Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers.
ABSTRACT To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated.
Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography.
Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion.
Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.
Article: Motexafin gadoliniumDrugs of the Future 01/2007; 32(7). DOI:10.1358/dof.2007.032.07.1113618 · 0.25 Impact Factor
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ABSTRACT: To determine the radiation dose to mouse cancer xenografts from serial micro-computed tomography (CT) examinations. A nude mouse with a 15-mm subcutaneous pancreatic cancer xenograft in the rightflank was used. Radiation exposure to the subcutaneous tumor and the mouse pancreas (to simulate an orthotopic pancreatic tumor model) was measured using lithium fluoride thermoluminescent dosimeters. Ultrafast micro-CT was performed using 80 kVp, 0.26 mA, 0.156 mm slice thickness, 256 slices, 0.7 mm Al filtration, and 60-second image acquisition time (15 mA second). Micro-CT imaging acquisitions were repeated four times. We measured consistently low tumor doses (0.014 to 0.02 Gy; average=0.017 Gy) per scan. Orthotopic doses in the region of the pancreas were also consistently low (0.014 to 0.018 Gy; average=0.016 Gy) per scan. Radiation doses delivered during ultrafast micro-CT serial imaging in the mouse are low and are likely below the threshold to affect tumor growth.Molecular Imaging & Biology 02/2007; 9(2):78-82. DOI:10.1007/s11307-007-0080-9 · 2.87 Impact Factor
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ABSTRACT: Motexafin gadolinium (MGd) is a novel, MRI-detectable, anticancer agent that enhances the cytotoxic potential of radiation therapy through several mechanisms, including depleting intracellular reducing metabolites that are necessary for repairing the oxidative damage induced by irradiation. It has tumor-specific uptake, normal tissue sparing, and tolerable and reversible toxicities in clinical trials. MGd's use in conjunction with whole-brain radiation therapy (WBRT) has demonstrated an improvement in neurocognitive decline, neurologic progression, and quality of life in patients with brain metastases from NSCLC. Its use in conjunction with radiosurgery and whole brain radiation therapy in the setting of brain metastases is currently being studied, as is MGd with radiation and temozolomide in patients with glioblastoma multiforme. MGd is also being actively investigated as a single agent or in combination with chemotherapy or radiation therapy in other tumors, including pediatric brain tumors, NSCLC, lymphoma, renal cell carcinoma, and pancreatic and biliary tumors.Expert Opinion on Pharmacotherapy 03/2007; 8(3):351-9. DOI:10.1517/146565220.127.116.111 · 3.09 Impact Factor