A phase I and pharmacokinetic clinical trial of oral administration of the acyclic retinoid NIK-333

Abstract

3108 Background: NIK-333 is an acyclic retinoid, polyprenoic acid, that prevents recurrence of hepatocellular carcinoma (HCC) after curative treatment (New Eng J Med 334:1561). We are conducting clinical trials of NIK-333 in HCC patients (pts) in order to establish its toxicity and pharmacokinetic profiles and to reconfirm its effectiveness. Methods: This study assessed the maximum tolerated dose [MTD], dose-limiting toxicities [DLT] and PK of NIK-333 administered orally at doses ranging from 300 to 900 mg/d. Thirty-three HCC pts who were free of disease after hepatic resection or percutaneous ethanol injection and met the entry criteria were enrolled. The total daily dose was taken as a single dose (single-dosing test) followed by a week of rest and then divided into two equal doses taken after breakfast and supper given for 48 consecutive weeks (repetitive-dosing test). Pharmacokinetic (PK) samples of blood and urine were collected in the single-dosing test, and blood samples were collected on days 1, 15, 29, 57, 85, 113, 141, 169, and 336 in the repetitive-dosing test, and on days 84 and 169 in the observation period after termination of administration. Results: Twelve pts treated at the starting dose level of 300 mg/d tolerated treatment well with no DLT noted. When dose was increased to 600 mg/d, 2 of 12 pts treated had grade 3 elevation of γ-glutamyl transpeptidase experienced twice during administration as a DLT. At the final dose level of 900 mg/d, 3 of 9 pts experienced grade 3 hypertension as a DLT. As the dose was increased from 300 to 900 mg/d in the single-dosing test, the mean AUC increased from 841.3 to 4009.7 ng · hr/mL, and the mean Cmax increased from 316.1 ng/mL to 906.9 ng/mL. In the repetitive-dosing test, there was no significant difference between days 1 and 169 in mean AUC0–6hr or Cmax. Conclusions: NIK-333 was well-tolerated when administrated orally at doses up to 600mg/d for 48 weeks. Hypertension was noted as a DLT at a dose level of 900mg/d. A phase II/III study is ongoing to confirm effectiveness in preventing recurrence of HCC. No significant financial relationships to disclose.