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Johnson D.B.,Vanderbilt University | Flaherty K.T.,Massachusetts General Hospital | Weber J.S.,Moffitt Cancer Center | Infante J.R.,Sarah Cannon Research Institute and Tennessee Oncology | And 23 more authors.
Journal of Clinical Oncology | Year: 2014

Purpose: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAFV600-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. Patients and Methods: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). Results: In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). Conclusion: Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy. © 2014 by American Society of Clinical Oncology. Source


Pezaro C.,Joint Ludwig Austin Oncology Unit | Pezaro C.,Ludwig Institute for Cancer Research | Liew M.S.,Joint Ludwig Austin Oncology Unit | Davis I.D.,Joint Ludwig Austin Oncology Unit | And 2 more authors.
Expert Review of Anticancer Therapy | Year: 2012

Urothelial carcinoma (transitional cell carcinoma) is the most common malignancy of the urinary tract. Urothelial carcinoma of the bladder is a common disease but has traditionally been underrepresented in both public awareness and cancer research. The purpose of this review is to provide an outline of the recent updates in understanding of urothelial cancer etiology, particularly with regards to lower tract muscle-invasive disease, and to discuss the identified mutations in high- and low-grade disease. We will consider evidence for the current systemic therapies for muscle-invasive and metastatic disease and review the targeted therapies under investigation for advanced urothelial cancer. © 2012 Expert Reviews Ltd. Source


Beeton-Kempen N.,University of Cape Town | Beeton-Kempen N.,Council for Scientific and Industrial Research | Duarte J.,University of Cape Town | Shoko A.,Center for Proteomic and Genomic Research | And 6 more authors.
International Journal of Cancer | Year: 2014

The cancer-testis antigens are a group of unrelated proteins aberrantly expressed in various cancers in adult somatic tissues. This aberrant expression can trigger spontaneous immune responses, a phenomenon exploited for the development of disease markers and therapeutic vaccines. However, expression levels often vary amongst patients presenting the same cancer type, and these antigens are therefore unlikely to be individually viable as diagnostic or prognostic markers. Nevertheless, patterns of antigen expression may provide correlates of specific cancer types and disease progression. Herein, we describe the development of a novel, readily customizable cancer-testis antigen microarray platform together with robust bioinformatics tools, with which to quantify anti-cancer testis antigen autoantibody profiles in patient sera. By exploiting the high affinity between autoantibodies and tumor antigens, we achieved linearity of response and an autoantibody quantitation limit in the pg/mL range - equating to a million-fold serum dilution. By using oriented attachment of folded, recombinant antigens and a polyethylene glycol microarray surface coating, we attained minimal non-specific antibody binding. Unlike other proteomics methods, which typically use lower affinity interactions between monoclonal antibodies and tumor antigens for detection, the high sensitivity and specificity realized using our autoantibody-based approach may facilitate the development of better cancer biomarkers, as well as potentially enabling pre-symptomatic diagnosis. We illustrated the usage of our platform by monitoring the response of a melanoma patient cohort to an experimental therapeutic NY-ESO-1-based cancer vaccine; inter alia, we found evidence of determinant spreading in individual patients, as well as differential CT antigen expression and epitope usage. © 2014 UICC. Source


Andrews M.C.,Ludwig Institute for Cancer Research | Andrews M.C.,Joint Ludwig Austin Oncology Unit | Woods K.,Ludwig Institute for Cancer Research | Cebon J.,Ludwig Institute for Cancer Research | And 2 more authors.
Future Oncology | Year: 2014

Human tumor rejection antigens recognized by T lymphocytes were first defined in the early 1990s and the identification of shared tumor-restricted antigens sparked hopes for the development of a therapeutic vaccination to treat cancer, including melanoma. Despite decades of intense preclinical and clinical research, the success of anticancer vaccines based on these antigens has been limited. While melanoma is a highly immunogenic tumor, the ability to prime immunity with vaccines has not generally translated into objective disease regression. However, with the development of small molecules targeting oncogenic proteins, such as V600-mutated BRAF, and immune checkpoint inhibitors with demonstrable long-lasting clinical benefit, new opportunities for antigen-targeted directed therapies are emerging. © 2014 Future Medicine Ltd. Source


Wong S.F.,Joint Ludwig Austin Oncology Unit | Seow J.,Austin Health | Profitis K.,Austin Health | Johns J.,Austin Health | And 2 more authors.
Internal Medicine Journal | Year: 2013

Non-bacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis, has been reported to occur in 0.3-9.3% of the adult population at autopsy. NBTE associated with malignancy is an underrecognised cause of thromboembolic disorders. The clinical spectrum encountered and investigation results can be non-specific, often mimicking other acute conditions such as infective endocarditis. We describe the case of a 34-year-old woman with non-localising and multifocal neurological symptoms, who was subsequently diagnosed with NBTE secondary to a resectable primary lung adenocarcinoma. © 2012 The Authors. Internal Medicine Journal © 2012 Royal Australasian College of Physicians. Source

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