Diindolylmethane in Treating Patients With Nonmetastatic Prostate Cancer That Has Not Responded To Previous Hormone Therapy

Phase I Study of Bioresponse-dim in Non-Metastatic, Hormone-Refractory Prostate Cancer Patients With Rising Serum PSA

RATIONALE: Diindolylmethane may slow the growth of prostate cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of diindolylmethane in treating patients with nonmetastatic prostate cancer that has not responded to previous hormone therapy.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: BR-DIM

Detailed Description

OBJECTIVES:

Primary

• Establish the maximum tolerated dose, dose-limiting toxicity, and a recommended phase II dose of absorption-enhanced diindolylmethane (BioResponse-DIM^® [BR-DIM]) in patients with nonmetastatic, hormone-refractory prostate cancer and rising serum prostate-specific antigen (PSA) levels.
• Evaluate the toxicities of BR-DIM.

Secondary

• Evaluate the plasma pharmacokinetics of twice daily oral administration of BR-DIM in this patient population.
• Evaluate the effect of BR-DIM supplementation on serum PSA level.
• Correlate changes in expression levels of lymphocytes NF-kB with serum PSA levels in patients taking BR-DIM supplementation.
• Determine quality of life measures in patients taking BR-DIM supplementation.

OUTLINE: This is an open-label, dose-escalation study.

Patients receive oral absorption-enhanced absorption-enhanced diindolylmethane (BioResponse-DIM^® [BR-DIM]) twice daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of BR-DIM until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

Quality of life is assessed at baseline, on day 1 of each course, and at the completion of study therapy.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Detroit, Michigan, United States, 48334
      • Weisberg Cancer Treatment Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

DISEASE CHARACTERISTICS:

• Histologically proven adenocarcinoma of the prostate
• Prostate specific antigen (PSA)-only failure after local therapy (surgery, radiation therapy, brachytherapy, or cryotherapy)

• Rising PSA despite androgen-deprivation therapy with castrate levels of testosterone (< 50 ng/dL)

  • Two successive rising PSA levels at least 1 week apart
  • PSA ≥ 5 ng/mL
• Patients with a history of combined hormonal therapy must continue luteinizing-hormone releasing-hormone agonist treatment but must demonstrate rising PSA after anti-androgen withdrawal
• No evidence of distant metastasis by bone scan and CT scan
• No known brain metastases requiring active therapy

PATIENT CHARACTERISTICS:

• ECOG performance status ≤ 3
• Life expectancy ≥ 12 weeks
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 8.0 g/dL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT and/or SGPT ≤ 2.5 times ULN AND alkaline phosphatase normal OR alkaline phosphatase ≤ 4 times ULN AND SGOT and/or SGPT normal
• Creatinine clearance ≥ 60 mL/min OR creatinine normal
• Fertile patients must use effective contraception

• None of the following conditions within the past 6 months:

  • Myocardial infarction
  • Severe or unstable angina
  • Symptomatic congestive heart failure
  • Cerebrovascular accident or transient ischemic attack
  • Coronary/peripheral artery bypass grafting
• No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 28 days since prior radiotherapy
• At least 28 days since prior investigational agents for treatment of prostate cancer
• At least 4 weeks since prior flutamide
• At least 6 weeks since prior bicalutamide
• No other concurrent antineoplastic agents
• No concurrent warfarin-related anticoagulants
• No concurrent proton-pump inhibitor drugs for gastroesophageal reflux disease (e.g., rabeprazole, esomeprazole magnesium, lansoprazole, omeprazole, or pantoprazole sodium)

• No concurrent micronutrient supplements or dietary soy products

  • One daily multivitamin allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BR-DIM; BR-DIM will be administered at a starting dose of 75 mg po twice daily. Patients will be instructed to take tablets twice daily with 8 ozs. of water, with/without food. A study calendar will be provided and patients will be asked to fill the appropriate boxes when they take their study capsules. One treatment cycle is 28 days.	Drug: BR-DIM; 75 mg orally (po) twice daily. May continue treatment for 12 months, however patients will be taken off study if their disease progresses, or have intolerable side effects.; Other Names: oral microencapsulated diindolylmethane

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose (MTD), Dose limiting toxicity (DLT) & toxicities during study and for 30 days after	During study and for 30 days after

Secondary Outcome Measures

Outcome Measure	Time Frame
Plasma pharmacokinetics as measured by occurrences of toxicity	At baseline; Cycle 1 Day 1 at 20, 60, 120, 180, 240, and 480 minutes
Serum prostate specific antigen as measured by complete plasma concentration-time profile	At baseline, Day 1 of each cycle and at study termination
Correlate changes in expression levels of NF-kB lymphocytes in with serum prostate specific antigen levels by serum prostate specific antigen level	At baseline, Cycle 2 and study termination
Quality of life (QOL) by Life Orient. Test-Rev., Duke-UNC Func. Social Support Questionnaire, EORTC QOL questionnaire, QLQ-PR25 questionnaire, and the Hosp. Anxiety & Depression Scale	At baseline, day 1 of each cycle and study termination

Collaborators and Investigators

• Sponsor: Barbara Ann Karmanos Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Elisabeth I. Heath, MD, Barbara Ann Karmanos Cancer Institute

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: March 21, 2006
• First Submitted That Met QC Criteria: March 21, 2006
• First Posted (Estimate): March 22, 2006

Study Record Updates

• Last Update Posted (Estimate): January 15, 2014
• Last Update Submitted That Met QC Criteria: January 14, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: stage III prostate cancer; stage IV prostate cancer; recurrent prostate cancer; adenocarcinoma of the prostate; stage I prostate cancer; stage II prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Anticarcinogenic Agents; 3,3'-diindolylmethane
• Other Study ID Numbers: CDR0000462637; P30CA022453 (U.S. NIH Grant/Contract); WSU-D-2979; WSU-0507002581