, The University of Chicago Medicine, Chicago, Illinois. · Department of Medicine, The University of Chicago Medicine, Chicago, Illinois. ·J Surg Oncol · Pubmed #29044544.

ABSTRACT: BACKGROUND AND OBJECTIVES: Surgery followed by gemcitabine and/or a fluoropyrimidine is standard therapy for resectable PDAC. mFOLFIRINOX (oxaliplatin 85 mg/m METHODS: Patients with resectable PDAC (ECOG PS 0/1) received four cycles of mFOLFIRINOX pre- and post-surgery. The primary endpoint was completion of preoperative chemotherapy plus resection. Secondary endpoints included completion of all therapy, R0 resection, treatment related toxicity, PFS, and OS. RESULTS: Twenty-one patients enrolled: median age 62 (47-78); 20/21 (95%) completed four cycles of preoperative mFOLFIRINOX; response by RECIST was 1 CR, 3 PR, 16 SD; 17/21 (81%) completed resection, 16/21 (76%) R0; 14/21 (66%) completed four cycles of postoperative mFOLFIRINOX. Grade 3 and 4 toxicity occurred in 23% and 14% patients pre-operatively, 26% and 6.0% post-operatively. Nine patients are alive with median follow-up of 27.7 (3.1-47.1) months. CONCLUSIONS: PST using mFOLFIRINOX in resectable PDAC is feasible and tolerable. R0 resection rate is high and survival promising, requiring longer follow-up and larger studies for definitive assessment.

9 Clinical Trial Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101. 2016

Katz, Matthew H G / Shi, Qian / Ahmad, Syed A / Herman, Joseph M / Marsh, Robert de W / Collisson, Eric / Schwartz, Lawrence / Frankel, Wendy / Martin, Robert / Conway, William / Truty, Mark / Kindler, Hedy / Lowy, Andrew M / Bekaii-Saab, Tanios / Philip, Philip / Talamonti, Mark / Cardin, Dana / LoConte, Noelle / Shen, Perry / Hoffman, John P / Venook, Alan P. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. · Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. · Department of Surgery, University of Cincinnati, Cincinnati, Ohio. · Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland. · Department of Medical Oncology, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, University of California-San Francisco, San Francisco. · Department of Radiology, Columbia University, New York, New York. · Department of Pathology, Ohio State University, Columbus. · Department of Surgery, University of Louisville, Louisville, Kentucky. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Surgery, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, University of Chicago, Chicago, Illinois. · Department of Surgery, University of California, San Diego. · Department of Medical Oncology, Ohio State University, Columbus. · Department of Medical Oncology, Karmanos Cancer Center, Detroit, Michigan. · Department of Surgery, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, Vanderbilt University, Nashville, Tennessee. · Department of Medical Oncology, University of Wisconsin-Madison, Madison, Wisconsin. · Department of Surgery, Wake Forest University, Winston Salem, North Carolina. · Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania. ·JAMA Surg · Pubmed #27275632.

ABSTRACT: IMPORTANCE: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. INTERVENTIONS: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01821612.

10 Clinical Trial A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma. 2016

Ko, Andrew H / LoConte, Noelle / Tempero, Margaret A / Walker, Evan J / Kate Kelley, R / Lewis, Stephanie / Chang, Wei-Chou / Kantoff, Emily / Vannier, Michael W / Catenacci, Daniel V / Venook, Alan P / Kindler, Hedy L. ·From the *Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA; †Division of Hematology/Oncology, University of Wisconsin, Madison, WI; ‡Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; and §Department of Radiology and ∥Division of Hematology/Oncology, University of Chicago, Chicago, IL. ·Pancreas · Pubmed #26390428.

ABSTRACT: OBJECTIVES: In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer. METHODS: Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion. RESULTS: The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination. CONCLUSIONS: This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.

