Dolastatin-10 (dola-10) is a potent
antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits
tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human
tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and
biological effects of dola-10 in patients with advanced solid
tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 microg/m2. Dose-limiting toxicity of
granulocytopenia was seen at 455 microg/m2 for minimally pretreated patients (two or fewer prior
chemotherapy regimens) and 325 microg/m2 for heavily pretreated patients (more than two prior
chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the
drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting
peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid
drug distribution with a prolonged plasma elimination phase (t 1/2z = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration-time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of
granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 microg/m2 for patients with minimal prior treatment (two or fewer prior
chemotherapy regimens) and 325 microg/m2 for patients who are heavily pretreated (more than two prior
chemotherapy regimens).