Investigation of Retention of the Radiation Enhancer, Motexafin Gadolinium (MGd), in Glioblastoma Multiforme When MGd is Given during Standard Radiation Therapy Using a Loading Plus Maintenance Dosage Regimen
G.W.: Genevieve Wu does not work for the company, does not own stocks from the company, and is not associated with the company. J.R.A.: Jeffry Alger has no association with the company J.M.F.: Judith Ford was the principle investigator of the Phase I clinical trial "Gadolinium texaphrin in Glioblastoma Multiforme". The company, Pharmacyclics, provided partial funding for the trial such as the funding used for MRI scans. Other than that, Judith Ford does not work for the company, nor owns stocks of the company.
Purpose/Objective: To investigate whether a loading plus maintenance MGd dosing regimen used over 6.0 to 6.5 weeks during standard radiation therapy for GBM, maintained levels of drug in tumor, using Magnetic Resonance Imaging signal as a surrogate marker of the presence of MGd. Materials/Methods: Thirty-three patients entered into a phase I clinical trial in which MGd was administered during standard radiation therapy. MGd was given for 5 or 10 doses on a daily (Monday to Friday) schedule as a loading regimen, followed by 3 times per week dosing as a maintenance schedule. The first cohort of patients had 10 doses (5 loading doses and 5 maintenance doses) and number of doses was increased with each cohort. Since MGd acts as an MRI contrast enhancing agent, T1-weighted MR imaging was undertaken 2 hours after the first, fifth (load end) and last doses of drug. For the early cohorts a scan was also done one week after the last dose. For later cohorts a scan was done on a day during dosing when drug was not scheduled. For 10 days loading regimen, the scans were done both after the 5th dose and after the 10th dose. For the final 2 cohorts, the baseline scan was done prior to the first dose not 2 hours after, to give standardized images without MGd present. All scans included calibration tubes of known concentrations of MGd in brain tissue equivalent agar. Results: Eighteen patients had images with adequate residual tumor for measurement. MRI signals from tumor regions of interest were normalized to the signal from tube 1 for each individual scan to correct for global between study variation in the MRI intensity. Taking maintenance of MRI signal as a surrogate for drug retention, each patient data was then expressed as ratios to their load end (day 5) signal intensity (Figure 1, error bars represent 1 standard deviation). There are clear trends in the imaging data, although the results are not statistically significant. Signal intensity in tumor on day 5, load end, is higher than on day 1 as expected. For the 3 patients who had 10 days loading, the day 10 result is higher than the day 5 result and this appears to be maintained through to the last dose (Figure 2, 1 standard deviation error bars). There is a small drop off to the last dose day, but not below day 1 on average, consistent with good drug retention. The non-dose days, including 7 days after last dose, are also in the same range, suggesting drug is retained in tumor with a half life of at least 7 days. Conclusions: Using MRI signal as a surrogate marker for MGd in tissue, a dosing regimen of 5 to 10 day loading daily Monday to Friday, and 3 times per week thereafter shows increase in signal during loading and maintenance without significant fall off on non-dosage days. The 10 day loading regimen yielded a higher peak dose which appeared maintained during the remainder of the 3 times per week maintenance schedule.