11 Clinical Trial Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer. 2015

Catenacci, Daniel V T / Junttila, Melissa R / Karrison, Theodore / Bahary, Nathan / Horiba, Margit N / Nattam, Sreenivasa R / Marsh, Robert / Wallace, James / Kozloff, Mark / Rajdev, Lakshmi / Cohen, Deirdre / Wade, James / Sleckman, Bethany / Lenz, Heinz-Josef / Stiff, Patrick / Kumar, Pankaj / Xu, Peng / Henderson, Les / Takebe, Naoko / Salgia, Ravi / Wang, Xi / Stadler, Walter M / de Sauvage, Frederic J / Kindler, Hedy L. ·Daniel V.T. Catenacci, Theodore Karrison, James Wallace, Mark Kozloff, Peng Xu, Les Henderson, Ravi Salgia, Walter M. Stadler, Hedy L. Kindler, University of Chicago Medical Center · Patrick Stiff, Loyola University Medical Center, Chicago · Robert Marsh, Northshore University Health System, Evanston · James Wallace, Mark Kozloff, Ingalls Hospital, Harvey · James Wade, Decatur Memorial Hospital, Decatur · Pankaj Kumar, Oncology/Hematology Associates, Peoria, IL · Melissa R. Junttila, Xi Wang, and Frederic J. de Sauvage, Genentech, South San Francisco · Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA · Nathan Bahary, University of Pittsburgh Cancer Institute, Pittsburgh, PA · Margit N. Horiba, University of Maryland Greenebaum Cancer Center, Baltimore, MD · Sreenivasa R. Nattam, Ft Wayne Medical Oncology/Hematology, Ft Wayne, IN · Lakshmi Rajdev, Montefiore Medical Center, Bronx · Deirdre Cohen, New York University Cancer Center, New York, NY · Bethany Sleckman, St John's Mercy Medical Center, St Louis, MO · and Naoko Takebe, National Cancer Institute, National Institutes of Health, Bethesda, MD. ·J Clin Oncol · Pubmed #26527777.

ABSTRACT: PURPOSE: Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. PATIENTS AND METHODS: Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (Kras(G12D); p16/p19(fl/fl); Pdx1-Cre and Kras(G12D); p53(R270H/wt); Pdx1-Cre) were studied. RESULTS: No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. CONCLUSION: The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

12 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.

13 Clinical Trial Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. 2013

McCaffery, Ian / Tudor, Yanyan / Deng, Hongjie / Tang, Rui / Suzuki, Samuel / Badola, Sunita / Kindler, Hedy L / Fuchs, Charles S / Loh, Elwyn / Patterson, Scott D / Chen, Li / Gansert, Jennifer L. ·Genentech, One DNA Way, South San Francisco, CA 94080, USA. mccaffery.ian@gene.com ·Clin Cancer Res · Pubmed #23741071.

ABSTRACT: PURPOSE: This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated. RESULTS: For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28-0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09-0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09-0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11-0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07-0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS. CONCLUSIONS: Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma.

14 Clinical Trial A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. 2012

Kindler, H L / Richards, D A / Garbo, L E / Garon, E B / Stephenson, J J / Rocha-Lima, C M / Safran, H / Chan, D / Kocs, D M / Galimi, F / McGreivy, J / Bray, S L / Hei, Y / Feigal, E G / Loh, E / Fuchs, C S. ·Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu ·Ann Oncol · Pubmed #22700995.

ABSTRACT: BACKGROUND: We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS: Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.

15 Clinical Trial Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the cancer and leukemia group B (CALGB 80303). 2012

Romanus, Dorothy / Kindler, Hedy L / Archer, Laura / Basch, Ethan / Niedzwiecki, Donna / Weeks, Jane / Schrag, Deborah / Anonymous4121223. ·Massachusetts General Hospital, Harvard School of Public Health, Boston, Massachusetts, USA. ·J Pain Symptom Manage · Pubmed #22104618.

