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

• Published in: Journal of clinical oncology Vol. 19; no. 7; pp. 2074 - 2083
• Main Authors: CARDE, Patrice, TIMMERMAN, Robert, MEHTA, Minesh P, KOPROWSKI, Christopher D, FORD, Judith, TISHLER, Roy B, MILES, Dale, MILLER, Richard A, RENSCHLER, Markus F
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01.04.2001; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain Neoplasms - radiotherapy; Brain Neoplasms - secondary; Combined Modality Therapy; Cranial Irradiation - methods; Diseases of the nervous system; Dose Fractionation; Dose-Response Relationship, Drug; Female; France - epidemiology; Humans; Male; Maximum Tolerated Dose; Medical sciences; Metalloporphyrins - administration & dosage; Metalloporphyrins - adverse effects; Metalloporphyrins - pharmacokinetics; Middle Aged; Photosensitizing Agents - administration & dosage; Photosensitizing Agents - adverse effects; Photosensitizing Agents - pharmacokinetics; Prospective Studies; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); ROC Curve; Survival Rate; Tissue Distribution; France; Human; Intracranial; Nervous system diseases; Prognosis; Maximal dose; Gadolinium compound; Malignant tumor; Metastasis; Radiotherapy; Cerebral disorder; Limit dose; Radiosensitizing agent; Treatment; Central nervous system disease; Phase II trial; Phase I trial; Localization; Pharmacokinetics
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2001.19.7.2074

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. 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. 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%. 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.