Primary Outcome Measures:
- Safety and toxicity [ Designated as safety issue: Yes ]
- Maximally biological effective dose [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Pharmacokinetics [ Designated as safety issue: No ]
- Biological correlates [ Designated as safety issue: No ]
OBJECTIVES:
Primary
- To assess the toxicity, safety, and pharmacokinetics of escalating doses of 1-methyl-d-tryptophan (1-MT), a competitive inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO), in patients with advanced malignancies.
- To establish a maximally tolerated dose (MTD) or maximally biological effective dose (MBED) of 1-MT for future phase II and III trials.
Secondary
- To assess the ratio of kynurenine to tryptophan in patient blood samples as a means of assessing the effect of 1MT on in vivo IDO activity.
- To ascertain the ability of 1-MT to decrease the number of T-regulatory cells thereby allowing the immune system to target tumor antigens more effectively.
- To analyze the IDO expression of different tumor types through IDO immunohistochemical staining of paraffin-preserved specimens.
- To perform high performance liquid chromatography on patient urine samples to assess how 1-MT is cleared renally.
OUTLINE: This is a multicenter study.
Patients receive oral 1-methyl-d-tryptophan (1-MT) once daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Blood and urine samples are assessed to characterize the pharmacokinetics of 1-MT and renal clearance rate by high performance liquid chromatography, measure tryptophan and kynurenine levels by functional assays, and measure the response of regulatory CD4+ CD25+ T cells by intracellular staining and flow cytometry. Paraffin-embedded tissue samples are analyzed for indoleamine 2,3-dioxygenase (IDO) expression by immunohistochemical staining.
After completion of study treatment, patients are followed for 4 weeks.