A Phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for five days every three weeks to patients with metastatic adenocarcinoma of the colon or rectum

Background: To evaluate the antitumor activity, toxicities, and pharmacokinetics (PK) of DX-895 If administered as a 30-min infusion daily for 5 days every 3 weeks in patients with fluorouracil-resistant metastatic colorectal carcinoma. Patients and methods: Sixteen patients were enrolled. All had metastatic colorectal carcinoma resistant to or progressing after chemotherapy containing 5-fluorouracil and no prior chemotherapy with camptothecin derivatives. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every two courses. Results: Fifteen patients were evaluable. Fifty-one courses of therapy were delivered (median 2). Responses were one minor response, six stable disease, and eight progressive disease. The principal adverse event was neutropenia, with grade 3 and 4 toxicities in three and eight patients, respectively. Non-hematologic toxicities were mild to moderate; the most common were fatigue, nausea, and diarrhea. Plasma concentrations of DX-8951 were well described using a linear two-compartment PK model. There was no evidence of nonlinearity in the elimination of PK or auto-inhibition or induction of DX-8951 clearance over the 5 days of administration. Conclusions: DX-8951f at this dose and schedule had no significant activity in this patient population. The toxicity profile, mainly hematologic, was consistent with previous reports. The clearance and volume of distribution were not different from those previously reported.