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


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%.


CONCLUSIONS
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.
Institut Gustave Roussy, Villejuif, France.
P
P
Carde
R
R
Timmerman
M P
MP
Mehta
C D
CD
Koprowski
J
J
Ford
R B
RB
Tishler
D
D
Miles
R A
RA
Miller
M F
MF
Renschler
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy / Q000556:secondary*; D003131:Combined Modality Therapy; D016371:Cranial Irradiation / Q000379:methods*; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011446:Prospective Studies; D012372:ROC Curve; D015996:Survival Rate; D014018:Tissue Distribution
D008665:Metalloporphyrins; D017319:Photosensitizing Agents; C102825:motexafin lutetium; C437683:motexafin gadolinium