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A phase I trial of perillyl alcohol in patients with advanced solid tumors
Christopher G Azzoli1, Vincent A Miller, Kenneth K Ng
1Department of Medicine, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. azzolic@mskcc.org
Purpose:
Perillyl alcohol is a plant-derived lipid with preclinical antitumor activity. Its proposed mechanism of action involves inhibition of post-translational isoprenylation of small G proteins, including the proto-oncogene p21- ras, thereby blocking signal transduction. This phase I trial was conducted to determine the optimal dose of perillyl alcohol.
Methods:
The study group comprised 21 adults with advanced solid tumors who were treated with perillyl alcohol, delivered orally, four times daily, without interruption. Doses ranged from 4,800 to 11,200 mg/m(2) per day.
Results:
The maximum tolerated dose (MTD) for this schedule was determined to be 8400 mg/m(2) per day. The dose-limiting toxicities in this trial were nausea and vomiting, encountered in all patients at the highest dose level. No antitumor activity was observed. Pharmacokinetic data suggest dose-dependent increases in C(max) of perillic acid, a metabolite of perillyl alcohol, but with high inter- and intrapatient variability.
Conclusions:
The MTD of perillyl alcohol for this schedule was determined to be 8400 mg/m(2) per day. This is higher than the MTDs determined in other similar phase I trials. This may have been due to the fact that the gastrointestinal symptoms caused by perillyl alcohol are highly subjective, with high interpatient variability. Phase II trials of perillyl alcohol in hormone-refractory prostate, breast, ovarian and colorectal cancer using doses in the range 4800-6400 mg/m(2) per day are underway.
Insights
The maximum tolerated dose of perillyl alcohol was determined to be 8400 mg/m(2) daily for advanced solid tumors. Nausea and vomiting were dose-limiting toxicities, with no observed antitumor activity in this phase I trial.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Perillyl alcohol is a plant-derived compound with preclinical evidence of antitumor effects.
- Its mechanism involves inhibiting the isoprenylation of small G proteins, crucial for signal transduction pathways like p21-ras.
- This inhibition is proposed to block cancer cell proliferation and survival.
Purpose of the Study:
- To determine the optimal dose of perillyl alcohol in patients with advanced solid tumors.
- To establish the maximum tolerated dose (MTD) for oral administration.
- To identify dose-limiting toxicities associated with perillyl alcohol treatment.
Main Methods:
- A phase I clinical trial involving 21 adult patients with advanced solid tumors.
- Oral administration of perillyl alcohol four times daily without interruption.
- Dose escalation from 4,800 to 11,200 mg/m(2) per day.
Main Results:
- The maximum tolerated dose (MTD) was established at 8,400 mg/m(2) per day.
- The primary dose-limiting toxicities were nausea and vomiting, observed at the highest dose level.
- No significant antitumor activity was observed in this phase I study.
Conclusions:
- The MTD of perillyl alcohol for the tested schedule is 8,400 mg/m(2) daily, which is higher than in previous trials.
- Gastrointestinal toxicities, such as nausea and vomiting, are subjective and exhibit high interpatient variability.
- Phase II trials are ongoing to evaluate perillyl alcohol in specific cancers at lower doses.