The feasibility of using randomization schemes early in the clinical trials of new chemotherapeutic agents: Hydroxyurea (NSC‐32065)

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Abstract
A randomization technique to help reduce possible bias was used in dose‐finding trials of a new cancer chemotherapeutic agent, hydroxyurea. The drug was given at fixed starting doses of 12.5, 25.0, 37.5, and 50.0 mg. per kilogram for a 6 week period by the oral and parenteral routes to 110 patients. Only downward modification of doses was allowed according to a fixed protocol. Leukopenia was the most common toxicity observed at doses of 25.0 mg. per kilogmm or more and appeared slightly more often in patients receiving the drug parenterally. The actual total dose administered was approximately the same at 25.0, 37.5, and 50.0 mg. per kilogram, and no difference in toxicity was noted between the single daily and three times daily oral administration. Recalculation of the dose by surface area indicated the biologically active dose to be about 1.4 Gm. per square meter. For hydroxyurea administered to adults, no better prediction of toxicity was noted for the dose calculated for individual patients on surface area when compared to the dose based on milligrams per kilogram. These procedures in dose‐finding trials are recommended: the usc of randomized assignment of patients, fixed nonescalating doses and the inclusion of a low (ineffective) dose (12.5 mg. per kilogram), and separation of drug toxicity from natural disease progression.

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