ABSTRACT: CONTEXT: Gemcitabine for advanced pancreatic cancer (APC) is palliative and the prognosis is poor, making health-related quality of life (HRQOL) particularly important. OBJECTIVES: We evaluated HRQOL with the EuroQol (EQ-5D™) in patients with APC participating in Cancer and Leukemia Group B 80303, a multicenter, double-blind, randomized trial comparing overall survival (OS) between two treatment arms: gemcitabine with bevacizumab or gemcitabine with placebo. METHODS: A consecutive subsample of patients was invited to complete the EQ-5D surveys. Because neither clinical nor HRQOL outcomes differed based on the study arm, analyses were pooled. Changes in mean scores from baseline to eight weeks and the prognostic value of the EQ-5D were evaluated. RESULTS: Mean index scores remained stable (0.78 at baseline [n=267], 0.79 at eight weeks [n=186], P=0.34, Wilcoxon signed rank test), attributable to a modest deterioration of physical function domain scores coincident with small improvements in pain and anxiety/depression scores. A small decline in visual analogue scale scores was observed (70.7 vs. 68.2, P=0.026). HRQOL changes within chemotherapy response strata revealed stable index scores but a trend of worsened physical function among patients with disease progression compared with those with stable or improved disease. Visual analogue scale scores trended downward over time irrespective of chemotherapy response status, with a statistically meaningful deterioration in patients who progressed (68.9 vs. 64.4, P=0.029). Baseline scores from both EQ-5D scales were significant predictors of OS in Cox proportional hazard models. CONCLUSION: Response to gemcitabine treatment in APC is not associated with appreciable improvement of global HRQOL. Small improvements in pain and mood are observed despite progressive functional decline. Those who respond to gemcitabine may experience a slight slowing of functional deterioration.

16 Clinical Trial Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. 2012

Kindler, Hedy Lee / Wroblewski, Kristen / Wallace, James A / Hall, Michael J / Locker, Gershon / Nattam, Sreenivasa / Agamah, Edem / Stadler, Walter M / Vokes, Everett E. ·Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu ·Invest New Drugs · Pubmed #20803052.

ABSTRACT: BACKGROUND: Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. PATIENTS AND METHODS: We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of a 28 day cycle. RESULTS: Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. CONCLUSION: Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.

17 Clinical Trial Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. 2011

Kindler, Hedy L / Ioka, Tatsuya / Richel, Dirk J / Bennouna, Jaafar / Létourneau, Richard / Okusaka, Takuji / Funakoshi, Akihiro / Furuse, Junji / Park, Young Suk / Ohkawa, Shinichi / Springett, Gregory M / Wasan, Harpreet S / Trask, Peter C / Bycott, Paul / Ricart, Alejandro D / Kim, Sinil / Van Cutsem, Eric. ·University of Chicago Comprehensive Cancer Center, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu ·Lancet Oncol · Pubmed #21306953.

ABSTRACT: BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. FUNDING: Pfizer.

18 Clinical Trial A Cancer and Leukemia Group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603). 2010

O'Reilly, Eileen M / Niedzwiecki, Donna / Hall, Margaret / Hollis, Donna / Bekaii-Saab, Tanios / Pluard, Timothy / Douglas, Kathe / Abou-Alfa, Ghassan K / Kindler, Hedy L / Schilsky, Richard L / Goldberg, Richard M / Anonymous2850681. ·Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. oreillye@mskcc.org ·Oncologist · Pubmed #21148613.

ABSTRACT: BACKGROUND: The Cancer and Leukemia Group B (CALGB) conducted a phase II study evaluating sunitinib in patients with progressive metastatic pancreas adenocarcinoma following prior gemcitabine-based therapy (trial CALGB 80603; ClinicalTrials.gov identifier, NCT00397787). The primary endpoint was to determine the disease control rate (DCR) as measured by the Response Evaluation Criteria in Solid Tumors (complete response, partial response [PR], and stable disease) at 6 weeks. PATIENTS AND METHODS: Patients aged ≥18 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 and with progressive pancreas adenocarcinoma following treatment with gemcitabine were eligible. Sunitinib was dosed at 50 mg orally days 1-28, every 42 days (1 cycle). The statistical plan called for a three-stage design. A DCR ≥15% was considered worthy of further study. RESULTS: In total, 77 patients were enrolled. Forty-two (54.6%) enrollees were male. The median age was 65 years. The ECOG performance status score distribution was: 0, 39%; 1, 50%; 2, 11%. The DCR was 21.6%; one patient (1.4%) had a PR and 15 patients (20.3%) had stable disease as their best response. The progression-free survival time was 1.31 months (95% confidence interval [CI] 1.25-1.38 months) and overall survival time was 3.68 months (95% CI, 3.06-4.24 months). CONCLUSIONS: The study met its primary endpoint; however sunitinib had minimal activity and moderate toxicity in a population of gemcitabine-refractory pancreas adenocarcinoma patients. For future studies, limiting enrollment to patients with an ECOG performance status score of 0-1 is recommended.

