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Pancreatic Neoplasms: HELP
Articles by Jeffrey R. Infante
Based on 9 articles published since 2009
(Why 9 articles?)
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Between 2009 and 2019, J. R. Infante wrote the following 9 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer. 2016

Liu, J F / Moore, K N / Birrer, M J / Berlin, S / Matulonis, U A / Infante, J R / Wolpin, B / Poon, K A / Firestein, R / Xu, J / Kahn, R / Wang, Y / Wood, K / Darbonne, W C / Lackner, M R / Kelley, S K / Lu, X / Choi, Y J / Maslyar, D / Humke, E W / Burris, H A. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston joyce_liu@dfci.harvard.edu. · Division of Gynecologic Oncology, Stephenson Oklahoma Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City. · Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston. · Department of Oncology, New England Cancer Care Specialists, Kennebunk. · Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville. · Early Development, Genentech, South San Francisco, USA. ·Ann Oncol · Pubmed #27793850.

ABSTRACT: BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

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

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

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

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

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

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

4 Clinical Trial A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. 2014

Infante, Jeffrey R / Somer, Bradley G / Park, Joon Oh / Li, Chung-Pin / Scheulen, Max E / Kasubhai, Saifuddin M / Oh, Do-Youn / Liu, Yuan / Redhu, Suman / Steplewski, Klaudia / Le, Ngocdiep. ·Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, United States. Electronic address: jinfante@tnonc.com. · The West Clinic, Memphis, TN, United States. · Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. · Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University School of Medicine, Taipei, Taiwan. · Department of Internal Medicine, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. · Northwest Medical Specialties, PLLC, Tacoma, WA, United States. · Seoul National University Hospital, Seoul, South Korea. · GlaxoSmithKline, Collegeville, PA, United States. · Novartis, East Hanover, NJ, United States. ·Eur J Cancer · Pubmed #24915778.

ABSTRACT: BACKGROUND: Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. METHODS: Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. RESULTS: Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. CONCLUSIONS: The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.

5 Clinical Trial Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. 2013

Forero-Torres, Andres / Infante, Jeffrey R / Waterhouse, David / Wong, Lucas / Vickers, Selwyn / Arrowsmith, Edward / He, Aiwu Ruth / Hart, Lowell / Trent, David / Wade, James / Jin, Xiaoping / Wang, Qiang / Austin, Tashara / Rosen, Michael / Beckman, Robert / von Roemeling, Reinhard / Greenberg, Jonathan / Saleh, Mansoor. ·University of Alabama at Birmingham, Birmingham, Alabama. ·Cancer Med · Pubmed #24403266.

ABSTRACT: Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m(2) once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3-64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2-5.4 months). Median OS was 8.2 months (95% CI, 5.1-9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.

6 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.).

7 Clinical Trial Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: a Sarah Cannon Research Institute phase II trial. 2013

Infante, Jeffrey R / Arkenau, Hendrik-Tobias / Bendell, Johanna C / Rubin, Mark S / Waterhouse, David / Jones, George Tripp / Spigel, David R / Lane, Cassie M / Hainsworth, John D / Burris, Howard A. ·Sarah Cannon Research Institute, Nashville, TN USA. jinfante@tnonc.com ·Cancer Biol Ther · Pubmed #23358470.

ABSTRACT: OBJECTIVES: To evaluate the 6-mo overall survival, safety and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer. METHODS: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas with metastases incurable by surgery/radiation therapy; ECOG PS 0-2; adequate organ function; prophylactic anticoagulation for venous thromboembolic events (VTEs). Patients received lenalidomide 25 mg PO (days 1-21) and gemcitabine 1,000 mg/m ( 2) IV (days 1, 8 and 15) each 28-day cycle, with response evaluations every eight weeks. RESULTS: Between 5/2009-4/2010, 72 patients (median age 64 years; 68% male; 42% ECOG PS 0) were enrolled in this multicenter, community-based study. Six-month OS was 37% (95% CI 26-48%). Median PFS and OS were 2.3 (95% CI 1.9-3.5) and 4.7 (95% CI 3.4-5.7) months, respectively. Eight partial responses (11%) were documented. Thirty-nine patients (54%) experienced thrombocytopenia (2 patients, 3% grade 4). Hematologic toxicities resulted in dose modifications for the majority of patients. Twenty patients (28%) developed VTEs during treatment. CONCLUSIONS: The observed 6-month OS (37%) of lenalidomide with gemcitabine does not suggest improvement compared with historical results with gemcitabine alone. Toxicities and dose modifications likely limited dose intensity. Further development of this regimen in pancreas cancer is not recommended.

8 Clinical Trial A phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer. 2011

Infante, Jeffrey R / Jones, Suzanne F / Bendell, Johanna C / Spigel, David R / Yardley, Denise A / Weekes, Colin D / Messersmith, Wells A / Hainsworth, John D / Burris, Howard A. ·Sarah Cannon Research Institute, Nashville, TN 37203, USA. jinfante@tnonc.com ·Eur J Cancer · Pubmed #21051221.

ABSTRACT: INTRODUCTION: Pomalidomide is an investigational immunomodulating drug (IMiD) that also inhibits angiogenesis and has direct anti-tumour effects. This phase I study was performed to identify the optimal dose of pomalidomide to be used in combination with gemcitabine in the treatment of patients with metastatic pancreatic cancer. METHODS: Eligible patients had histologically documented metastatic adenocarcinoma of the pancreas. No prior gemcitabine for metastatic disease or for primary treatment of locally advanced disease was allowed although prior radiation therapy with 5-flourouracil (5-FU) or gemcitabine as a radiosensitizer was allowed. All patients received gemcitabine 1000 mg/m(2) IV on days 1, 8 and 15 of a 28 day cycle. Pomalidomide was administered orally on days 1-21 at doses escalated from 2 to 10mg daily. Patients were re-evaluated every 8 weeks; treatment continued until disease progression or intolerable toxicity occurred. RESULTS: Twenty-three patients were enrolled with a median age of 62 and Eastern Cooperative Oncology Group (ECOG) performance status 0 (87%) and 1 (13%). The maximum tolerated dose (MTD) was 10mg/day on days 1-21. Neutropaenia was the most common grade 3/4 toxicity (38%); other grade 3/4 toxicity included deep vein thrombosis (DVT) (22%) and anaemia (9%). While efficacy was not a primary end-point of this study, 3 of 20 evaluable patients (15%) had partial responses and 10 patients (50%) had >50% decrease in CA 19-9 levels. CONCLUSIONS: The combination of pomalidomide and gemcitabine was feasible and safe in most patients receiving first-line chemotherapy for metastatic pancreatic cancer. Neutropaenia, the dose-limiting toxicity, was brief and reversible. Intermittent dosing of pomalidomide allowed substantially higher doses than were previously reported with a continuous schedule. This combination merits further evaluation in the treatment of metastatic pancreatic cancer.

9 Article Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment. 2014

Kultti, Anne / Zhao, Chunmei / Singha, Netai C / Zimmerman, Susan / Osgood, Ryan J / Symons, Rebecca / Jiang, Ping / Li, Xiaoming / Thompson, Curtis B / Infante, Jeffrey R / Jacobetz, Michael A / Tuveson, David A / Frost, Gregory I / Shepard, H Michael / Huang, Zhongdong. ·Halozyme Therapeutics, Inc., 11388 Sorrento Valley Road, San Diego, CA 92121, USA. · Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 250 25th Avenue North, Nashville, TN 37203, USA. · Labfinity, 8110 Cordova Road, Suite 119, Cordova, TN 38016, USA. · Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. · Intrexon Corporation, 6620 Mesa Ridge Road, San Diego, CA 92121, USA. ·Biomed Res Int · Pubmed #25147816.

ABSTRACT: Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.