Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer

Purpose: D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. Methods: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m(2) per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of D-limonene at 8 g/m(2) per day. Intratumoral monoterpene levels were measured in two patients. Results: The MTD was 8 g/m(2) per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m(2) per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (C-max) for D-limonene ranged from 10.8 +/- 6.7 to 20.5 +/- 11.2 mu M. Predominant circulating metabolites were perillic acid (C-max 20.7 +/- 13.2 to 71 +/- 29.3 mu M), dihydroperillic acid (C-max 16.6 +/- 7.9 to 28.1 +/- 3.1 mu M), limonene-1,2-diol (C-max 10.1 +/- 8 to 20.7 +/- 8.6 mu M), uroterpenol (C-max 14.3 +/- 1.5 to 45.1 +/- 1.8 mu M), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of D-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. Conclusions. D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.