19 Clinical Trial Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). 2010

Kindler, Hedy Lee / Niedzwiecki, Donna / Hollis, Donna / Sutherland, Susan / Schrag, Deborah / Hurwitz, Herbert / Innocenti, Federico / Mulcahy, Mary Frances / O'Reilly, Eileen / Wozniak, Timothy F / Picus, Joel / Bhargava, Pankaj / Mayer, Robert J / Schilsky, Richard L / Goldberg, Richard M. ·University of Chicago Cancer Research Center, Chicago, IL 60637-1470, USA. hkindler@medicine.bsd.uchicago.edu ·J Clin Oncol · Pubmed #20606091.

ABSTRACT: PURPOSE: The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients. PATIENTS AND METHODS: Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m(2) over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. RESULTS: Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P < .001) and proteinuria (5% v 1%; P = .002); venous thrombosis grade > or = 3 was equivalent in both arms (14% and 15%, respectively). CONCLUSION: The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients.

20 Clinical Trial Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904. 2009

Kulke, Matthew H / Tempero, Margaret A / Niedzwiecki, Donna / Hollis, Donna R / Kindler, Hedy L / Cusnir, Michael / Enzinger, Peter C / Gorsch, Stefan M / Goldberg, Richard M / Mayer, Robert J. ·Dana-Farber Cancer Institute, Boston, MA, USA. matthew_kulke@dfci.harvard.edu ·J Clin Oncol · Pubmed #19858396.

ABSTRACT: PURPOSE: The relative value of gemcitabine-based combination chemotherapy therapy and prolonged infusions of gemcitabine in patients with advanced pancreatic cancer remains controversial. We explored the efficacy and toxicity of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in a multi-institutional, randomized, phase II study. PATIENTS AND METHODS: Patients with metastatic pancreatic cancer were randomly assigned to one of the following four regimens: gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 with cisplatin 50 mg/m(2) on days 1 and 15 (arm A); gemcitabine 1,500 mg/m(2) at a rate of 10 mg/m(2)/min on days 1, 8, and 15 (arm B); gemcitabine 1,000 mg/m(2) with docetaxel 40 mg/m(2) on days 1 and 8 (arm C); or gemcitabine 1,000 mg/m(2) with irinotecan 100 mg/m(2) on days 1 and 8 (arm D). Patients were observed for response, toxicity, and survival. Results Two hundred fifty-nine patients were enrolled onto the study, of whom 245 were eligible and received treatment. Anticipated rates of myelosuppression, fatigue, and expected regimen-specific toxicities were observed. The overall tumor response rates were 12% to 14%, and the median overall survival times were 6.4 to 7.1 months among the four regimens. CONCLUSION: Gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan have similar antitumor activity in metastatic pancreatic cancer. In light of recent negative randomized studies directly comparing several of these regimens with standard gemcitabine, none of these approaches can be recommended for routine use in patients with this disease.

21 Article Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. 2018

Kanteti, Rajani / Mirzapoiazova, Tamara / Riehm, Jacob J / Dhanasingh, Immanuel / Mambetsariev, Bolot / Wang, Jiale / Kulkarni, Prakash / Kaushik, Garima / Seshacharyulu, Parthasarathy / Ponnusamy, Moorthy P / Kindler, Hedy L / Nasser, Mohd W / Batra, Surinder K / Salgia, Ravi. ·a Department of Hematology/Oncology , University of Chicago Medical Center , Chicago , IL , USA. · b Department of Medical Oncology and Therapeutics Research , City of Hope, Duarte , CA , USA. · d Oncology Center, Zhujiang Hospital, Southern Medical University , Guangzhou, Guangdong Province , China. · c Department of Biochemistry and Molecular Biology , University of Nebraska Medical Center , Omaha , NE , USA. ·Cancer Biol Ther · Pubmed #29303405.

