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Gilbert J.,Vanderbilt University | Rudek M.A.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Higgins M.J.,Massachusetts General Cancer Center | Zhao M.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | And 4 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Erlotinib, an orally active selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, has synergistic activity with radiation and with cisplatin. The EGFR is overexpressed in the majority of head and neck cancers. The primary objective of this phase I study was to determine the maximum-tolerated dose (MTD) of erlotinib in combination with low-dose daily cisplatin and radiotherapy. We also sought evidence of biologic activity of erlotinib alone using serial 18-FDG positron emission tomography (PET) imaging. Experimental Design: Oral erlotinib was taken daily starting with a 14-day run-in and continued until radiation therapy (RT) was completed. Low-dose daily cisplatin, 6 mg/m 2 i.v. was given concurrently with standard fractionation RT to a total dose of 66 to 70 Gy. Dose escalation followed a modified Fibonacci dose escalation design. Results: Twenty-two patients were enrolled and 18 patients received therapy on protocol. MTD of the combination of erlotinib, cisplatin, and RT was not reached. The recommended phase II dose of erlotinib is 150 mg per day in combination with cisplatin and RT, the highest dose of erlotinib evaluated in this study. 18F-FDG PET showed evidence for metabolic response to single-agent erlotinib. Per PERCIST criteria, the overall metabolic response rate at day 14 was 38.8% (95% CI: 17.3-64.3). On completion of concurrent chemoradiotherapy, overall response rate derived from tumor measurements based on imaging studies was 83% for all dose levels combined. Conclusions: Erlotinib in combination with low-dose daily cisplatin and RT is well tolerated and shows evidence of clinical efficacy. The combination should be evaluated further. ©2012 AACR.

Richardson P.G.,Dana-Farber Cancer Institute | Wolf J.,University of California at San Francisco | Jakubowiak A.,University of Michigan | Zonder J.,Karmanos Cancer Center | And 18 more authors.
Journal of Clinical Oncology | Year: 2011

Purpose: Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM. Patients and Methods: In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m 2, with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone. Results: An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients). Conclusion: Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib. © 2011 by American Society of Clinical Oncology.

Blackburn J.S.,Massachusetts General Hospital | Blackburn J.S.,Massachusetts General Cancer Center | Blackburn J.S.,Harvard Stem Cell Institute | Liu S.,Massachusetts General Hospital | And 12 more authors.
Nature Protocols | Year: 2011

Zebrafish are a useful vertebrate model for the study of development, behavior, disease and cancer. A major advantage of zebrafish is that large numbers of animals can be economically used for experimentation; however, high-throughput methods for imaging live adult zebrafish had not been developed. Here, we describe protocols for building a light-emitting diode (LED) fluorescence macroscope and for using it to simultaneously image up to 30 adult animals that transgenically express a fluorescent protein, are transplanted with fluorescently labeled tumor cells or are tagged with fluorescent elastomers. These protocols show that the LED fluorescence macroscope is capable of distinguishing five fluorescent proteins and can image unanesthetized swimming adult zebrafish in multiple fluorescent channels simultaneously. The macroscope can be built and used for imaging within 1 day, whereas creating fluorescently labeled adult zebrafish requires 1 hour to several months, depending on the method chosen. The LED fluorescence macroscope provides a low-cost, high-throughput method to rapidly screen adult fluorescent zebrafish and it will be useful for imaging transgenic animals, screening for tumor engraftment, and tagging individual fish for long-term analysis. © 2011 Nature America, Inc. All rights reserved.

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