title: A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging.
abstract: Gadolinium Texaphyrin (Gd-Tex) is a radiation sensitizer with a novel mechanism of action that sensitizes both oxic and hypoxic cells, localizes selectively in tumors, and is detectable by magnetic resonance imaging (MRI). This Phase I single-dose trial of Gd-Tex administered concurrently with radiation therapy was carried out to determine the maximally tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and biolocalization of Gd-Tex as determined by MRI. Adults with incurable cancers of any histology requiring radiation therapy were eligible. A single i.v. dose of Gd-Tex was followed at least 2 h later by radiation therapy. The Gd-Tex dose was escalated in cohorts of 3 to 5 patients. Thirty-eight patients (median age, 58 years; range, 35-77 years) with incurable cancers of the lung (26), cervix (3), or other solid tumors (9) received a total of 41 single administrations of Gd-Tex. The Gd-Tex dose was escalated from 0.6 to 29.6 mg/kg. Irradiated sites included the thorax, brain, pelvis, bone, soft tissue, and sites of nodal metastases. The MTD was 22.3 mg/kg, determined by reversible acute tubular necrosis as the dose-limiting toxicities. Gd-Tex selectively accumulated in primary and metastatic tumors as demonstrated by MRI. No increase in radiation toxicity to normal tissues was seen. The median half-life of Gd-Tex after single-dose administration is 7.4 h. This study demonstrates that Gd-Tex is well tolerated in doses below the MTD, and that there is selective biolocalization in tumors. The maximum recommended dose for single administrations is 16.7 mg/kg.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania Medical Center, Philadelphia 19104-4283, USA.
authors.forename: D I
authors.initials: DI
authors.lastname: Rosenthal
authors.forename: P
authors.initials: P
authors.lastname: Nurenberg
authors.forename: C R
authors.initials: CR
authors.lastname: Becerra
authors.forename: E P
authors.initials: EP
authors.lastname: Frenkel
authors.forename: D P
authors.initials: DP
authors.lastname: Carbone
authors.forename: B L
authors.initials: BL
authors.lastname: Lum
authors.forename: R
authors.initials: R
authors.lastname: Miller
authors.forename: J
authors.initials: J
authors.lastname: Engel
authors.forename: S
authors.initials: S
authors.lastname: Young
authors.forename: D
authors.initials: D
authors.lastname: Miles
authors.forename: M F
authors.initials: MF
authors.lastname: Renschler
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D003131:Combined Modality Therapy; D004064:Digestive System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D008665:Metalloporphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D011838:Radiation-Sensitizing Agents; C437683:motexafin gadolinium