Phase I and pharmacokinetic study of CI-980 in recurrent pediatric solid tumor cases: A pediatric oncology group study

To establish the maximum tolerated dosage (MTD), the dose-limiting toxiciti es (DLTs), and pharmacokinetic parameters of CI-980, a novel tubulin binder , in children with solid tumors refractory to standard therapy. Patients 21 years of age or younger with adequate nutritional, hematopoietic, renal, a nd hepatic function were eligible. The patient must not have been pregnant. Patients with brain tumors were not eligible for any dosage level until it was demonstrated the level did not produce DLT in patients with extracrani al solid tumors. The starting dosage level was 3.5 mg/m(2)/day, for 3 days, administered as a continuous intravenous infusion (80% of the adult MTD). If a dosage level was associated with dose-limiting myelotoxicity, growth f actors were to be added. Thirty-three patients received CI-980. Twenty-four had solid tumor; 9 had brain tumor. The MTD achieved without granulocyte c olony stimulating factor (G-CSF) was 3.5 mg/m2/day (DLT: neutropenia) and w ith G-CSF, it was as follows: patients with brain tumor, 4.2 mg/m(2)/day (D LT: myelosupression); and patients with solid tumor, 5 mg/m(2)/day (DLT: co rtical toxicity). Several responses were seen, most notably prolonged stabl e disease in two of five patients with medulloblastoma. Pharmacokinetic dat a showed a mean steady state level of 1.74 ng/mL for two patients treated w ith the 5 mg/m(2)/day regimen, with rapid decay after the termination of th e infusion. CI-980 showed preliminary evidence of activity in recurrent ped iatric malignancies, with tolerable, reversible toxicities.