ABSTRACT: The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines. Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines. Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines. Using the ECIS (Electric cell-substrate impedance sensing) system, we found that treatment of both PF compounds suppressed adherence and migration of PDAC cells on fibronectin. Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death. Taken together, our results show that FAK is an important target for mesothelioma and pancreatic cancer therapy that merit further translational studies.

22 Article Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. 2017

Golan, Talia / Sella, Tal / O'Reilly, Eileen M / Katz, Matthew H G / Epelbaum, Ron / Kelsen, David P / Borgida, Ayelet / Maynard, Hannah / Kindler, Hedy / Friedmen, Eitan / Javle, Milind / Gallinger, Steven. ·Department of Oncology, Sheba Medical Center, Ramat Gan 52621, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. · Department of Medicine, Memorial Sloan Kettering Cancer Center New York, New York, NY 10065, USA. · Weill Cornell Medical College New York, New York, NY 10065, USA. · Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. · Department of Oncology, Rambam Health Care Campus, Haifa 3109601, Israel. · The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. · Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. · The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Ramat Gan 52621, Israel. · Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. ·Br J Cancer · Pubmed #28183138.

ABSTRACT: BACKGROUND: BRCA1/BRCA2 germ line (GL) mutation carriers with pancreatic adenocarcinoma (PDAC) may have distinct outcomes. We recently described an apparent more favourable prognosis of surgically resected BRCA-associated PDAC patients in a single-arm, uncontrolled, retrospective study. However, the prognostic impact of GL BRCA1/2 mutations in surgically resected PDAC has not been compared with a matched control population. METHODS: A larger multi-centre, case-control retrospective analysis was performed. Cases were patients with surgically resected, BRCA1/2-associated PDAC from 2004 to 2013. Controls included surgically resected PDAC cases treated during the same time period that were either BRCA non-carriers, or had no family history of breast, ovarian or pancreatic cancers. Cases and controls were matched by: age at diagnosis (within ±5-year period) and institution. Demographics, clinical history, overall survival (OS) and disease-free survival (DFS) were abstracted from patient records. Statistical comparisons were assessed using χ RESULTS: Twenty-five patients with BRCA1-(n=4) or BRCA2 (N=21)-associated resectable PDAC were identified. Mean age was 55.7 years (range, 34-78 years), 48% (n=12) were females and 76% (n=19) were Jewish. Cases were compared (1 : 2) with 49 resectable PDAC controls, and were balanced for age, ethnicity and other relevant clinical and pathological features. BRCA-associated PDAC patients received neoadjuvant, or adjuvant platinum-based treatment more frequently than controls (7 out of 8 vs 6 out of 14) and (7 out of 21 vs 3 out of 44), respectively. No significant difference in median OS (37.06 vs 38.77 months, P=0.838) and in DFS (14.3 vs 12.0 months, P=0.303) could be demonstrated between cases and controls. A trend to increased DFS was observed among BRCA-positive cases treated with neoadjuvant/adjuvant platinum-containing regimens (n=10) compared with similarly treated controls (n=7) (39.1 vs 12.4 months, P=0.255). CONCLUSIONS: In this retrospective analysis, the prognosis of surgically resectable BRCA-associated PDAC is no different than that of sporadic PDAC from the same institution. The role of platinum-based adjuvant therapy in this setting requires prospective investigation.

