Nordihydroguaiaretic Acid in Treating Patients With Nonmetastatic Relapsed Prostate Cancer

A Phase I Study of NDGA in Patients With Non-Metastatic Biochemically Relapsed Prostate Cancer

RATIONALE: Nordihydroguaiaretic acid may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of nordihydroguaiaretic acid in treating patients with nonmetastatic relapsed prostate cancer.

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of nordihydroguaiaretic acid (NDGA) in patients with nonmetastatic, biochemically relapsed prostate cancer.

Secondary

• Determine prostate-specific antigen-modulating effects of NDGA in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive oral nordihydroguaiaretic acid (NDGA) twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of NDGA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed prostate cancer, meeting 1 of the following criteria:

  • Androgen-dependent disease (testosterone ≥ 250 ng/mL)
  • Androgen-independent disease (testosterone < 50 ng/mL)

• Received prior definitive therapy for primary prostate cancer comprising any of the following:

  • External-beam radiotherapy with or without hormonal therapy
  • Brachytherapy with or without pelvic external-beam radiotherapy or hormonal therapy
  • Radical prostatectomy with or without adjuvant or salvage radiotherapy
  • Cryotherapy

• Must have evidence of disease progression, as evidenced by elevated prostate-specific antigen (PSA) that has risen serially from post-definitive therapy nadir on 2 determinations taken ≥ 1 week apart

  • Elevated PSA, meeting 1 of the following criteria:

    • At least 1.0 ng/mL post radiotherapy or cryotherapy
    • At least 4 ng/mL post radical prostatectomy

  • Must show disease progression after discontinuation of the antiandrogen (for patients with androgen-dependent disease receiving antiandrogen as part of primary androgen ablation)

• No metastatic disease, confirmed by negative bone scan and negative CT scan or MRI of abdomen/pelvis

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• Absolute neutrophil count ≥ 1,500/mm³
• Hemoglobin ≥ 8.0 g/dL
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• AST ≤ 1.5 times ULN
• No other medical condition that would interfere with study therapy or compliance
• No other active malignancy except previously treated squamous cell or basal cell skin cancer or cancer that has been treated and considered to be at < 30% risk of relapse
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• More than 8 weeks since prior strontium-chloride Sr 89

• More than 4 weeks since first dose of bisphosphonates

• More than 4 weeks since prior major surgery or radiotherapy

• At least 4 weeks since prior hormonal agents, including megestrol or steroids

  • Concurrent luteinizing hormone-releasing hormone analogs allowed to maintain castrate levels of testosterone

• At least 4 weeks since prior and no concurrent saw palmetto, finasteride, or any herbal agent intended to lower PSA

• Prior adjuvant or neoadjuvant androgen-deprivation therapy allowed for androgen-dependent prostate cancer provided that all of the following are met:

  • No more than 8 months of androgen deprivation
  • At least 12 months since last day of effective androgen deprivation
  • Testosterone > 250 ng/mL at enrollment

• Prior hormonal therapy, chemotherapy, or investigational therapy for biochemical relapse allowed

• No concurrent chemotherapeutic, immunotherapeutic, or other investigational agents

• No concurrent radiotherapy

• No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)