motexafin-gadolinium and Glioblastoma

Motexafin gadolinium (MGd, PCI-0120, Xcytrin, a metallotexaphyrin developed by Pharmacyclics, is a redox active drug that selectively targets tumour cells with a potential action as a radiosensitiser. In vitro and in vivo models showed radiation enhancement when radiation followed MGd administration. Phase I and II clinical studies showed that MGd was well-tolerated with a maximum-tolerated dose set at 6.3 mg/kg. Acute side effects of discolouration of the sclera, skin and urine are reversible. The clinical efficacy was determined in an international Phase III trial for brain metastases with a significant difference in time to neurological progression for lung cancer brain metastases in favour of MGd and whole brain radiation versus whole brain radiation only. For the treatment of glioblastoma multiforme, promising results are found in a Phase I trial with a median survival of 17.3 months. Further investigation of the combination of MGd and radiotherapy will be worthwhile.

Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Metalloporphyrins; Radiation-Sensitizing Agents

The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls.. Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method.. In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy.. Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Dacarbazine; Disease-Free Survival; Dose Fractionation, Radiation; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Metalloporphyrins; Multivariate Analysis; Supratentorial Neoplasms; Temozolomide

Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 doses) of MGd with radiotherapy for glioblastoma multiforme.. A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied.. The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94).. The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide.

Topics: Adult; Aged; Brain Neoplasms; Drug Administration Schedule; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Matched-Pair Analysis; Maximum Tolerated Dose; Metalloporphyrins; Middle Aged; Radiation-Sensitizing Agents

Motexafin gadolinium (MGd) is an investigational pharmaceutical with radiation enhancing properties. Magnetic Resonance Imaging (MRI) was used to measure brain and tumor MGd levels to evaluate (1) the degree to which MGd passes through the intact blood brain barrier, and (2) the retention of MGd in tumor in patients with glioblastoma multiforme (GBM).. MRI studies were performed on GBM patients who participated in a phase I clinical trial in which MGd was given during standard fractionated radiation therapy. MGd was administered daily (Monday to Friday) for five or 10 doses as a loading regimen, followed by three times per week dosing as a maintenance schedule. T1-weighted MRI was performed at intervals throughout the course of the MGd administration and radiation therapy in the 33 participating patients. Eleven patients had pre- and post-MGd scans, allowing for study of MGd's normal blood brain barrier penetration. Twenty-two patients had adequate residual tumor for measurements to evaluate MGd retention in tumor during the course of MGd and radiation administration.. The studies of uninvolved brain tissue support the conclusion that MGd does not cross the intact blood brain barrier in detectable quantities. The tumor study showed MGd uptake during loading and maintenance without measurably significant fall off on non-dosage days during the maintenance dosing. Although the number of cases is small, the 10-day loading regimen showed greater drug loading and retention compared with the 5 days loading regimen.

Topics: Antineoplastic Agents; Blood-Brain Barrier; Brain; Brain Neoplasms; Cohort Studies; Dose Fractionation, Radiation; Drug Administration Schedule; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Metalloporphyrins; Radiation-Sensitizing Agents; Radiotherapy Dosage

We present preclinical data showing the in vitro intranuclear uptake of motexafin gadolinium by glioblastoma multiforme cells, which could serve as a prelude to the future development of radiosensitizing techniques, such as gadolinium synchrotron stereotactic radiotherapy (GdSSR), a new putative treatment for glioblastoma multiforme.. In this approach, administration of a tumor-seeking Gd-containing compound would be followed by stereotactic external beam radiotherapy with 51-keV photons from a synchrotron source. At least two criteria must be satisfied before this therapy can be established: Gd must accumulate in cancer cells and spare the normal tissue; Gd must be present in almost all the cancer cell nuclei. We address the in vitro intranuclear uptake of motexafin gadolinium in this article. We analyzed the Gd distribution with subcellular resolution in four human glioblastoma cell lines, using three independent methods: two novel synchrotron spectromicroscopic techniques and one confocal microscopy. We present in vitro evidence that the majority of the cell nuclei take up motexafin gadolinium, a drug that is known to selectively reach glioblastoma multiforme.. With all three methods, we found Gd in at least 90% of the cell nuclei. The results are highly reproducible across different cell lines. The present data provide evidence for further studies, with the goal of developing GdSSR, a process that will require further in vivo animal and future clinical studies.

Topics: Brain Neoplasms; Cell Line, Tumor; Cell Nucleus; Glioblastoma; Humans; In Vitro Techniques; Magnetic Resonance Imaging; Metalloporphyrins; Microscopy, Confocal; Microscopy, Electron, Scanning Transmission; Radiation-Sensitizing Agents

The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alkaline Phosphatase; Anticonvulsants; Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Creatinine; Data Interpretation, Statistical; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Metabolic Clearance Rate; Metalloporphyrins; Middle Aged; Models, Biological; Neoplasm Metastasis; Phenytoin; Sex Factors; Software

Radiation therapy is a central modality in the treatment of glioblastoma multiforme (GBM). Integral to adequate radiation therapy delivery is the appropriate determination of tumor volume and extent at the time treatment is being delivered. As a matter of routine practice, radiation therapy treatment fields are designed based on tumor volumes evident on pre-operative or immediate post-operative MRIs; another MRI is generally not obtained for planning boost fields. In some instances the time interval from surgery to radiotherapy initiation is up to 5 weeks and the boost or "cone-down phase" commences 4-5 weeks later. The contrast enhanced T1 MRI may not be a totally reliable indicator of active tumor, especially in regions where such blood-brain barrier breakdown has not occurred. Moreover, these volumes may change during the course of treatment. This may lead to a geographic miss when mid-treatment boost volumes are designed based on a pre-radiotherapy MRI. The goal of this study is to examine how a mid-treatment MRI impacts the delineation and definition of the boost volume in GBM patients in comparison to the pre-treatment MRI scan, particularly when the tumor-specific agent Motexafin-Gadolinium is used.

Topics: Brain Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Contrast Media; Glioblastoma; Humans; Magnetic Resonance Imaging; Metalloporphyrins; Postoperative Period; Radiotherapy; Radiotherapy Planning, Computer-Assisted; Tumor Burden