23 Article Generalizability of trial results to elderly Medicare patients with advanced solid tumors (Alliance 70802). 2015

Lamont, Elizabeth B / Schilsky, Richard L / He, Yulei / Muss, Hyman / Cohen, Harvey Jay / Hurria, Arti / Meilleur, Ashley / Kindler, Hedy L / Venook, Alan / Lilenbaum, Rogerio / Niell, Harvey / Goldberg, Richard M / Joffe, Steven / Anonymous320813. ·Massachusetts General Hospital Cancer Center, Boston, MA (EL) · Departments of Medicine, and Health Care Policy, Harvard Medical School, Boston, MA (EL, YH, AM) · American Society of Clinical Oncology, Alexandria, VA (RLS) · Department of Medicine, University of North Carolina, Chapel Hill, NC (HM) · Department of Medicine, Duke University, Durham, NC (HJC) · City of Hope, Duarte, CA (AH) · Department of Medicine, University of Chicago, Chicago, IL (HLK) · Department of Medicine, University of California San Francisco, San Francisco, CA (AV) · Yale Cancer Center, New Haven, CT (RL) · Department of Medicine, the University of Tennessee, Memphis, TN (HN) · Department of Medicine, Ohio State University, Columbus, OH (RMG) · Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (SJ). ·J Natl Cancer Inst · Pubmed #25432408.

ABSTRACT: BACKGROUND: In the United States, patients who enroll in chemotherapy trials seldom reflect the attributes of the general population with cancer, as they are often younger, more functional, and have less comorbidity. We compared survival following three chemotherapy regimens according to the setting in which care was delivered (ie, clinical trial vs usual care) to determine the generalizability of clinical trial results to unselected elderly Medicare patients. METHODS: Using SEER-Medicare data, we estimated survival for elderly patients (ie, age 65 years or older, n = 14097) with advanced pancreatic or lung cancer following receipt of one of three guideline-recommended first-line chemotherapy regimens. We compared their survival to that of similarly treated clinical trial enrollees, without age restrictions, with the same diagnosis and stage (n = 937). All statistical tests were two-sided. RESULTS: Trial patients were 9.5 years younger than elderly Medicare patients. Medicare patients were more often white and tended to live in areas of greater educational attainment than trial enrollees. For each tumor type, Medicare patients who were 75 years or older had median survivals that were six to eight weeks shorter than those of trial patients (4.3 vs 5.8 months following treatment with single agent gemcitabine for advanced pancreatic cancer, P = .03; 7.3 vs 8.9 months following treatment with carboplatin and paclitaxel for stage IV non-small cell lung cancer, P = .91; 8.2 vs 10.2 months following treatment with CDDP/ VP16 for extensive stage small cell lung cancer, P ≤ .01), whereas younger Medicare patients had survival times that were similar to those of trial patients. CONCLUSIONS: Results of clinical trials for advanced pancreatic cancer and lung cancers tended to correctly estimate survival for Medicare patients aged 65 to 74 years, but to overestimate survival for older Medicare patients by six to eight weeks. These estimates of Medicare patients' survival may aid subsequent patients and their oncologists in treatment decision-making.

24 Article 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). 2014

Van Loon, Katherine / Owzar, Kouros / Jiang, Chen / Kindler, Hedy L / Mulcahy, Mary F / Niedzwiecki, Donna / O'Reilly, Eileen M / Fuchs, Charles / Innocenti, Federico / Venook, Alan P / Anonymous5350802. ·Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA (KVL, APV); Department of Biostatistics and Bioinformatics, Duke University, Durham, NC (KO, DN); Alliance Statistics and Data Center, Duke University, Durham, NC (KO, CJ, DN); The University of Chicago Medical Center, Chicago, IL (HLK); Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (MFM); Memorial Sloan-Kettering Cancer Center, New York, NY (EMO); Dana-Farber Cancer Institute, Boston, MA (CF); University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC (FI) katherine.vanloon@ucsf.edu. · Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA (KVL, APV); Department of Biostatistics and Bioinformatics, Duke University, Durham, NC (KO, DN); Alliance Statistics and Data Center, Duke University, Durham, NC (KO, CJ, DN); The University of Chicago Medical Center, Chicago, IL (HLK); Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (MFM); Memorial Sloan-Kettering Cancer Center, New York, NY (EMO); Dana-Farber Cancer Institute, Boston, MA (CF); University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC (FI). ·J Natl Cancer Inst · Pubmed #25099612.

