Von Hoff D.D.,Translational Genomics Research Institute |
Von Hoff D.D.,Virginia per Cancer Center |
Ervin T.,Cancer Specialists |
Arena F.P.,Arena Oncology Associates |
And 21 more authors.
New England Journal of Medicine | Year: 2013
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. Copyright © 2013 Massachusetts Medical Society.
Goldstein D.,University of New South Wales |
El-Maraghi R.H.,Royal Victoria Regional Health Center |
Hammel P.,Hopital Beaujon |
Heinemann V.,Ludwig Maximilians University of Munich |
And 13 more authors.
Journal of the National Cancer Institute | Year: 2015
Background: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. Methods: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. Results: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P <. 001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P <. 001 for CA19-9 level ≥ median and HR = 0.81, P =. 079 for NLR > 5). Conclusions: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer. © The Author 2015. Published by Oxford University Press. All rights reserved.
Martin P.J.,Fred Hutchinson Cancer Research Center |
Rizzo J.D.,Medical College of Wisconsin |
Wingard J.R.,Florida College |
Ballen K.,Massachusetts General Hospital |
And 9 more authors.
Biology of Blood and Marrow Transplantation | Year: 2012
Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of aGVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of aGVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of aGVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Because the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous results and the design of future studies. © 2012 American Society for Blood and Marrow Transplantation.
Bao P.Q.,State University of New York at Stony Brook |
Ramanathan R.K.,Virginia per Cancer Center |
Krasinkas A.,University of Pittsburgh |
Bahary N.,University of Pittsburgh |
And 6 more authors.
Annals of Surgical Oncology | Year: 2011
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 singlecenter 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. © 2010 Society of Surgical Oncology.
Northfelt D.W.,Mayo Medical School |
Ramanathan R.K.,Virginia per Cancer Center |
Ramanathan R.K.,Translational Genomics Research Institute TGen |
Cohen P.A.,Mayo Medical School |
And 10 more authors.
Clinical Cancer Research | Year: 2014
Purpose: This phase I, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma. Experimental Design: VTX-2337 doses (0.1-3.9mg/m2) were administered subcutaneously on days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AE); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLT) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Antitumor activity was assessed. Results: Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range, 1-8 cycles). Most AEs were grades 1 to 2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m2). The MTD was considered the highest dose administered. Peak drug plasma levels and total systemic exposure were generally dose proportional. At doses ≥0.4 mg/m2, increases above baseline levels were observed for plasma levels of G-CSF, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and TNFα. Eight subjects (24.2%) had a best response of stable disease (median duration, 54.5 days). Conclusions: VTX-2337 is clinically well tolerated and biologically active with a predictable pharmacokinetic profile. Suitable doses for testing in combination studies were identified. Phase II placebo-controlled studies of VTX-2337 in combination with doxorubicin in ovarian cancer, and in combination with platinum chemotherapy, 5 FU, and cetuximab in head and neck cancer have been initiated (NCT #01666444 and NCT#01836029). ©2014 AACR.
Christoforides A.,Translational Genomics Research Institute |
Christoforides A.,Arizona State University |
Carpten J.D.,Translational Genomics Research Institute |
Weiss G.J.,Translational Genomics Research Institute |
And 5 more authors.
BMC Genomics | Year: 2013
Background: The field of cancer genomics has rapidly adopted next-generation sequencing (NGS) in order to study and characterize malignant tumors with unprecedented resolution. In particular for cancer, one is often trying to identify somatic mutations - changes specific to a tumor and not within an individual's germline. However, false positive and false negative detections often result from lack of sufficient variant evidence, contamination of the biopsy by stromal tissue, sequencing errors, and the erroneous classification of germline variation as tumor-specific.Results: We have developed a generalized Bayesian analysis framework for matched tumor/normal samples with the purpose of identifying tumor-specific alterations such as single nucleotide mutations, small insertions/deletions, and structural variation. We describe our methodology, and discuss its application to other types of paired-tissue analysis such as the detection of loss of heterozygosity as well as allelic imbalance. We also demonstrate the high level of sensitivity and specificity in discovering simulated somatic mutations, for various combinations of a) genomic coverage and b) emulated heterogeneity.Conclusion: We present a Java-based implementation of our methods named Seurat, which is made available for free academic use. We have demonstrated and reported on the discovery of different types of somatic change by applying Seurat to an experimentally-derived cancer dataset using our methods; and have discussed considerations and practices regarding the accurate detection of somatic events in cancer genomes. Seurat is available at https://sites.google.com/site/seuratsomatic. © 2013 Christoforides et al.; licensee BioMed Central Ltd.
