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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


Phase 1
18 Years
N/A
Not Enrolling
Male
Adenocarcinoma of the Prostate, Prostate Cancer, Stage I Prostate Cancer, Stage II Prostate Cancer

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Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Tissue levels of DIM

Outcome Description:

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).

Outcome Time Frame:

Up to 5 years

Safety Issue:

No

Principal Investigator

Jason Gee

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00905

NCT ID:

NCT00450229

Start Date:

February 2007

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Prostate
  • Prostate Cancer
  • Stage I Prostate Cancer
  • Stage II Prostate Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001