Phase II study of 4-ipomeanol, a naturally occurring alkylating furan, in patients with advanced hepatocellular carcinoma

Background/purpose: 4-Ipomeanol (IPO; NSC 394438), a naturally occurring fu ran isolated from common sweet potatoes (Ipomoea batatas) infected with the fungus Fusarium solani was the first agent to be developed by the National Cancer Institute based on a biochemical-biological rationale as an antican cer agent targeted specifically against lung cancer. Prior to clinical deve lopment, IPO was shown to induce pulmonary toxicity in the lungs of several mammalian species because the agent is metabolized to a highly reactive fu ran epoxide by specific cytochrome P450 monooxygenases found in pulmonary C lara cells and type II pneumocytes, which share biochemical features with b ronchogenic carcinoma. However, instead of inducing the anticipated lung to xicity in patients with lung cancer in disease-directed phase I studies, he patotoxicity was the principal toxic effect of IPO in humans. Based on the presumption that IPO may be preferentially activated by cytochrome P450 mon ooxygenases in liver cells and biochemically-related hepatic malignancies, a phase II study was conducted to determine the activity and evaluate the t oxicity of IPO in patients with advanced hepatocellular carcinoma. Patients and methods: Nineteen patients with advanced measurable hepatocellular car cinoma were enrolled on the phase II trial. All patients had an Eastern Coo perative Oncology Group performance status of at least two, no evidence of pulmonary dysfunction, and had either no prior treatment or minimal prior t herapy. Patients were treated with IPO at a dose of either 1032 mg/m(2), wh ich was the maximum tolerated and recommended phase II dose previously deri ved for patients with normal hepatic function (15 patients) or 826 mg/m(2) if they had serum bilirubin concentrations in the range of 2.0 to 3.0 mg/dL (four patients). Treatment was repeated every three weeks. Objective tumor response, the primary endpoint of the study, was assessed after every two courses of treatment, and both pulmonary function and lung density were rig orously monitored using successive pulmonary function testing and computeri zed tomography. Results: All nineteen patients were evaluable for both resp onse and toxicity. No major objective responses were observed. One patient had a minor, brief reduction in lung metastases. Although marker lesions an d overall disease remained stable for at least 12 and 24 months in three an d two patients, respectively, the median time to progression was three mont hs and the median survival was five months for all patients. The principal toxicity was reversible elevations in hepatic transaminases, which occasion ally resulted in dose reduction. No clinically-significant pulmonary toxici ty was noted. Conclusion: IPO at a dose of either 826 or 1032 mg/m(2) admin istered every three weeks did not demonstrate a relevant degree of clinical activity against advanced hepatocellular carcinoma. Further evaluations of TO is not recommended for this disease.