Kuske R.,Virginia per Cancer Center
Journal of Contemporary Brachytherapy | Year: 2014
Purpose: To describe a breast-conserving technique using interstitial brachytherapy after lumpectomy and axillary nodal sampling in selected women who are diagnosed with breast cancer in the presence of augmentation mammoplasty. Material and methods: Over the past 20 years, we have developed and improved a technique of "pinch view" image-guided catheter insertion that avoids implant puncture. Selection criteria include: 1) women of any age with either subpectoral or retroglandular, augmentation implants (silicone or saline) who were diagnosed with stages Tis, T1, T2, N0, or N1 breast cancer; 2) any pathologic subtype of malignant breast cancer was accepted; 3) microscopic tumor extent < 3 cm; 4) axillary node negative or metastasis to 1 to 3 nodes without extracapsular extension; and 5) surgical margins clear by the NSABP "no ink on tumor" definition. More than 250 women have been successfully treated. Patients were treated with high dose rate Iridium-192 brachytherapy to 34 Gy in 10 or 32 Gy in 8 twice daily fractions. The target volume was the surgical cavity edge with 1.5 to 2 cm margin using 3-D treatment planning systems. Results: The implant technique as currently employed is described. There have been no implant ruptures, and the Planning Treatment Volume (PTV-eval) exhibited at least 90% coverage by the 90% isodose line in the vast majority of cases. Dose Homogeneity Index exceeded 70% in most cases. The maximum skin dose was below the prescription dose in every case. Other than some patients with pre-existing capsular contracture, less than 5% experience new capsular contracture after interstitial brachytherapy. Conclusions: A technique of reliable and reproducible accelerated partial breast irradiation is described that minimizes the risk of capsular contracture by avoiding circumferential dose to the foreign body in the breast.
Borazanci E.,Translational Genomics Research Institute |
Von Hoff D.D.,Virginia per Cancer Center
Expert Review of Gastroenterology and Hepatology | Year: 2014
Adenocarcinoma of the pancreas or pancreatic cancer as we will refer to it here, is a cancer of poor prognosis with a high mortality, particularly in the advanced or metastatic setting. Until 2011 and the Phase III results of FOLFIRINOX, standard treatment options were limited to gemcitabine. Combination therapy had shown either a lack of or very limited improvement versus monotherapy with gemcitabine. With the positive results of the MPACT study in 2013 showing improved survival with nab-paclitaxel plus gemcitabine combination therapy, there are now more options for oncologists to treat patients with advanced pancreatic cancer. This paper will highlight the Phase I/II and Phase III trials of nab-paclitaxel plus gemcitabine along with discussing their biology and further possible development in treating patients with pancreatic cancer. © 2014 Informa UK, Ltd.
Weiss G.J.,Virginia per Cancer Center |
Weiss G.J.,Translational Genomics Research Institute |
Von Hoff D.D.,Virginia per Cancer Center |
Von Hoff D.D.,Translational Genomics Research Institute
Clinical Pharmacology and Therapeutics | Year: 2010
Since the observation nearly 50 years ago of cyclopic newborn lambs borne by ewes grazing on California corn lily, an explosion of discovery has ensued. The Hedgehog (HH) signaling pathway is perhaps one of the most exciting targets in cancer research today. Here we provide a summary of the HH signaling pathway and detail its clinical relevance for treatment of patients and future research directions. © 2010 American Society for Clinical Pharmacology and Therapeutics.
Bussey K.J.,Translational Genomics Research Institute |
Demeure M.J.,Translational Genomics Research Institute |
Demeure M.J.,Virginia per Cancer Center
Current Opinion in Oncology | Year: 2011
Purpose of review: Adrenocortical carcinoma is an aggressive, lethal malignancy of the adrenal cortex. The rarity of the disease has stymied therapeutic development. Recent work toward understanding the molecular pathogenesis of the disease has identi?ed several potential new diagnostic and therapeutic targets. Recent ?ndings: The molecular characterization of adrenocortical carcinoma has identi?ed dysregulation of the Gap 2/mitosis transition and the insulin-like growth factor 1 receptor signaling cascade as two major pathways for therapeutic development. These studies have also highlighted an unappreciated heterogeneity of the disease at the gene level that nevertheless seems to converge onto common cellular pathways. Additionally, the characterization of Wnt signaling through b-catenin in adrenal development, the demonstration of the involvement of BMP signaling in adrenocortical carcinoma growth regulation, and the discovery that ERCC1 expression levels can predict therapeutic response to platinum are just a few of the recent advances that promise to shed light on adrenocortical carcinoma biology. Summary: Short-term, therapeutic development should target the Gap 2/mitosis transition and the downstream signaling of the insulin-like growth factor 1 receptor receptor. Long-term, additional characterization of patient samples, particularly at the sequence level, is required to fully understand adrenocortical carcinoma biology and apply that knowledge to clinical practice. © 2010 Wolters Kluwer Health | Llpplncott Williams & Wilkins.