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Multicenter Phase Ib/II Trial of the Radiation Enhancer Motexafin Gadolinium in Patients With Brain Metastases

From the Institut Gustave Roussy, Villejuif, France; Indiana University, Indianapolis, IN; University of Wisconsin, Madison, WI; Cooper Hospital, Camden, NJ; University of California, Los Angeles; Pharmacyclics, Inc., Sunnyvale, CA; and Joint Center for Radiation Therapy, Harvard, Boston, MA.

Address reprint requests to Markus F. Renschler, MD, Pharmacyclics, Inc., 995 E Arques Ave, Sunnyvale, CA 94085; email: markus{at}pcyc.com

PURPOSE: Motexafin gadolinium is a magnetic resonance imaging (MRI)–detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival.

PATIENTS AND METHODS: Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range.

RESULTS: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium’s tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%.

CONCLUSION: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.

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