De Bono J.S.,Royal Marsden Hospital |
Logothetis C.J.,University of Texas M. D. Anderson Cancer Center |
Molina A.,Ortho Biotech Oncology Research and Development a Unit of Cougar Biotechnology |
Fizazi K.,Institute Gustave Roussy |
And 28 more authors.
New England Journal of Medicine | Year: 2011
BACKGROUND: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo - prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo - prednisone group. CONCLUSIONS: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 Clinical Trials. gov number, NCT00638690.) Copyright © 2011 Massachusetts Medical Society.
Shalowitz D.I.,University of Pennsylvania |
Spillman M.A.,Texas Oncology Baylor Charles mmons Cancer Center |
Morgan M.A.,University of Pennsylvania
American Journal of Obstetrics and Gynecology | Year: 2016
The Problem Clinicians may be unaware that industry payments to physicians are now publicly searchable under the Physician Payments Sunshine Act. Furthermore, the extent of industry's financial involvement in subspecialty practice has not been previously accessible. As an example, 6948 direct, research-unrelated payments totaling $1,957,004 were made to 765 gynecologic oncologists in 2014, the first full year of data available. A total of 153 companies reported at least 1 payment; however, the 10 manufacturers reporting the highest total payment amount accounted for 82% of all payments to physicians. In all, 48 gynecologic oncologists received >$10,000 from manufacturers, accounting for $1,202,228, or 61%, of total payments. A Solution Obstetrician-gynecologists, including gynecologic oncologists, should be aware of their publicly reported payments from industry and ensure reports' accuracy. Professional organizations, including the Society of Gynecologic Oncology (SGO), should strongly consider proactively developing guidelines regarding interactions with industry for their general memberships. © 2015 Elsevier Inc. All rights reserved.
Infante J.R.,Sarah Cannon Research Institute Tennessee Oncology PLLC |
Fecher L.A.,University of Pennsylvania |
Falchook G.S.,University of Houston |
Nallapareddy S.,Aurora University |
And 15 more authors.
The Lancet Oncology | Year: 2012
Background: Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. Methods: We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. Findings: We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. Interpretation: The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. Funding: GlaxoSmithKline. © 2012 Elsevier Ltd.
McIntyre K.,Texas Oncology Dallas Presbyterian Hospital |
O'Shaughnessy J.,Texas Oncology Baylor Charles mmons Cancer Center |
Schwartzberg L.,West Clinic |
Gluck S.,University of Miami |
And 4 more authors.
Breast Cancer Research and Treatment | Year: 2014
Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ≥12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ≥6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1-43); 6 (11 %) received treatment for ≥12 months. ORR was 29 % (95 % CI 17.3-42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety. © 2014 The Author(s).
Marty F.M.,Dana-Farber Cancer Institute |
Winston D.J.,University of California at Los Angeles |
Rowley S.D.,Hackensack University Medical Center |
Vance E.,Texas Oncology Baylor Charles mmons Cancer Center |
And 7 more authors.
New England Journal of Medicine | Year: 2013
BACKGROUND: The use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation. METHODS: From December 2009 through June 2011, a total of 230 patients with data that could be evaluated were enrolled in the study. We randomly assigned these adult CMV-seropositive transplant recipients from 27 centers to oral administration of CMX001 or placebo. Patients were assigned in a 3:1 ratio to five sequential study cohorts according to a dose-escalating, double-blind design. Randomization was stratified according to the presence or absence of acute graft-versus-host disease and CMV DNA in plasma. Patients received the study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. Polymerase-chain-reaction analysis of CMV DNA in plasma was performed weekly. Patients in whom CMV DNA was detected at a level that required treatment discontinued the study drug and received preemptive treatment against CMV infection. The primary end point was a CMV event, defined as CMV disease or a plasma CMV DNA level greater than 200 copies per milliliter when the study drug was discontinued. The analysis was conducted in the intention-to-treat population. RESULTS: The incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, -27 percentage points; 95% confidence interval, -42 to -12; P = 0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed. CONCLUSIONS: Treatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly. Copyright © 2013 Massachusetts Medical Society.
Porta C.,University of Pavia |
Calvo E.,Hospital Madrid Norte Sanchinarro |
Climent M.A.,Instituto Valenciano Of Oncologia |
Vaishampayan U.,Barbara Ann Karmanos Cancer Institute |
And 10 more authors.
