1-Methyl-D-Tryptophan in Treating Patients With Metastatic or Refractory Solid Tumors That Cannot Be Removed By Surgery

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.

Inclusion Criteria:

- Histologically confirmed solid malignancy that is metastatic or unresectable and for
which standard effective antineoplastic therapy does not exist or is no longer
effective

- Patients are eligible for enrollment into the trial regardless of the types of
previous therapies administered

- Patients with known brain metastases will only be eligible after their tumors have
been treated with definitive resection and/or radiotherapy and they are
neurologically stable for at least 1 month off steroids

- No known untreated brain metastases

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Life expectancy > 4 months

- WBC ≥ 3,000/μL

- ANC ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- No history of gastrointestinal disease causing malabsorption or obstruction,
including, but not limited to, any of the following:

- Crohn's disease

- Celiac sprue

- Tropical sprue

- Bacterial overgrowth/blind-loop syndrome

- Strictures

- Adhesions

- Achalasia

- Bowel obstruction

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective double-method contraception during and for at
least 1 month after completion of study treatment

- No history of allergic reactions (significant urticaria, angioedema, anaphylaxis)
attributed to compounds of similar chemical or biologic composition to
1-methyl-d-tryptophan (including L-tryptophan or 5-hydroxy-tryptophan supplements)

- No active autoimmune disease (i.e., psoriasis, extensive atopic dermatitis, asthma,
inflammatory bowel disorder, multiple sclerosis, uveitis, vasculitis), chronic
inflammatory condition, or any condition requiring concurrent use of any systemic
immunosuppressants or steroids for any reason

- Mild-intermittent asthma requiring only occasional beta-agonist inhaler use or mild
localized eczema allowed

- No uncontrolled concurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Myocardial infarction or percutaneous coronary interventions within the past 6
months

- Cardiac arrhythmia

- Active autoimmune diseases

- Major psychiatric illness or social situation that would limit compliance with
study requirements as judged by the primary investigator at each site

- Patients with well-controlled, chronic medical conditions under the supervision of
the patient's primary physician (i.e., hypertension, hyperlipidemia, coronary heart
disease, diabetes mellitus) are eligible

- No HIV-positive patients or patients with other acquired/inherited immunodeficiencies

- No other active malignancy

- No concurrent immunosuppressants, including steroids

- Recovered from all prior therapy

- No prior gastric bypass surgery

- No prior extensive small bowel resection

- No prior experimental active immunotherapy consisting of targeted monoclonal
antibodies or pharmaceutical compounds

- Commercially available active immunotherapy (e.g., adjuvant interferon) must
have completed therapy over 1 year prior to enrollment and have no evidence of
autoimmune sequelae

- Prior therapy with approved monoclonal antibodies (e.g., bevacizumab, cetuximab,
panitumumab, or trastuzumab) allowed

- At least 4 weeks since prior and no other concurrent investigational agents

- More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas
or mitomycin C)

- No concurrent supplements containing L-tryptophan or derivatives

- No patients with an allo-transplant of any kind (including those with a xenograft
heart valve)

- No other concurrent commercial agents or therapies