Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases

Purpose: Motexafin gadolinium is a magnetic resonance imaging (MRI)-detecta ble redox active drug that localizes selectively in tumor cells and enhance s the effect of radiation therapy. This phase Ib/II trial of motexafin gado linium, administered concurrently with 30 Gy in 10 fractions whole-brain ra diation therapy (WBRT), was conducted to determine maximum-tolerated dose ( MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in pati ents with brain metastases. Additional endpoints were radiologic response r ate and survival. Patients and Methods: Motexafin gadolinium was administered before each rad iation treatment in this open-label, multicenter, international trial. In p hase Ib, drug dose was escalated until the MTD was exceeded. In phase II, d rug was evaluated in a narrow dose range. Results: In phase Ib, the motexafin gadolinium dose was escalated in 39 pat ients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg t o 6.3 mg/kg motexafin gadolinium. Ten once daily treatments were well toler ated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium's tumor selectivity was established using MRI. The rad iologic response rate was 72% in phase II. Median survival was 4.7 months f or 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 su rvival for all patients was 25%. Conclusion: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/k g, was selectively accumulated in tumors, and, when combined with WBRT of 3 0 Gy in 10 fractions, was associated with a high radiologic response rate. (C) 2001 by American Society of Clinical Oncology.