Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.
OBJECTIVE
XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks.


METHODS
Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m2/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([11C]XR5000) pharmacokinetics.


RESULTS
The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m2/120 hours, and the MTD was 3,010 mg/m2/120 hours. Other grade 3-4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [11C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean +/- SD in m2/mL/sec) increased when [(11)C]XR5000 was administered during an infusion of XR5000 (0.242 +/- 0.4), compared with [11C]XR5000 given alone (0.209 +/- 0.04; P <.05), indicating that tumor drug exposure was not saturated [corrected].


CONCLUSIONS
The recommended dose for XR5000 in phase II studies is 3,010 mg/m2/120 hours. PET studies with 11C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.
Propper
D J
DJ
CRC Department of Medical Oncology, Beatson Oncology Centre, Glasgow, UK.
de Bono
J
J
Saleem
A
A
Ellard
S
S
Flanagan
E
E
Paul
J
J
Ganesan
T S
TS
Talbot
D C
DC
Aboagye
E O
EO
Price
P
P
Harris
A L
AL
Twelves
C
C
D000166:Acridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D000166:Acridines; D002250:Carbon Radioisotopes; C121181:DACA, acridine