European Urology | Year: 2012
Background: Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy. Objective: To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1. Design, setting, and participants: The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416). Intervention: Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity. Measurements: Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety. Results and limitations: In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation. Conclusions: Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered. © 2011 European Association of Urology.
PubMed | Helios Klinikum Berlin Buch, Amgen, Klinikum Frankfurt Hoechst, Evangelina Hospital Bethesda and 3 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017
120 Background: New data are available from two trials of ESA use in patients with breast cancer receiving chemotherapy. We conducted a meta-analysis of trials of ESA use in this population.A literature search identified reports from 1997-2012 that included mortality data from controlled ESA trials (epoetin alfa, epoetin beta, darbepoetin alfa, biosimilars) in patients with breast cancer receiving chemotherapy. We used data from company databases for Amgen Inc. or Janssen Products LP studies and published data for other studies. Random-effects odds ratios (OR) were calculated to compare results for patients randomized to ESA to patients randomized to control. Analyses were stratified by metastatic stage; mixed stage or treatment; and adjuvant/neoadjuvant treatment.We analyzed 9 studies (N = 4,713; ESA n = 2,346, control n = 2367) (Table).The overall stratified random-effects OR for death was 1.17 (95% confidence interval, 0.99-1.39). Details are presented in the Table.Overall survival OR remains consistent with prior data after including recent results. [Table: see text].
Choueiri T.K.,Dana-Farber Cancer Institute |
Choueiri T.K.,Brigham and Women's Hospital |
Choueiri T.K.,Harvard University |
Fay A.P.,Dana-Farber Cancer Institute |
And 13 more authors.
Clinical Cancer Research | Year: 2013
Purpose: Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking. Experimental Design: We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent. Results: The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib. Conclusions: In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC. © 2013 American Association for Cancer Research.
Lin T.L.,University of Kansas |
Yair Levy M.,Texas Oncology Baylor Charles mmons Cancer Center
Clinical Medicine Insights: Oncology | Year: 2012
Acute myeloid leukemia (AML) is a heterogeneous disease with variable clinical outcomes. Cytogenetic analysis reveals which patients may have favorable risk disease, but 5-year survival in this category is only approximately 60%, with intermediate and poor risk groups faring far worse. Advances in our understanding of the biology of leukemia pathogenesis and prognosis have not been matched with clinical improvements. Unsatisfactory outcomes persist for the majority of patients with AML, particularly the elderly. Novel agents and treatment approaches are needed in the induction, post-remission and relapsed settings. The additions of clofarabine for relapsed or refractory disease and the hypomethylating agents represent recent advances. Clinical trials of FLT3 inhibitors have yielded disappointing results to date, with ongoing collaborations attempting to identify the optimal role for these agents. Potential leukemia stem cell targeted therapies and treatments in the setting of minimal residual disease are also under investigation. In this review, we will discuss recent advances in AML treatment and novel therapeutic strategies. © the author(s), publisher and licensee Libertas Academica Ltd.
Divers J.,Texas Oncology Baylor Charles mmons Cancer Center |
O'Shaughnessy J.,Texas Oncology Baylor Charles mmons Cancer Center
Clinical Journal of Oncology Nursing | Year: 2015
Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved (in combination with exemestane) for the treatment of postmenopausal women with advanced hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer resistant to endocrine therapy. Stomatitis is among the most frequently reported dose-limiting adverse events associated with everolimus use, often requiring treatment interruption or dose reduction. Objectives: This article aims to educate nurses on the identification and management of stomatitis associated with mTOR inhibitors in hormone receptor−positive advanced breast cancer and to assist nurses with additional management techniques to improve patient outcomes. Methods: An evaluation of the literature highlighting the incidence, identification, and management of stomatitis in cancer was performed with a particular focus on breast cancer. In addition, the experiences of the authors’ cancer center on managing stomatitis are described. Findings: A growing body of clinical evidence shows the benefits of adding steroid-based mouth rinses to the treatment plan. Clinical experience provides additional insight into stomatitis preventive and management strategies for patients with breast cancer receiving treatment with everolimus. © 2015 by the Oncology Nursing Society.