Diindolylmethane in Treating Patients Undergoing Surgery for Stage I or Stage II Prostate Cancer

PRIMARY OBJECTIVES:

I. Compare neoadjuvant prostatic diindolylmethane (DIM^) concentrations in patients with
stage I or II adenocarcinoma of the prostate treated with DIM vs placebo prior to radical
prostatectomy.

SECONDARY OBJECTIVES:

I. Compare the ratio of urinary 2-hydroxyestrone:16-hydroxyestrone in patients treated with
these regimens.

II. Compare plasma levels of total prostate-specific antigen (PSA) in patients treated with
these regimens.

III. Compare serum testosterone levels in patients treated with these regimens. IV. Compare
the ratio of plasma insulin-like growth factor (IGF)-1:IGF binding protein-3 in patients
treated with these regimens.

V. Compare cytochrome p450 mRNA expression of CYP1A1, CYP1A2, CYP2B1, and CYP3A enzymes in
circulating polymorphonuclear leukocytes (PMNs) and in fresh frozen tissue in patients
treated with these regimens.

VI. Compare DIM blood steady-state concentrations in patients treated with these regimens.

VII. Identify polymorphisms of CYP1A1, CYP1A2, CYP2B1, and CYP3A in circulating PMNs in
patients treated with these regimens.

VIII. Compare tissue levels of PSA, androgen receptor, Ki-67, and caspase 3 in patients
treated with these regimens.

OUTLINE:

This is a randomized, placebo-controlled, multicenter study. Patients are randomized to 1 of
3 treatment arms.

Arm I: Patients receive low-dose, nutritional-grade oral diindolylmethane (DIM) twice daily
for 21-28 days in the absence of disease progression or unacceptable toxicity. Treatment may
continue for up to 60 days, if surgery is delayed.

Arm II: Patients receive high-dose, nutritional-grade oral DIM twice daily as in arm I.

Arm III: Patients receive oral placebo twice daily for 21-28 days in the absence of disease
progression or unacceptable toxicity. Treatment may continue for up to 60 days, if surgery
is delayed.

Patients in all arms undergo surgical resection of their tumor within 1 day after completion
of DIM or placebo.

Patients undergo blood, tissue, and urine sample collection periodically during study for
immunohistochemical (IHC)/molecular analyses and pharmacokinetic and pharmacogenomic
correlative studies. Patient specimens are assessed for DIM levels in plasma and tissue (by
liquid chromatography/mass spectrometry [LC/MS]) and for biologic response to DIM (by TUNEL
assay). Intermediate biomarkers of DIM activity are also assessed, including urinary
2-hydroxyestrone:16-hydroxyestrone ratio (by LC/MS assay), plasma total prostate-specific
antigen (PSA), plasma insulin-like growth factor (IGF)-1:IGF binding protein-3 ratio (by
ELISA), and tissue androgen receptor, PSA, Ki-67, and caspase 3 (by immunohistochemistry).
Cytochrome p450 induction and gene expression (CYP1A1, CYP1A2, CYP2B1, CYP3A) are also
assessed in tissue and plasma by semiquantitative real-time polymerase chain reaction.

Criteria:

- Histologically confirmed adenocarcinoma of the prostate

- Clinical stage T1 or T2 a, b, or c (stage I-II disease)

- Disease is confined within the prostate gland

- Candidate for radical prostatectomy

- ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100%

- WBC normal

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 10 g/dL

- AST =< 1.5 times upper limit of normal

- Creatinine =< 2.0 mg/dL

- Fertile patients must use effective contraception

- No history of allergic reactions attributed to diindolylmethane (DIM^), any of the
inactive ingredients contained in BioResponse-DIM^NG or placebo, or to compounds of
similar chemical or biologic composition

- No concurrent uncontrolled illness including, but not limited to, any of the
following: Ongoing or active infection, Symptomatic congestive heart failure,
Unstable angina pectoris, Cardiac arrhythmia, No psychiatric illness or social
situation that would preclude study compliance

- No prior chemotherapy, hormonal therapy, brachytherapy, or external radiotherapy for
prostate cancer

- No concurrent nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid,
ibuprofen, naproxen sodium, or cyclooxygenase-2 inhibitors

- No concurrent systemic therapy for any other cancer

- No other concurrent investigational agents

- No concurrent p450 inducers or inhibitors, including any of the following:
Carbamazepine, Clarithromycin, Fluconazole, Fosphenytoin, Itraconazole, Ketoconazole,
Phenobarbital, Phenytoin, Rifabutin, Rifampin

- No concurrent finasteride or dutasteride

- No more than 1 serving of cruciferous vegetables per day for duration of study

- Cruciferous vegetables include the following: broccoli, cauliflower, brussels
sprouts, cabbage, arugula, watercress, bok-choy, turnip greens, mustard greens,
collard greens, rutabaga, Napa or Chinese cabbage, radishes, turnips, kohlrabi, and
kale

- Bilirubin normal

- At least 21 days since prior surgery