Horn L.,Ingram Medical |
Castellanos E.L.,Vanderbilt University |
Johnson D.H.,University of Texas at Dallas
Expert Opinion on Investigational Drugs | Year: 2011
Introduction: Small cell lung cancer (SCLC) will account for 25,000 to 32,000 new lung cancer cases in the USA in 2010. Current treatment approaches include platinum-based chemotherapy and etoposide with or without radiation therapy depending on stage and performance status. Five-year survival is approximately 25% for patients with limited stage disease and 1 - 2% for patients with extensive stage disease and has not improved in almost two decades. Areas covered: This article reviews the results of recent clinical trials that have evaluated targeted agents and novel cytotoxic agents alone or in combination with standard chemotherapy in the treatment of patients with SCLC. Expert opinion: The lack of a targeted approach to the treatment of patients with SCLC has led investigators to evaluate a multitude of agents with overwhelmingly negative results. A more systematic approach to clinical trials in patients is needed to improve outcomes for patients with this disease. © 2011 Informa UK, Ltd.
Herbst R.S.,Yale University |
Soria J.-C.,Gustave Roussy South Paris University |
Kowanetz M.,Genentech |
Fine G.D.,Genentech |
And 18 more authors.
Nature | Year: 2014
The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system1-4. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment5. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing6-10. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections11. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH 1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment. © 2014 Macmillan Publishers Limited. All rights reserved.
Crawford J.,Duke University |
Swanson P.,Hematology Oncology Asociates |
Schwarzenberger P.,Louisiana State University Health Sciences Center |
Sandler A.,Hematology Oncology Asociates |
And 6 more authors.
Journal of Thoracic Oncology | Year: 2013
Introduction: This two-part phase 2 study evaluated the efficacy and safety of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, combined with carboplatin/paclitaxel in patients with previously untreated advanced non-small-cell lung cancer. Methods: In part 1, patients were sequentially enrolled to receive paclitaxel 200 mg/m2 and carboplatin (area under the concentration-versus-time curve, 6 mg/min/ml) plus panitumumab (1.0, 2.0, or 2.5 mg/kg). In part 2, patients were randomized 2:1 to receive paclitaxel/carboplatin with (arm A) or without (arm B) the maximum tolerated dose of panitumumab identifed in part 1. Primary endpoints in parts 1 and 2 were the incidence of dose-limiting toxicities and time to progression (TTP), respectively. Results: In part 1, four of 19 patients had dose-limiting toxicities: three at 2.0 mg/kg (fatigue, pain in extremity, dyspepsia) and one at 2.5 mg/kg (rash). The maximum tolerated dose was not reached; panitumumab 2.5 mg/kg was selected for part 2. In part 2, TTP was 18.1 weeks (95% confidence interval [CI], 13.6-23.3) in arm A and 23.0 weeks (95% CI, 15.9-24.1) in arm B (hazard ratio, 0.9; 90% CI, 0.66-1.21; p = 0.555). Progression-free survival in arms A and B was 17.6 weeks and 18.3 weeks, respectively, and the objective response rate was 15.2% and 11.1%. Adverse events occurring more frequently in arm A than in arm B included skin toxicity, diarrhea, stomatitis, vomiting, and dizziness. Exploratory analyses did not demonstrate associations between potential biomarkers and outcomes. Conclusion: Although toxicity was predictable and manageable, the addition of panitumumab to paclitaxel/carboplatin did not improve TTP in patients with previously untreated advanced non-small-cell lung cancer. Copyright © 2013 by the International Association for the Study of Lung Cancer.
Puzanov I.,Ingram Medical |
Lindsay C.R.,Beatson West of Scotland Cancer Center |
Goff L.,Ingram Medical |
Sosman J.,Ingram Medical |
And 10 more authors.
Clinical Cancer Research | Year: 2015
Purpose: OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors. Patients and Methods: This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules. Results: Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified. Conclusions: At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); ©2014 American Association for Cancer Research.
Rush S.Z.,Vanderbilt Medical Center |
Rush S.Z.,University of Colorado at Denver |
Abel T.W.,Vanderbilt Medical Center |
Valadez J.G.,Vanderbilt Medical Center |
And 3 more authors.
