PHASE-I CLINICAL INVESTIGATION OF HOMOHARRINGTONINE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 68  (9) , 1085-1091
Abstract
Homorharringtonine is a cephalotaxine ester derived from Cephalotaxus harringtonia, which is a Chinese evergreen tree. A limited clinical evaluation of this drug is China revealed antileukemic activity, which prompted clinical trials in the USA. Patients (43) with a variety of refractory malignancies were treated using a daily i.v. treatment for 5 days at 3-4 wk intervals. The starting dose of homoharringtonine was 0.2 mg/m2 per day and it was escalated to a maximum of 8 mg/m2 per day. The dose-limiting toxic effect was hypotension, which was generally mild with daily dose levels of 3-4.5 mg/m2 per day and required no specific treatment besides i.v. fluid supplements in some patients. Hypotension became increasingly severe at the higher dose levels and resulted in cardiovascular collapse in 4 of 16 patients treated with dose levels of 5-6 mg/m2 per day. A moderately severe degree of myelosuppression was observed with homoharringtonine doses of .gtoreq. 3 mg/m2. Myelosuppression was clearly related to the extent of prior treatment and was minimal in patients who had not received extensive prior treatment. Gastrointestinal toxic effects of nausea, vomiting and diarrhea were observed in .apprx. 2/3 of the patients but these side effects were generally mild and self-limited. Drug-related fever and alopecia were also observed in some patients. No major responses were observed, although 3 patients with solid tumors evidenced minor responses and 3 or 5 patients with acute leukemia showed some degree of antileukemic activity. For phase II studies of homoharringtonine in solid tumors, a daily dose of 3 mg/m2 for 5 days in patients with extensive prior treatment and 4 mg/m2 per day for 5 days in patients with good bone marrow reserve will be utilized. The daily dose must not exceed 4 mg/m2 to avoid serious hypotension; further dose escalations should be accomplished by extending the number of days of treatment beyond 5 days.

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