A Phase 1 Study of 1-Methyl-D-tryptophan in Patients With Advanced Malignancies
I. 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.
II. To establish a maximally tolerated dose (MTD) or maximally biological effective dose
(MBED) of 1-MT for future phase II and III trials.
I. 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.
II. 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.
III. To analyze the IDO expression of different tumor types through IDO immunohistochemical
staining of paraffin-preserved specimens.
IV. To perform high performance liquid chromatography on patient urine samples to assess how
1-MT is cleared renally.
OUTLINE: This is a dose-escalation study.
Patients receive oral 1-methyl-d-tryptophan (1-MT) once or twice daily on days 1-28.
Treatment repeats every 28 days for up to 12 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 up for 4 weeks.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and toxicity
Toxicity will be graded using the standard Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patients who receive any amount of the study drug will be evaluable for toxicity.
Weekly, assessed up to 4 weeks
H. Lee Moffitt Cancer Center and Research Institute
United States: Food and Drug Administration
|H. Lee Moffitt Cancer Center and Research Institute||Tampa, Florida 33612|
|Virginia Commonwealth University||Richmond, Virginia|