Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Closed	18 and over	NCI	WCCC-CO05186 WCCC-H2006-0255, WCCC-06-1270-02, UWI05-7-01, NCT00450229

Objectives

Primary

1. 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

1. Compare the ratio of urinary 2-hydroxyestrone:16-hydroxyestrone in patients treated with these regimens.
2. Compare plasma levels of total prostate-specific antigen (PSA) in patients treated with these regimens.
3. Compare serum testosterone levels in patients treated with these regimens.
4. Compare the ratio of plasma insulin-like growth factor (IGF)-1:IGF binding protein-3 in patients treated with these regimens.
5. 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.
6. Compare DIM blood steady-state concentrations in patients treated with these regimens.
7. Identify polymorphisms of CYP1A1, CYP1A2, CYP2B1, and CYP3A in circulating PMNs in patients treated with these regimens.
8. Compare tissue levels of PSA, androgen receptor, Ki-67, and caspase 3 in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• 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

Prior/Concurrent Therapy:

• No prior chemotherapy, hormonal therapy, brachytherapy, or external radiotherapy for prostate cancer
• At least 21 days since prior surgery
• 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

Patient Characteristics:

• ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100%
• WBC normal
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL
• Bilirubin normal
• 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

Expected Enrollment

A total of 45 patients will be accrued for this study.

Outcomes

Tissue levels of diindolylmethane (DIM) as measured by liquid chromatography/mass spectrometry (LC/MS) assay after completion of study treatment

Ratio of urinary 2-hydroxyestrone:16-hydroxyestrone as measured by LC/MS assay at 2 weeks and after completion of study treatment
Ratio of plasma insulin-like growth factor (IGF)-1:IGF binding protein-3 and plasma total prostate-specific antigen (PSA) as measured by ELISA at 2 weeks and after completion of study treatment
Serum testosterone as measured at 2 weeks and after completion of study treatment
mRNA expression of CYP1A1, CYP1A2, CYP2B1, and CYP3A enzymes in serum and fresh frozen tissue as measured by semiquantitative real-time polymerase chain reaction
Polymorphisms of CYP1A1, CYP1A2, CYP2B1, and CYP3A enzymes in polymorphonuclear leukocytes (PMNs) as measured by genotyping at 2 weeks and after completion of study treatment
DIM blood steady-state concentrations as measured by LC/MS at 2 weeks and after completion of study treatment
PSA, androgen receptor, Ki-67, and caspase 3 as measured by immunohistochemistry at 2 weeks and after completion of study treatment
Safety as measured by NCI CTCAE v3.0

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.

Trial Contact Information

Trial Lead Organizations

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center

Jason Gee, MD, Principal investigator		Ph: 608-262-2369; 800-622-8922

Registry Information
Official Title		Phase Ib Placebo-Controlled Trial of Diindolylmethane (BR-DIMNG) in the Study of Modulation of Intermediate Endpoint Markers in Patients with Prostate Cancer who are Undergoing Prostatectomy
Trial Start Date		2006-10-01
Registered in ClinicalTrials.gov		NCT00450229
Date Submitted to PDQ		2007-01-31
Information Last Verified		2009-02-23
NCI Grant/Contract Number		CN35153, CA14520