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Phase II Study of 4-Ipomeanol, a Naturally Occurring Alkylating Furan, in Patients with Advanced Hepatocellular Carcinoma

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Abstract

Background/purpose: 4-Ipomeanol (IPO; NSC394438), anaturally occurring furan isolated from common sweet potatoes(Ipomoea batatas) infected with the fungus Fusariumsolani was the first agent to be developed by theNationalCancer Institute based on a biochemical-biological rationaleas an anticancer agent targeted specifically against lungcancer. Prior to clinical development, IPO was shown to inducepulmonary toxicity in the lungs of several mammalian speciesbecause the agent is metabolized to a highly reactive furanepoxide by specific cytochrome P450 monooxygenases found inpulmonary Clara cells and type II pneumocytes, which sharebiochemical features with bronchogenic carcinoma. However,instead of inducing the anticipated lung toxicity in patientswith lung cancer in disease-directed phase I studies,hepatotoxicity was the principal toxic effect of IPO inhumans. Based on the presumption that IPO may bepreferentially activated by cytochrome P450 monooxygenases inliver cells and biochemically-related hepatic malignancies, aphase II study was conducted to determine the activity andevaluate the toxicity of IPO in patients with advancedhepatocellular carcinoma.Patients and methods: Nineteen patients with advancedmeasurable hepatocellular carcinoma were enrolled on the phaseII trial. All patients had an Eastern Cooperative OncologyGroup performance status of at least two, no evidence ofpulmonary dysfunction, and had either no prior treatment orminimal prior therapy. Patients were treated with IPO at adose of either 1032 mg/m2, which was the maximumtolerated and recommended phase II dose previously derived forpatients with normal hepatic function (15 patients) or 826mg/m2 if they had serum bilirubin concentrations intherange of 2.0 to 3.0 mg/dL (four patients). Treatment wasrepeated every three weeks. Objective tumor response, theprimary endpoint of the study, was assessed after every twocourses of treatment, and both pulmonary function and lungdensity were rigorously monitored using successive pulmonaryfunction testing and computerized tomography.Results: All nineteen patients were evaluable forbothresponse and toxicity. No major objective responses wereobserved. One patient had a minor, brief reduction in lungmetastases. Although marker lesions and overall diseaseremained stable for at least 12 and 24 months in three and twopatients, respectively, the median time to progression wasthree months and the median survival was five months for allpatients. The principal toxicity was reversible elevations inhepatic transaminases, which occasionally resulted in dosereduction. No clinically-significant pulmonary toxicity wasnoted.Conclusion: IPO at a dose of either 826 or 1032mg/m2 administered every three weeks did notdemonstratea relevant degree of clinical activity against advancedhepatocellular carcinoma. Further evaluations of TO is notrecommended for this disease.

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Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas

    Shailendra Lakhanpal, Ross C. Donehower & Eric K. Rowinsky

  2. University of Texas Health Science Center, San Antonio, TX, USA

    Shailendra Lakhanpal, Ross C. Donehower & Eric K. Rowinsky

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  1. Shailendra Lakhanpal
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  2. Ross C. Donehower
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Lakhanpal, S., Donehower, R.C. & Rowinsky, E.K. Phase II Study of 4-Ipomeanol, a Naturally Occurring Alkylating Furan, in Patients with Advanced Hepatocellular Carcinoma. Invest New Drugs 19, 69–76 (2001). https://doi.org/10.1023/A:1006408803734

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