ABSTRACT: BACKGROUND: Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown. METHODS: Participants in this correlative study (CALGB 151006) were enrolled in CALGB 80303, which was a randomized trial of patients with advanced pancreatic cancer that demonstrated no difference in overall survival (OS) among patients treated with gemcitabine plus placebo vs gemcitabine plus bevacizumab. We measured baseline serum 25-hydroxyvitamin D (25[OH]D) levels and examined associations between baseline 25(OH)D levels and progression-free survival and OS using the Cox rank score test. All statistical tests were two-sided. RESULTS: Of 256 patients with available serum, the median 25(OH)D level was 21.7ng/mL (range 4 to 77). 44.5% of patients were vitamin D deficient (25[OH]D <20ng/mL), and 32.4% were insufficient (25[OH]D ≥20 and <30ng/mL). 25(OH)D levels were lower in black patients compared with white patients, and patients of other/undisclosed race (10.7 vs 22.4 vs 20.9ng/mL, P < .001). Baseline 25(OH)D levels were not associated with PFS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .60) or OS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .95). CONCLUSION: Vitamin D deficiency was highly prevalent among patients with a new diagnosis of advanced pancreatic cancer. Black patients had statistically significantly lower 25(OH)D levels than white patients. In this cohort of patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.

25 Article Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance). 2013

Nixon, Andrew B / Pang, Herbert / Starr, Mark D / Friedman, Paula N / Bertagnolli, Monica M / Kindler, Hedy L / Goldberg, Richard M / Venook, Alan P / Hurwitz, Herbert I / Anonymous3240771. ·Authors' Affiliations: Division of Medical Oncology; Alliance Statistics and Data Center, Duke University Medical Center; Durham, North Carolina; Section of Hematology/Oncology, University of Chicago Cancer Research Center; Chicago, Illinois; Department of Surgery, Brigham and Women's Hospital & Harvard Medical School; Boston, Massachusetts; Department of Internal Medicine, Ohio State University; Columbus, Ohio; and Division of Medical Oncology, University of California, San Francisco, California. ·Clin Cancer Res · Pubmed #24097873.

ABSTRACT: PURPOSE: CALGB80303 was a phase III trial of 602 patients with locally advanced or metastatic pancreatic cancer comparing gemcitabine/bevacizumab versus gemcitabine/placebo. The study found no benefit in any outcome from the addition of bevacizumab to gemcitabine. Blood samples were collected and multiple angiogenic factors were evaluated and then correlated with clinical outcome in general (prognostic markers) and with benefit specifically from bevacizumab treatment (predictive markers). EXPERIMENTAL DESIGN: Plasma samples were analyzed via a novel multiplex ELISA platform for 31 factors related to tumor growth, angiogenesis, and inflammation. Baseline values for these factors were correlated with overall survival (OS) using univariate Cox proportional hazard regression models and multivariable Cox regression models with leave-one-out cross validation. Predictive markers were identified using a treatment by marker interaction term in the Cox model. RESULTS: Baseline plasma was available from 328 patients. Univariate prognostic markers for OS were identified including: Ang2, CRP, ICAM-1, IGFBP-1, TSP-2 (all P < 0.001). These prognostic factors were found to be highly significant, even after adjustment for known clinical factors. Additional modeling approaches yielded prognostic signatures from multivariable Cox regression. The gemcitabine/bevacizumab signature consisted of IGFBP-1, interleukin-6, PDGF-AA, PDGF-BB, TSP-2; whereas the gemcitabine/placebo signature consisted of CRP, IGFBP-1, PAI-1, PDGF-AA, P-selectin (both P < 0.0001). Finally, three potential predictive markers of bevacizumab efficacy were identified: VEGF-D (P < 0.01), SDF1 (P < 0.05), and Ang2 (P < 0.05). CONCLUSION: This study identified strong prognostic markers for pancreatic cancer patients. Predictive marker analysis indicated that plasma levels of VEGF-D, Ang2, and SDF1 significantly predicted for benefit or lack of benefit from bevacizumab in this population.

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