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Scottsdale, AZ, United States

Johnson F.M.,University of Texas M. D. Anderson Cancer Center | Agrawal S.,Bristol Myers Squibb | Burris H.,Sarah Cannon Cancer Center | Rosen L.,Premiere Oncology | And 8 more authors.
Cancer | Year: 2010

BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. © 2010 American Cancer Society.

Houk B.E.,Pfizer | Bello C.L.,Pfizer | Poland B.,Pharsight | Rosen L.S.,Premiere Oncology | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: In this pharmacokinetic/pharmacodynamic metaanalysis, we investigated relationships between clinical endpoints and sunitinib exposure in patients with advanced solid tumors, including patients with gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC). Methods: Pharmacodynamic data were available for 639 patients of whom 443 had pharmacokinetic data. Sunitinib doses ranged from 25 to 150 mg QD or QOD. Models to express endpoint values and/or changes from baseline by the highest-correlating exposure measures were developed in S-PLUS or NONMEM using fixed- and mixed-effects modeling. Results: Tentative relationships were identified between (1) steady-state AUC of total drug (sunitinib + its active metabolite SU12662) and time to tumor progression (TTP), overall survival (OS), with AUC significantly associated with longer TTP and OS in patients with GIST and mRCC, and incidence, but not severity, of fatigue; (2) steady-state AUC of sunitinib and response probability, with AUC significantly associated with objective response in patients with mRCC and stable disease in patients with both mRCC and GIST (with no such correlations in patients with solid tumors); (3) dose and tumor size reductions; (4) total drug concentration and diastolic blood pressure (DBP), with a typical patient on sunitinib 50 mg QD (the recommended dose) predicted to experience a maximum DBP increase of 8 mmHg; and (5) cumulative AUC of total drug and absolute neutrophil count (ANC), with ANC reductions occurring predominantly after one treatment cycle. Conclusions: The results of this meta-analysis indicate that increased exposure to sunitinib is associated with improved clinical outcomes (longer TTP, longer OS, greater chance of antitumor response), as well as some increased risk of adverse effects. A sunitinib 50-mg starting dose seems reasonable, providing clinical benefit with acceptably low risk of adverse events.

Gerber D.E.,University of Texas Southwestern Medical Center | Stopeck A.T.,Arizona Cancer Center | Wong L.,Scott and White Hospital | Rosen L.S.,Premiere Oncology | And 3 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Bavituximab is a chimeric immunoglobulin G1 phosphatidylserine- targeting monoclonal antibody that triggers vascular disruption and enhances antitumor immune response. This phase I study assessed the safety and pharmacokinetics of bavituximab in patients with advanced solid tumors. Experimental Design: Patients with refractory advanced solid tumors were enrolled into four sequential dose-escalation cohorts (0.1, 0.3, 1, or 3 mg/kg bavituximab weekly) with two dosing schedules. Patients in the 0.1 and 0.3 mg/kg cohorts received bavituximab on days 0, 28, 35, and 42. Patients in the 1 and 3 mg/kg cohorts were administered bavituximab on days 0, 7, 14, and 21. Safety, pharmacokinetics, and tumor response were assessed. Results: Twenty-six patients were accrued. No maximum tolerated dose was reached. Six serious adverse events occurred in five patients, including one pulmonary embolism at 3 mg/kg, which was the only dose-limiting toxicity (DLT) in the study. Bavituximab half-life ranged from 37 to 47 hours, with no accumulation seen following administration of multiple doses. Activated partial thromboplastin time was modestly prolonged in vitro at the highest dose tested. As assessed on day 56, a total of 18 patients were evaluable for efficacy, of whom 10 had disease progression and none had an objective response. Conclusions: Bavituximab was well tolerated at doses ranging up to 3 mg/kg weekly. Pharmacokinetic studies support a weekly dosing regimen. Additional phase I and II clinical trials are in progress to investigate bavituximab in combination with chemotherapy and other molecularly targeted agents. ©2011 AACR.

Background and Purpose: Recently, megavoltage (MV) photon volumetric modulated arc therapy (VMAT) has gained widespread acceptance as the technique of choice for prostate cancer patients undergoing external beam radiation therapy. However, radiation treatment planning for patients with metallic hip prostheses composed of high-Z materials can be challenging due to (1) presence of streak artifacts from prosthetic hips in computed tomography dataset, and (2) inhomogeneous dose distribution within the target volume. The purpose of this study was to compare the dosimetric quality of VMAT techniques in the form of Rapid Arc (RA) for treating low-risk prostate cancer patient with bilateral prostheses. Materials and Methods: Three treatment plans were created using RA techniques utilizing 2 arcs (2-RA), 3 arcs (3-RA), and 4 arcs (4-RA) for 6 MV photon beam in Eclipse treatment planning system. Each plan was optimized for total dose of 79.2 Gy prescribed to the planning target volume (PTV) over 44 fractions. All three RA plans were calculated with anisotropic analytical algorithm. Results : The mean and maximum doses to the PTV as well as the homogeneity index among all three RA plans were comparable. The plan conformity index was highest in the 2-Arc plan (1.19) and lowest in the 4-Arc plan (1.10). In comparison to the 2-RA technique, the 4-RA technique reduced the doses to rectum by up to 18.8% and to bladder by up to 7.8%. In comparison to the 3-RA technique, the 4-RA technique reduced the doses to rectum by up to 14.6% and to bladder by up to 3.5%. Conclusion: Based on the RA techniques investigated for a low-risk prostate cancer patient with bilateral prostheses, the 4-RA plan produced lower rectal and bladder dose and better dose conformity across the PTV in comparison with the 2-RA and 3-RA plans. © 2014. The South Asian Journal of Cancer.

Pokharel S.,Premiere Oncology | Rana S.,Proton Therapy | Blikenstaff J.,Premiere Oncology | Prestidge B.,Memorial Hermanan Healthcare System
Journal of Applied Clinical Medical Physics | Year: 2013

The purpose of this study is to investigate the effectiveness of the HIPO planning and optimization algorithm for real-time prostate HDR brachytherapy. This study consists of 20 patients who underwent ultrasound-based real-time HDR brachytherapy of the prostate using the treatment planning system called Oncentra Prostate (SWIFT version 3.0). The treatment plans for all patients were optimized using inverse dose-volume histogram-based optimization followed by graphical optimization (GRO) in real time. The GRO is manual manipulation of isodose lines slice by slice. The quality of the plan heavily depends on planner expertise and experience. The data for all patients were retrieved later, and treatment plans were created and optimized using HIPO algorithm with the same set of dose constraints, number of catheters, and set of contours as in the real-time optimization algorithm. The HIPO algorithm is a hybrid because it combines both stochastic and deterministic algorithms. The stochastic algorithm, called simulated annealing, searches the optimal catheter distributions for a given set of dose objectives. The deterministic algorithm, called dose-volume histogram-based optimization (DVHO), optimizes three-dimensional dose distribution quickly by moving straight downhill once it is in the advantageous region of the search space given by the stochastic algorithm. The PTV receiving 100% of the prescription dose (V100) was 97.56% and 95.38% with GRO and HIPO, respectively. The mean dose (Dmean) and minimum dose to 10% volume (D10) for the urethra, rectum, and bladder were all statistically lower with HIPO compared to GRO using the student pair t-test at 5% significance level. HIPO can provide treatment plans with comparable target coverage to that of GRO with a reduction in dose to the critical structures.

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