Neuro-Oncology | Year: 2010
Pilocytic astrocytoma is commonly viewed as a benign lesion. However, disease onset is most prevalent in the first two decades of life, and children are often left with residual or recurrent disease and significant morbidity. The Hedgehog (Hh) pathway regulates the growth of higher WHO grade gliomas, and in this study, we have evaluated the activation and operational status of this regulatory pathway in pilocytic astrocytomas. Expression levels of the Hh pathway transcriptional target PTCH were elevated in 45% of tumor specimens analyzed (ages 1-22 years) and correlated inversely with patient age. Evaluation of a tissue array revealed oligodendroglioma-like features, pilomyxoid features, infiltration, and necrosis more commonly in specimens from younger patients (below the median patient age of 10 years). Immunohistochemical staining for the Hh pathway components PTCH and GLI1 and the proliferation marker Ki67 demonstrated that patients diagnosed before the age of 10 had higher staining indices than those diagnosed after the age of 10. A significant correlation between Ki67 and PTCH and GLI1 staining indices was measured, and 86% of Ki67-positive cells also expressed PTCH. The operational status of the Hh pathway was confirmed in primary cell culture and could be modulated in a manner consistent with a ligand-dependent mechanism. Taken together, these findings suggest that Hh pathway activation is common in pediatric pilocytic astrocytomas and may be associated with younger age at diagnosis and tumor growth. © The Author(s) 2010.
Picozzi V.J.,Virginia Mason Medical Center |
Abrams R.A.,Rush University Medical Center |
Decker P.A.,Mayo Medical School |
Traverso W.,Virginia Mason Medical Center |
And 7 more authors.
Annals of Oncology | Year: 2011
Background: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. Patients and methods: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m2 i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m2/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m2/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. Results: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0-20.1 months) and 25.4 months (95% CI 23.4-34.1 months), respectively. Conclusions: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Sengsayadeth S.M.,Ingram Medical |
Jagasia M.,Ingram Medical |
Engelhardt B.G.,Ingram Medical |
Kassim A.,Ingram Medical |
And 6 more authors.
Bone Marrow Transplantation | Year: 2012
Seventy-nine patients with AML in CR1 received allo-SCT between May 2006 and May 2011, and the prognostic impact of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutation was evaluated in the context of other clinical prognostic factors. Patients with FLT3/ITD+ AML had significantly inferior DFS (2-year DFS: 19% vs 64%, P=0.0027), increased risk of relapse (1-year: 59% vs 19%, P=0.01), and a trend towards decreased OS (P=0.08) compared with patients without FLT3/ITD. Multivariate analysis confirmed FLT3/ITD+ independently predicted a shorter DFS (HR, 3.0; 95% CI), 1.4-6.5; P=0.01) and increased risk of relapse (HR, 4.9; 95% CI, 2.0-12.3, P=0.01). Time to relapse in patients with FLT3/ITD+ was short with 100-day cumulative risk of 45% (95% CI, 33-57). Our data suggest that the poor prognostic implication of FLT3/ITD positivity remains even after early allo-SCT in patients with FLT3/ITD+ AML, and patients remain at high risk of early relapse. FLT3/ITD positivity also outweighs other conventional prognostic markers in predicting relapse. © 2012 Macmillan Publishers Limited.
Tinker C.,Ingram Medical
Omega (United States) | Year: 2013
Songs from the Heart is an annual palliative care and outreach/support project done in partnership with the Vanderbilt-Ingram Cancer Center Henry Joyce Cancer Clinic and Gilda's Club Nashville. It is a two-evening songwriters' workshop and concert that gives cancer survivors, family members and healthcare professionals the opportunity to tell their story about cancer through the art of music in a safe therapeutic environment. It is a unique project through the art of music helping others of all ages and from all walks of life find healing and hope; as well as an opportunity to give back to others. A professional singer/songwriter and a social worker co-facilitate the two-evening songwriters workshop. Two musicians perform songs the workshop songwriters have written at a community wide concert. Those who have participated in Songs from the Heart have communicated through the workshop evaluations that this experience has been life changing and a unique opportunity in being able to: explore and express their deep felt emotional feelings and thoughts; release their creative juices; ability to be alone with the group, yet feel included as a whole; express their journey through music; and benefit from being involved with others affected by cancer who have had similar difficulties. Others who have attended the concert or listened to the CD have expressed the significant impact these songs have had on their lives and their journey with cancer. © 2013, Baywood Publishing Co., Inc.
News Article | September 5, 2013
Ingram Medical, a Salt Lake City-based provider of a distribution platform for chronic care products, raised $30m in Series B funding. The round was led by Mercato Partners, with participation from Intermountain Healthcare and StepStone Group. The company intends to use the funds to expand in other chronic care groups. Led by Jeff Smith, CEO, Ingram Medical provides home-delivered, diabetic testing supplies, serving customers nationwide and operates an online Diabetes Health Center, which offers quality information developed by a staff of expert nurses, nutritionists, educators, and physicians.