To establish the maximum tolerated dosage (MTD), the dose-limiting toxicities (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, and 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 extracranial solid
tumors. The starting dosage level was 3.5 mg/m2/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 factors were to be added. Thirty-three patients received
CI-980. Twenty-four had solid
tumor; 9 had
brain tumor. The MTD achieved without
granulocyte colony stimulating factor (
G-CSF) was 3.5 mg/m2/day (DLT:
neutropenia) and with
G-CSF, it was as follows: patients with
brain tumor, 4.2 mg/m2/day (DLT: myelosupression); and patients with solid
tumor, 5 mg/m2/day (DLT: cortical toxicity). Several responses were seen, most notably prolonged stable disease in two of five patients with
medulloblastoma. Pharmacokinetic data showed a mean steady state level of 1.74 ng/mL for two patients treated with the 5 mg/m2/day regimen, with rapid decay after the termination of the infusion.
CI-980 showed preliminary evidence of activity in recurrent pediatric
malignancies, with tolerable, reversible toxicities.