Results of the lead-in phase of an ongoing randomized phase III trial of motexafin (Xcytrin) in patients with brain metastases, as well as preliminary results of an ongoing phase I trial of motexafin for glioblastoma multiforme, were presented at the 42nd annual meeting of the American Society for Therapeutic Radiology and Oncology.
"Xcytrin appeared to improve local control in the brain, with very few patients experiencing neurologic progression, neurocognitive deterioration, or death due to tumor progression," said Minesh Mehta, MD, associate professor and interim chair, department of human oncology, University of Wisconsin Medical School, and cochairman of the phase III trial. "The findings that radiologic responses were correlated with improved survival, and that neurocognitive performance was an independent predictor of survival give us confidence that the phase III trial is well designed to meet the efficacy end points."
Phase III Trial
In the open-label lead-in phase of the phase III trial, 25 patients with brain metastases received an injection of motexafin followed by standard whole-brain irradiation once a day for 10 days. Investigators assessed the effect of this treatment on tumor control via several methods, including magnetic resonance imaging (MRI) scans to measure tumor response and a battery of tests to evaluate neurologic and neurocognitive function.
A tumor response was seen in 68% of patients evaluable by MRI (13 out of 19), with a median reduction in tumor volume of 83%; 77% of all 25 patients were free from neurologic progression. Radiologic response and neurocognitive test scores were found to correlate with survival. Median survival for all 25 patients was 5 months, and only 23% of patients died as a result of neurologic progression.
Treatment Well Tolerated
Treatment with motexafin was well tolerated with no serious drug-related toxicities observed (94% [236 of 250] of the planned motexafin doses were delivered). Side effects were generally reversible and relatively minor, including temporary skin discoloration, change in urine color, nausea, hypertension, and liver enzyme abnormalities in some patients. Patients enrolled in the study had very advanced disease and were not eligible for radiosurgery. On average, each patient had 11 brain tumors. The majority of patients in the lead-in phase of the trial had advanced lung or breast cancer that had spread to the brain.
"The lead-in data, which confirm the results of our previously reported phase Ib/II study are encouraging in that they appear to support the coprimary efficacy end points of the phase III trial," said Markus Renschler, MD, senior director of clinical development at Pharmacyclics, the manufacturer of motexafin. "We and our collaborators believe this is the most comprehensive clinical trial ever performed for this disease. Many important clinical parameters are being measured, including survival, neurologic function, neurocognitive function, and radiologic response. We expect to capture a large amount of important clinical information from this trial."
Enrollment in the phase III trial is nearing completion at more than 50 medical centers in the United States, Canada, and Europe. Patients are being randomly assigned to treatment with either standard radiation plus motexafin or standard radiation alone. Improvement in either survival or time to neurologic progression are the coprimary end points of the trial.
Phase I Trial
Dr. Mehta also reported the interim results of the ongoing phase I trial in patients with glioblastoma multiforme who are receiving motexafin combined with whole-brain irradiation. Researchers observed a median survival rate of 22.8 months among the 21 patients evaluated so far.
"While preliminary, these results are encouraging considering the expected survival for this type of cancer is approximately 11 months," said Dr. Mehta. Because the treatments have been well tolerated, dose escalation is continuing. The study is being conducted at the University of California at Los Angeles (UCLA) Medical Center by lead investigator, Judith Ford, MD, under a Cooperative Research and Development Agreement between Pharmacyclics and the National Cancer Institute.