Clinical trial NCT00450229: Diindolylmethane in Treating Patients Undergoing Surgery for Stage I or Stage II Prostate Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Adenocarcinoma of the Prostate
Prostate Cancer
Stage I Prostate Cancer
Stage II Prostate Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2007-03-22
Enrollment: 45
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Tissue levels of DIM
timeFrame: Up to 5 years
Secondary outcomes:
measure: Urinary 2-hydroxyestrone/16-hydroxyestrone ratio
timeFrame: Up to 5 years
measure: Total PSA
timeFrame: Up to 5 years
measure: Serum testosterone
timeFrame: Up to 5 years
measure: IGF1:IGFBP-3 ratio
timeFrame: Up to 5 years
measure: Tissue measures of messenger RNA of CYPs (CYP1A2, CYP1A1, CYP2B1, CYP3A)
timeFrame: Up to 5 years
measure: DIM blood steady-state concentrations
timeFrame: Up to 5 years
measure: Measures of androgen receptor, PSA, Ki-67, caspase 3, and TUNEL
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Jason Gee
role: PRINCIPAL_INVESTIGATOR
References: