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Pancreatic Neoplasms: HELP
Articles by Ramesh K. Ramanathan
Based on 31 articles published since 2008
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Between 2008 and 2019, R. K. Ramanathan wrote the following 31 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. 2016

Sohal, Davendra P S / Mangu, Pamela B / Khorana, Alok A / Shah, Manish A / Philip, Philip A / O'Reilly, Eileen M / Uronis, Hope E / Ramanathan, Ramesh K / Crane, Christopher H / Engebretson, Anitra / Ruggiero, Joseph T / Copur, Mehmet S / Lau, Michelle / Urba, Susan / Laheru, Daniel. ·Davendra P.S. Sohal and Alok A. Khorana, Cleveland Clinic, Cleveland, OH · Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA · Manish A. Shah, The Weill Cornell Medical Center · Philip A. Philip, Karmanos Cancer Institute, Detroit · Susan Urba, University of Michigan Cancer Center, Ann Arbor, MI · Eileen M. O'Reilly, Memorial Sloan Kettering Cancer Center · Joseph T. Ruggiero, Weill Cornell Medical College, New York, NY · Hope E. Uronis, Duke University, Durham, NC · Ramesh K. Ramanathan, Mayo Clinic, Scottsdale · Michelle Lau, Community Hospital Based Cancer Center, Tempe, AZ · Christopher H. Crane, The University of Texas MD Anderson Cancer Center, Houston, TX · Anitra Engebretson, Patient Representative, Portland, OR · Mehmet S. Copur, St Francis Medical Center, Grand Island, NE · and Daniel Laheru, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. ·J Clin Oncol · Pubmed #27247222.

ABSTRACT: PURPOSE: To provide evidence-based recommendations to oncologists and others for the treatment of patients with metastatic pancreatic cancer. METHODS: American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts to conduct a systematic review of the literature from April 2004 to June 2015. Outcomes were overall survival, disease-free survival, progression-free survival, and adverse events. RESULTS: Twenty-four randomized controlled trials met the systematic review criteria. RECOMMENDATIONS: A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. Goals of care, patient preferences, treatment response, psychological status, support systems, and symptom burden should guide decisions for treatments. A palliative care referral should occur at first visit. FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin; favorable comorbidity profile) or gemcitabine plus nanoparticle albumin-bound (NAB) -paclitaxel (adequate comorbidity profile) should be offered to patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1 based on patient preference and support system available. Gemcitabine alone is recommended for patients with ECOG PS 2 or with a comorbidity profile that precludes other regimens; the addition of capecitabine or erlotinib may be offered. Patients with an ECOG PS ≥ 3 and poorly controlled comorbid conditions should be offered cancer-directed therapy only on a case-by-case basis; supportive care should be emphasized. For second-line therapy, gemcitabine plus NAB-paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX, an ECOG PS 0 to 1, and a favorable comorbidity profile; fluorouracil plus oxaliplatin, irinotecan, or nanoliposomal irinotecan should be offered to patients with first-line treatment with gemcitabine plus NAB-paclitaxel, ECOG PS 0 to 1, and favorable comorbidity profile, and gemcitabine or fluorouracil should be offered to patients with either an ECOG PS 2 or a comorbidity profile that precludes other regimens. Additional information is available at www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki.

2 Review Pancreatic adenocarcinoma: treating a systemic disease with systemic therapy. 2014

Sohal, Davendra P S / Walsh, R Matthew / Ramanathan, Ramesh K / Khorana, Alok A. ·Affiliations of authors: Taussig Cancer Institute and Lerner College of Medicine (DPSS, AAK) and Digestive Disease Institute and Lerner College of Medicine (RMW), Cleveland Clinic, Cleveland, OH · Virgina G. Piper Cancer Center, Translational Genomics Research Institute, Scottsdale, AZ (RKR). ·J Natl Cancer Inst · Pubmed #24563516.

ABSTRACT: Pancreatic adenocarcinoma, even when resectable, remains highly lethal. Although surgical outcomes have improved considerably, median overall survival after surgery and adjuvant therapy such as single-agent gemcitabine remains less than 2 years. We discuss preclinical and clinical data supporting the contention that even early-stage pancreatic cancer is a systemic disease. Autopsy series reveal that 70% to 85% of patients die of systemic recurrence, rather than local disease, after pancreatic cancer resection. Preclinical studies using genomics and mouse models reveal evidence of metastatic spread even before histopathologic evidence of a pancreatic tumor. Analogous to breast cancer, we propose that the Halstedian approach of treating pancreatic cancer as a local, surgical problem should be replaced by Fisher's alternative hypothesis of cancer as a systemic disease. Newer multiagent chemotherapy regimens have shown meaningful response rates and improvement in overall survival in the metastatic setting and, for the first time, offer investigators an opportunity to use effective systemic therapy. We emphasize that a surgery-first approach is not resonant with our current understanding of pancreatic adenocarcinoma biology and that an upfront systemic approach for even resectable pancreatic cancer warrants testing in clinical trials.

3 Clinical Trial A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer. 2019

Ramanathan, Ramesh K / Thomas, Gary W / Khorana, Alok A / Shah, Satish / Zhou, Cathy / Wong, Sofia / Cole, George / James, Danelle / Gabrail, Nashat Y. ·Honor Health Research Institute/Translational Genomics Research Institute, Scottsdale, Arizona, USA. · South Carolina Cancer Specialists, Hilton Head Island, South Carolina, USA. · University of Rochester, Rochester, New York, USA. · Gettysburg Cancer Center, Gettysburg, Pennsylvania, USA. · Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California, USA. · Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California, USA, gecole@pcyc.com. · Gabrail Cancer Center, Canton, Ohio, USA. ·Oncology · Pubmed #30844808.

ABSTRACT: OBJECTIVES: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor. METHODS: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483-gemcitabine versus gemcitabine alone. RESULTS: Target international normalized ratio (between 2.0-3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483-gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483-gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months). CONCLUSIONS: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483-gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.

4 Clinical Trial None 2017

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

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

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

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

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

6 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.

7 Clinical Trial Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas. 2016

Ramanathan, R K / Goldstein, D / Korn, R L / Arena, F / Moore, M / Siena, S / Teixeira, L / Tabernero, J / Van Laethem, J-L / Liu, H / McGovern, D / Lu, B / Von Hoff, D D. ·Division of Hematology/Oncology, Mayo Clinic, Scottsdale, USA ramanathan.ramesh@mayo.edu. · Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia. · Diagnostic Radiology, Scottsdale Medical Imaging, Ltd, Scottsdale. · Hematology/Oncology, NYU Langone Arena Oncology, Lake Success, USA. · Provencial Health Services Authority, BC Cancer Agency, Vancouver, Canada. · Falck Division of Oncology, Department of Oncology and Hematology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda and Università degli Studi di Millano, Milan, Italy. · Department of Medical Oncology, Hôpital Saint-Antoine, Paris, France. · Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. · University Clinic of Brussels, Hôpital Erasme, Brussels, Belgium. · Biostatistics and Research and Design, Celgene Corporation, Summit. · Clinical Research, Translational Genomics Research Institute and Honor Health, Scottsdale, USA. ·Ann Oncol · Pubmed #26802153.

ABSTRACT: BACKGROUND: In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial. PATIENTS AND METHODS: Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity. RESULTS: PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001). CONCLUSION: Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response. CLINICALTRIALSGOV: NCT00844649.

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

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

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

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

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

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

10 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.

11 Clinical Trial Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). 2014

Philip, Philip A / Goldman, Bryan / Ramanathan, Ramesh K / Lenz, Heinz-Josef / Lowy, Andrew M / Whitehead, Robert P / Wakatsuki, Takeru / Iqbal, Syma / Gaur, Rakesh / Benedetti, Jacqueline K / Blanke, Charles D. ·Wayne State University, Karmanos Cancer Institute, Detroit, Michigan. ·Cancer · Pubmed #25041791.

ABSTRACT: BACKGROUND: Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS: This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS: The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS: Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.

12 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.).

13 Clinical Trial Phase II study of induction fixed-dose rate gemcitabine and bevacizumab followed by 30 Gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma. 2013

Van Buren, George / Ramanathan, Ramesh K / Krasinskas, Alyssa M / Smith, Ryan P / Abood, Gerard J / Bahary, Nathan / Lembersky, Barry C / Shuai, Yongli / Potter, Douglas M / Bartlett, David L / Zureikat, Amer H / Zeh, Herbert J / Moser, A James. ·Division of Surgical Oncology, UPMC Pancreatic Cancer Center, Pittsburgh, PA, USA. ·Ann Surg Oncol · Pubmed #23904005.

ABSTRACT: BACKGROUND: Eighty percent of patients with resected pancreatic ductal carcinoma (PDC) experience treatment failure within 2 years. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with the angiogenesis inhibitor bevacizumab (BEV) and accelerated 30 Gy radiotherapy (RT) would improve outcomes among patients with potentially resectable PDC. METHODS: This phase II trial tested induction FDR GEM (1,500 mg/m(2)) plus BEV (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin. Subjects underwent laparoscopy and resection after day 85. Therapy was considered effective if the complete pathologic response rate exceeded 10 % and the margin-negative resection rate exceeded 80%. RESULTS: Fifty-nine subjects were enrolled; 29 had potential portal vein involvement. Two grade 4 (3.4%) and 19 grade 3 toxicities (32.8%) occurred. Four subjects manifested radiographic progression, and 10 had undetected carcinomatosis. Forty-three pancreatic resections (73%) were performed, including 19 portal vein resections (44%). Margin-negative outcomes were observed in 38 (88%, 95% confidence interval [CI] 75-96), with one complete pathologic response (2.3%; 95% CI 0.1-12). There were seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival for the entire cohort was 16.8 months (95% CI 14.9-21.3) and 19.7 months (95% CI 16.5-28.2) after resection. CONCLUSIONS: Induction therapy with FDR GEM and BEV, followed by accelerated BEV/RT to 30 Gy, was well tolerated. Although both effectiveness criteria were achieved, survival outcomes were equivalent to published regimens.

14 Clinical Trial Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. 2013

Mahadevan, Daruka / Chalasani, Pavani / Rensvold, Diane / Kurtin, Sandy / Pretzinger, Chris / Jolivet, Jacques / Ramanathan, Ramesh K / Von Hoff, Daniel D / Weiss, Glen J. ·Arizona Cancer Center, Tucson, AZ 85724, USA. dmahadevan@azcc.arizona.edu ·Am J Clin Oncol · Pubmed #22441342.

ABSTRACT: OBJECTIVES: AEG35156 is an antisense oligonucleotide (ASO) that targets the X-linked inhibitor of apoptosis mRNA. Preclinical studies showed potent activity of AEG35156 in combination with gemcitabine in pancreatic ductal adenocarcinoma (PDA). A phase I study was conducted to establish the maximum-tolerated dose, safety, and antitumor activity of AEG35156 plus gemcitabine in metastatic PDA. METHODS: Fourteen patients with metastatic PDA were enrolled. Nine patients were treated at 350 mg IV and 5 patients at 500 mg IV of AEG35156, 3 weeks on/1 week off of a 28-day cycle. Gemcitabine was administered at 1000 mg/m(2) IV over 30 minutes immediately after AEG35156 in both groups. Because of perceived neurotoxicity dose deescalation to 350 mg was recommended. RESULTS: All 14 patients were evaluable for tolerability and toxicity. Toxicities include neutropenia (grade 3/4, 6 patients), thrombocytopenia (grade 3, 2 patients), peripheral neuropathy (grade 3, 2 patients), fatigue (grade 3, 4 patients), ascites (grade 3, 2 patients), and nausea/vomiting (grade 4, 2 patients). Five patients (45%) experienced stable disease with a median progression-free survival of 58 days (95% CI, 52-107 d). CONCLUSIONS: The maximum-tolerated dose is AEG35156 500 mg plus gemcitabine 1000 mg/m(2) given on days 1, 8, and 15 every 28 days. AEG35156 plus gemcitabine failed to show significant clinical activity in advanced PDA.

15 Clinical Trial A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer. 2012

El-Khoueiry, A B / Ramanathan, R K / Yang, D Y / Zhang, W / Shibata, S / Wright, J J / Gandara, D / Lenz, H J. ·Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 3440, Los Angeles, CA 90033, USA. elkhouei@usc.edu ·Invest New Drugs · Pubmed #21424698.

ABSTRACT: PURPOSE: Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. METHODS: Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). RESULTS: Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. CONCLUSIONS: Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.

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

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

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

17 Clinical Trial Phase II study of gemcitabine and erlotinib as adjuvant therapy for patients with resected pancreatic cancer. 2011

Bao, Philip Q / Ramanathan, Ramesh K / Krasinkas, Alyssa / Bahary, Nathan / Lembersky, Barry C / Bartlett, David L / Hughes, Steven J / Lee, Kenneth K / Moser, A James / Zeh, Herbert J. ·Department of Surgery, Stony Brook University Hospital, Stony Brook, NY, USA. ·Ann Surg Oncol · Pubmed #21104328.

ABSTRACT: BACKGROUND: There is currently no consensus about the most effective adjuvant therapy for adenocarcinoma of the pancreas. Both gemcitabine and erlotinib have been demonstrated to improve survival in patients with metastatic disease. This study was designed to evaluate the efficacy of gemcitabine and erlotinib as adjuvant therapy, and to explore potential biomarkers associated with response. METHODS: An institutional review board-approved single-center phase II trial of adjuvant biweekly fixed-dose rate gemcitabine (1500 mg/m(2)) and daily erlotinib (150 mg/day) for 4 months followed by maintenance erlotinib (150 mg/day) over 8 months was initiated. Primary end point was recurrence-free survival (RFS). Epidermal growth factor receptor (EGFR) expression in the resected tumors was assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). RESULTS: The study completed planned accrual of 25 patients. Median follow-up was 18.2 (range 11.6-23.5) months. Recurrences were observed in 17 subjects (68%). Median RFS was 14.0 months (95% confidence interval [95% CI], 8.2-24.5) with 1-year and 2-year RFS of 56% (95% CI, 35-73) and 26% (95% CI, 6-52), respectively. Median overall survival was not reached. Estimated 1-year and 2-year overall survival was 84% (95% CI, 63-94) and 53% (95% CI, 22-76), respectively. Nine patients (36%) had a grade 3 event and only 1 (4%) had a grade 4 (neutropenia). Most toxicities were dermatologic, gastrointestinal, and constitutional. There were nonsignificant trends to longer RFS and lower recurrence rates while receiving therapy in subjects with fluorescence in situ hybridization-positive tumors and greater immunohistochemistry expression. CONCLUSIONS: Our phase II results suggest that adjuvant gemcitabine and erlotinib is a promising regimen that merits further investigation.

18 Clinical Trial A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination. 2011

Ramanathan, Ramesh K / Abbruzzese, James / Dragovich, Tomislav / Kirkpatrick, Lynn / Guillen, Jose M / Baker, Amanda F / Pestano, Linda A / Green, Sylvan / Von Hoff, Daniel D. ·Virgina G Piper Cancer Center, TGen, Scottsdale, AZ, 85259, USA. rramanathan@tgen.org ·Cancer Chemother Pharmacol · Pubmed #20461382.

ABSTRACT: PURPOSE: This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC). METHODS: PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued. RESULTS: Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively. CONCLUSIONS: Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

19 Clinical Trial Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. 2009

Brell, Joanna M / Matin, Khalid / Evans, Terry / Volkin, Robert L / Kiefer, Gauri J / Schlesselman, James J / Dranko, Shelley / Rath, Linda / Schmotzer, Amy / Lenzner, Diana / Ramanathan, Ramesh K. ·University Hospitals Case Medical Center, Ireland Cancer Center, Cleveland, Ohio, USA. ·Oncology · Pubmed #19258727.

ABSTRACT: BACKGROUND: There is no standard second-line therapy for advanced pancreatic cancer (APC). We evaluated the epidermal growth factor receptor (EGFR) inhibitor gefitinib and docetaxel in a phase II study following gemcitabine failure. METHODS: EGFR overexpression was not required. The initial docetaxel dose was 75 mg/m(2) on day 1 every 21 days. Due to febrile neutropenia in 8 of the first 18 patients, the dose was reduced to 60 mg/m(2). Gefitinib, 250 mg/day orally, was given continuously. RESULTS: Forty-one patients received treatment and were evaluable. Febrile neutropenia was seen in 11 patients (27%), with most events occurring at the docetaxel dose of 75 mg/m(2) (8 of 18 patients). Common treatment-related grade 3/4 toxicities were: fatigue (7%), nausea (7%), diarrhea (5%) and vomiting (2%). There was 1 partial response and stable disease in 19 patients. Time to progression was 1.8 months and median survival was 4.5 months (95% CI 2.9-5.7). CONCLUSION: The tolerability and feasibility of second-line therapy for APC was demonstrated. The combination of gefitinib and docetaxel showed evidence of limited efficacy.

20 Article Targeting the stroma in pancreatic cancer. 2017

Ahn, Daniel H / Ramanathan, Ramesh K. ·Department of Hematology/Medical Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA. · Department of Hematology/Medical Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA. Ramanathan.Ramesh@mayo.edu. ·Chin Clin Oncol · Pubmed #29307204.

ABSTRACT: The tumor stroma in pancreatic adenocarcinoma is recognized as an integral component in tumorigenesis through its effects on cell signaling, immunosuppression and inhibitory effect on therapeutic agents. Promising preclinical activity has been observed with novel therapeutic agents that target the tumor microenvironment and represent one of many potential treatment strategies of interest in this disease. Herein, we will highlight and review therapeutic novel agents aimed at tumor stroma in pancreas cancer.

21 Article Second-line treatment in patients with pancreatic ductal adenocarcinoma: A meta-analysis. 2017

Sonbol, Mohamad Bassam / Firwana, Belal / Wang, Zhen / Almader-Douglas, Diana / Borad, Mitesh J / Makhoul, Issam / Ramanathan, Ramesh K / Ahn, Daniel H / Bekaii-Saab, Tanios. ·Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona. · University of Arkansas for Medical Sciences, Little Rock, Arkansas. · Evidence-Based Practice Center, Mayo Clinic, Rochester, New York. · Mayo Clinic Libraries, Mayo Clinic, Phoenix, Arizona. ·Cancer · Pubmed #28817187.

ABSTRACT: BACKGROUND: There are limited therapeutic options for treatment-refractory pancreatic ductal adenocarcinoma (PDAC), with a paucity of data to support the best option after progression on gemcitabine-based regimens. The authors performed a meta-analysis to determine the effectiveness of adding oxaliplatin (OX) or various irinotecan formulations to a fluoropyrimidine (FP) after first-line treatment progression in patients with PDAC. METHODS: Different databases, including PubMed, EMBASE, and Cochrane, were searched to identify randomized controlled trials comparing FP monotherapy versus FP combination therapy that included either oxaliplatin (FPOX) or various irinotecan formulations (FPIRI) in patients with PDAC who progressed after first-line treatment. Secondary analyses were planned to assess the effectiveness of FPOX and FPIRI compared with FP. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). RESULTS: Five studies with 895 patients were identified. Patients randomized to receive FPIRI/FPOX had a significantly improved PFS and a trend toward improved OS compared with those who received FP monotherapy. When comparing FPIRI with FP, there was an improvement in both PFS (hazard ratio, 0.64; 95% confidence interval, 0.47-0.87; P = .005) and OS (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004) in patients who received the combination. Conversely, FPOX produced only a modest improvement in PFS with no improvement in OS. CONCLUSIONS: Combination chemotherapy with OX or various IRI formulations appears to improve PFS compared with single-agent FP. FPIRI, but not FPOX, appears to confer an OS advantage. The combination of FP with irinotecan formulations appears to be the appropriate next line of treatment upon progression after gemcitabine-based chemotherapy regimens. Cancer 2017;123:4680-4686. © 2017 American Cancer Society.

22 Article Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. 2017

Barrett, Michael T / Deiotte, Ray / Lenkiewicz, Elizabeth / Malasi, Smriti / Holley, Tara / Evers, Lisa / Posner, Richard G / Jones, Timothy / Han, Haiyong / Sausen, Mark / Velculescu, Victor E / Drebin, Jeffrey / O'Dwyer, Peter / Jameson, Gayle / Ramanathan, Ramesh K / Von Hoff, Daniel D. ·Mayo Clinic in Arizona, Scottsdale, AZ 85259, USA. · ISSAC Corp, Colorado Springs, CO 80919, USA. · Northern Arizona University, Flagstaff, AZ 86011, USA. · Translational Genomics Research Institute, Phoenix, AZ 85004, USA. · Johns Hopkins University, Baltimore, MD 21218, USA. · University of Pennsylvania, Philadelphia, PA 19104, USA. · Virginia G Piper Cancer Center at Honor Health, Scottsdale, AZ 85258, USA. · Mayo Clinic Cancer Center, Phoenix, AZ 85054, USA. ·Br J Cancer · Pubmed #28720843.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed. RESULTS: We defined: (a) CDKN2A homozygous deletions that included the adjacent MTAP gene, only its' 3' region, or excluded MTAP; (b) SMAD4 homozygous deletions that included ME2; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection. CONCLUSIONS: We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.

23 Article Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. 2015

Barrett, Michael T / Anderson, Karen S / Lenkiewicz, Elizabeth / Andreozzi, Mariacarla / Cunliffe, Heather E / Klassen, Christine L / Dueck, Amylou C / McCullough, Ann E / Reddy, Srikanth K / Ramanathan, Ramesh K / Northfelt, Donald W / Pockaj, Barbara A. ·Department of Research, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. · Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America. · Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. · Division of General Surgery, Section of Surgical Oncology, Mayo Clinic in Arizona, Phoenix, Arizona, United States of America. · Section of Biostatistics, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. · Department of Pathology and Laboratory Medicine, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. · Vanderbilt University, Nashville, Tennessee, United States of America. · Division of Hematology-Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. ·Oncotarget · Pubmed #26317899.

ABSTRACT: We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥ 1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.

24 Article Disseminated intravascular coagulation secondary to advanced pancreatic cancer treated successfully with combination chemotherapy. 2014

Mast, Cathy / Ramanathan, Ramesh K / Feinstein, Donald I / Rosen, Peter. ·Virginia G. Piper Cancer Center, Scottsdale, Ariz., USA. ·Oncology · Pubmed #25139314.

ABSTRACT: Both solid and hematologic malignancies may be complicated by coagulopathies. Disseminated intravascular coagulation (DIC) in the presence of pancreatic cancer is generally unrecognized and may have fatal consequences. The diagnosis of DIC in a patient with advanced cancer is a poor prognostic indicator. Presented here is a case study consisting of two patients presenting with a new diagnosis of pancreatic cancer complicated by DIC. Aggressive supportive treatment in addition to systemic chemotherapy consisting of gemcitabine and nab-paclitaxel was initiated and DIC was controlled. An early diagnosis of DIC and the administration of systemic chemotherapy with a high response rate and an ability to reduce tumor bulk rapidly may offer some patients the probability of recovery.

25 Article Genomic analysis and selected molecular pathways in rare cancers. 2012

Liu, Stephen V / Lenkiewicz, Elizabeth / Evers, Lisa / Holley, Tara / Kiefer, Jeffrey / Ruiz, Christian / Glatz, Katharina / Bubendorf, Lukas / Demeure, Michael J / Eng, Cathy / Ramanathan, Ramesh K / Von Hoff, Daniel D / Barrett, Michael T. ·Norris Comprehensive Cancer Center, Division of Medical Oncology, University of Southern California, Los Angeles, CA, USA. ·Phys Biol · Pubmed #23196986.

ABSTRACT: It is widely accepted that many cancers arise as a result of an acquired genomic instability and the subsequent evolution of tumor cells with variable patterns of selected and background aberrations. The presence and behaviors of distinct neoplastic cell populations within a patient's tumor may underlie multiple clinical phenotypes in cancers. A goal of many current cancer genome studies is the identification of recurring selected driver events that can be advanced for the development of personalized therapies. Unfortunately, in the majority of rare tumors, this type of analysis can be particularly challenging. Large series of specimens for analysis are simply not available, allowing recurring patterns to remain hidden. In this paper, we highlight the use of DNA content-based flow sorting to identify and isolate DNA-diploid and DNA-aneuploid populations from tumor biopsies as a strategy to comprehensively study the genomic composition and behaviors of individual cancers in a series of rare solid tumors: intrahepatic cholangiocarcinoma, anal carcinoma, adrenal leiomyosarcoma, and pancreatic neuroendocrine tumors. We propose that the identification of highly selected genomic events in distinct tumor populations within each tumor can identify candidate driver events that can facilitate the development of novel, personalized treatment strategies for patients with cancer.

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