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

Shailendra Lakhanpal, Ross C Donehower, Eric K. Rowinsky

Research output: Contribution to journalArticle

Abstract

Background/purpose: 4-Ipomeanol (IPO; NSC 394438), a naturally occurring furan 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 anticancer agent targeted specifically against lung cancer. Prior to clinical development, IPO was shown to induce pulmonary toxicity in the lungs of several mammalian species because the agent is metabolized to a highly reactive furan epoxide by specific cytochrome P450 monooxygenases found in pulmonary Clara cells and type II pneumocytes, which share biochemical features with bronchogenic carcinoma. However, instead of inducing the anticipated lung toxicity in patients with lung cancer in disease-directed phase I studies, hepatotoxicity was the principal toxic effect of IPO in humans. Based on the presumption that IPO may be preferentially activated by cytochrome P450 monooxygenases in liver cells and biochemically-related hepatic malignancies, a phase II study was conducted to determine the activity and evaluate the toxicity of IPO in patients with advanced hepatocellular carcinoma. Patients and methods: Nineteen patients with advanced measurable hepatocellular carcinoma were enrolled on the phase II trial. All patients had an Eastern Cooperative Oncology Group performance status of at least two, no evidence of pulmonary dysfunction, and had either no prior treatment or minimal prior therapy. Patients were treated with IPO at a dose of either 1032 mg/m2, which was the maximum tolerated and recommended phase II dose previously derived for patients with normal hepatic function (15 patients) or 826 mg/m2 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 rigorously monitored using successive pulmonary function testing and computerized tomography. Results: All nineteen patients were evaluable for both response and toxicity. No major objective responses were observed. One patient had a minor, brief reduction in lung metastases. Although marker lesions and overall disease remained stable for at least 12 and 24 months in three and two patients, respectively, the median time to progression was three months and the median survival was five months for all patients. The principal toxicity was reversible elevations in hepatic transaminases, which occasionally resulted in dose reduction. No clinically-significant pulmonary toxicity was noted. Conclusion: IPO at a dose of either 826 or 1032 mg/m2 administered 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.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalInvestigational New Drugs
Volume19
Issue number1
DOIs
StatePublished - 2001

Fingerprint

Hepatocellular Carcinoma
Lung
Ipomoea batatas
Liver
Mixed Function Oxygenases
furan
4-ipomeanol
Cytochrome P-450 Enzyme System
Lung Neoplasms
Alveolar Epithelial Cells
National Cancer Institute (U.S.)
Bronchogenic Carcinoma
Poisons
Epoxy Compounds
Fusarium
Therapeutics
Transaminases
Bilirubin
Antineoplastic Agents
Neoplasms

Keywords

  • 4-Ipomeanol
  • Alkylating agent
  • Hepatocellular carcinoma
  • Hepatoma
  • Liver cancer
  • Phase II

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Phase II study of 4-Ipomeanol, a naturally occurring alkylating furan, in patients with advanced hepatocellular carcinoma. / Lakhanpal, Shailendra; Donehower, Ross C; Rowinsky, Eric K.

In: Investigational New Drugs, Vol. 19, No. 1, 2001, p. 69-76.

Research output: Contribution to journalArticle

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abstract = "Background/purpose: 4-Ipomeanol (IPO; NSC 394438), a naturally occurring furan 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 anticancer agent targeted specifically against lung cancer. Prior to clinical development, IPO was shown to induce pulmonary toxicity in the lungs of several mammalian species because the agent is metabolized to a highly reactive furan epoxide by specific cytochrome P450 monooxygenases found in pulmonary Clara cells and type II pneumocytes, which share biochemical features with bronchogenic carcinoma. However, instead of inducing the anticipated lung toxicity in patients with lung cancer in disease-directed phase I studies, hepatotoxicity was the principal toxic effect of IPO in humans. Based on the presumption that IPO may be preferentially activated by cytochrome P450 monooxygenases in liver cells and biochemically-related hepatic malignancies, a phase II study was conducted to determine the activity and evaluate the toxicity of IPO in patients with advanced hepatocellular carcinoma. Patients and methods: Nineteen patients with advanced measurable hepatocellular carcinoma were enrolled on the phase II trial. All patients had an Eastern Cooperative Oncology Group performance status of at least two, no evidence of pulmonary dysfunction, and had either no prior treatment or minimal prior therapy. Patients were treated with IPO at a dose of either 1032 mg/m2, which was the maximum tolerated and recommended phase II dose previously derived for patients with normal hepatic function (15 patients) or 826 mg/m2 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 rigorously monitored using successive pulmonary function testing and computerized tomography. Results: All nineteen patients were evaluable for both response and toxicity. No major objective responses were observed. One patient had a minor, brief reduction in lung metastases. Although marker lesions and overall disease remained stable for at least 12 and 24 months in three and two patients, respectively, the median time to progression was three months and the median survival was five months for all patients. The principal toxicity was reversible elevations in hepatic transaminases, which occasionally resulted in dose reduction. No clinically-significant pulmonary toxicity was noted. Conclusion: IPO at a dose of either 826 or 1032 mg/m2 administered 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.",
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