Rhizoxin is a
tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant
antineoplastic activity in several murine and human
tumor models. In this Phase I study, the
drug was administered by i.v. bolus injection at 3-wk intervals. Twenty-four patients with refractory solid
tumors were treated; 60 courses of
rhizoxin were given, at doses ranging from 0.8 to 2.6 mg/m2. Grade 3
mucositis, Grade 4
leukopenia, and Grade 3
diarrhea were dose limiting but reversible at 2.6 mg/m2, the maximum tolerated dose for both previously untreated and heavily pretreated patients.
Alopecia and moderate discomfort at the injection site occurred at all doses. Other sequelae, including
peripheral neuropathy,
phlebitis, and
nausea and
vomiting, were sporadic and mild. Two heavily pretreated patients with recurrent
breast cancer had minor responses to
rhizoxin, one at 1.6 mg/m2 and the other at 2.6 mg/m2. Plasma concentrations of
rhizoxin were measured by high-performance liquid chromatography. The
drug was not detectable (less than 5 ng/ml) at doses of 0.8 mg/m2 and 1.6 mg/m2 and was not measurable 10 min after injection at 2.0 mg/m2. At 2.6 mg/m2, there was considerable intersubject variation in the plasma concentration-time profiles; the area under the curve ranged from 0.29 to 0.96 microgram/ml.min.
Rhizoxin has shown some clinical activity in this Phase I study, and a dose of 2.0 mg/m2 is recommended for Phase II studies using this schedule.