This phase I trial is studying the side effects and best dose of 1-methyl-D-tryptophan in treating patients with metastatic or refractory solid tumors that cannot be removed by surgery. Biological therapies, such as 1-methyl-D-tryptophan, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by stimulating the immune system.
PRIMARY OBJECTIVES: 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. SECONDARY OBJECTIVES: 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
52
Given orally
Correlative studies
Correlative studies
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States
Virginia Commonwealth University
Richmond, Virginia, United States
Incidence of adverse events, graded according to 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.
Time frame: Up to 4 weeks
MTD or MBED of 1-Methyl-D-tryptophan
A dose limiting toxicity (DLT) will be defined as any adverse events (AEs) occurring during any course when considered possibly, probably, or definitely related to therapy that is part of this study. Unacceptable AEs including any grade 3 or greater toxicity possibly, probably, or definitely due to the study drug (except oral intolerance). The MBED will be determined retrospectively after all data has been collected and an MTD has been determined.
Time frame: Up to 4 weeks
Pharmacokinetics of 1-methy-D-tryptophan
Analyses of secondary endpoints will mainly be of exploratory nature. If needed, non-parametric methods such as the signed rank test and/or Spearman correlation coefficient will be considered to explore preliminarily the treatment effect on the secondary endpoints and its relationships with various potential biomarkers and therapeutic targets.
Time frame: At 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after administration
Change in the tryptophan kynurenine ratio
Descriptive statistics such as means, medians, interquartiles, and standard deviations (SDs) or frequencies and percentages will be reported. When appropriate, confidence intervals also will be included. Change data contrasting post-treatment vs baseline will be summarized similarly. If needed, non-parametric methods such as the signed rank test and/or Spearman correlation coefficient will be considered to explore preliminarily the treatment effect on the secondary endpoints and its relationships with various potential biomarkers and therapeutic targets.
Time frame: Baseline to up to week 5
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Change in the number of circulating CD4+ CD25+ Treg cells
Descriptive statistics such as means, medians, interquartiles, and SDs or frequencies and percentages will be reported. When appropriate, confidence intervals also will be included. Change data contrasting post-treatment vs baseline will be summarized similarly. If needed, non-parametric methods such as the signed rank test and/or Spearman correlation coefficient will be considered to explore preliminarily the treatment effect on the secondary endpoints and its relationships with various potential biomarkers and therapeutic targets.
Time frame: Baseline to up to 4 weeks after completion of study treatment
IDO expression in tumor tissue
Descriptive statistics such as means, medians, interquartiles, and SDs or frequencies and percentages will be reported. When appropriate, confidence intervals also will be included. Change data contrasting post-treatment vs baseline will be summarized similarly. If needed, non-parametric methods such as the signed rank test and/or Spearman correlation coefficient will be considered to explore preliminarily the treatment effect on the secondary endpoints and its relationships with various potential biomarkers and therapeutic targets.
Time frame: At baseline