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

Study Overview
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Brief Summary
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Giving diindolylmethane, a substance found in cruciferous vegetables, may help doctors learn more about how diindolylmethane is used by the body. This randomized phase I trial is studying the side effects and best dose of diindolylmethane compared with a placebo in treating patients undergoing radical prostatectomy for stage I or stage II prostate cancer.

Detailed Description
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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.

Official Title
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Phase Ib Placebo-Controlled Trial of Diindolylmethane (BR-DIM) in the Study of the Modulation of Intermediate Endpoint Markers in Patients With Prostate Cancer Who Are Undergoing Prostatectomy

Conditions
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Adenocarcinoma of the Prostate, Prostate Cancer, Stage I Prostate Cancer, Stage II Prostate Cancer

Intervention / Treatment
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* Drug: diindolylmethane
* Drug: placebo
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: diindolylmethane<br>* Given PO<br>* Other names: DIM;Procedure: therapeutic conventional surgery<br>* Undergo surgical resection<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Arm II<br>Patients receive high-dose, nutritional-grade oral DIM twice daily as in arm I. | Drug: diindolylmethane<br>* Given PO<br>* Other names: DIM;Procedure: therapeutic conventional surgery<br>* Undergo surgical resection<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Placebo Comparator: Arm III<br>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. | Drug: placebo<br>* Given PO<br>* Other names: PLCB;Procedure: therapeutic conventional surgery<br>* Undergo surgical resection<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tissue levels of DIM | The distribution of levels of DIM will be summarized by treatment arm with descriptive statistics. For the primary comparison between the placebo group and the DIM groups combined, tissue levels of DIM will be compared using Student t-test. In the case of violation of normality assumptions, an appropriate transformation of the data such as logarithm will be considered or a nonparametric test such as Wilcoxon rank-sum test will be used for comparison. A dose-response relation will be explored based on the analysis of covariance (ANCOVA). | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary 2-hydroxyestrone/16-hydroxyestrone ratio | Will be summarized by treatment arm with descriptive statistics. | Up to 5 years | 
| Total PSA | Will be summarized by treatment arm with descriptive statistics. | Up to 5 years | 
| Serum testosterone | Will be summarized by treatment arm with descriptive statistics. | Up to 5 years | 
| IGF1:IGFBP-3 ratio | Will be summarized by treatment arm with descriptive statistics. | Up to 5 years | 
| Tissue measures of messenger RNA of CYPs (CYP1A2, CYP1A1, CYP2B1, CYP3A) | Will be summarized by treatment arm with descriptive statistics. | Up to 5 years | 
| DIM blood steady-state concentrations | Will be summarized by treatment arm with descriptive statistics. | Up to 5 years | 
| Measures of androgen receptor, PSA, Ki-67, caspase 3, and TUNEL | Will be summarized by treatment arm with descriptive statistics. | Up to 5 years |