Perillyl alcohol, a major component of lavender plant extract, is an oral monoterpene, which has antitumor properties in animal mammary cancer models. The drug's mechanism of action has not been fully elucidated, but appears to be distinct from that of cytotoxic chemotherapy, and may be related to modification of cellular growth factors or growth factor receptors. Primary toxicities from animal studies included gastrointestinal (emesis, diarrhea) and renal toxicities (rising BUN and renal lesions). The main toxicities noted in recent Phase I studies at multiple institutions were grade 1-2 gastrointestinal toxicity (nausea, vomiting, eructation, early satiety, anorexia) and fatigue. Additional toxicities observed included diarrhea, constipation, headache, increased creatinine, increased transaminases, and two cases of transient leukopenia. The dosing schedule determined from the Phase I study, and employed in this Phase II trial is 1200 mg/m2 po QID. However, since many patients in the Phase I trial tolerated a dose of 1600 mg/m2/dose without significant problem, patients experiencing minimal toxicities after Cycle 1 will be escalated to 1500 mg/m2 po QID. Forty to fifty metastatic breast cancer patients with measurable disease and no brain metastases, who have failed at least one prior metastatic chemotherapy regimen will be enrolled onto this study. Toxicity data, as well as data on tumor response rate, time to treatment failure, and survival will be collected. Patients will have monthly physical exams, hematology surveys, serum chemistries, electrolytes, serum lipid profiles, and urinalyses while enrolled on the study. Hematology surveys and serum chemistries will be obtained weekly for the first cycle, then every two weeks until cycle 6, then monthly. Additional hematology surveys, serum chemistries, electrolytes, and lipid profiles will be obtained after a dose escalation. Serum and urine pharmacokinetics will be assessed on the majority of patients, over six hours, during Day 1 of Cycles 1 and 2. Pharmacokinetic assessments may continue during subsequent cycles at the investigator's discretion. The effect of perillyl alcohol on plasma TGF-beta, and tumor-cell IGF II receptors and IGF II receptor heterozygosity will also be assessed when available. Disease response will be evaluated every eight weeks, and patients will remain on study until progression, prohibitive toxicity, or consent withdrawal.
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