Primary Outcome Measures:
- Adverse events, vital signs, physical examination findings, concomitant medications and laboratory tests (hematology, serum chemistry, cardiac enzymes endocrine levels and urinalysis). [ Time Frame: Cycle 1: Weeks 1, 2, 3 and 4, then every 4 weeks thereafter. ] [ Designated as safety issue: No ]
- Chest x-ray. [ Time Frame: Done at screening only - then, as clinically indicated. ] [ Designated as safety issue: No ]
- Electrocardiogram. [ Time Frame: Cycle 1: Weeks: 1 and 2, then week 1 of each subsequent cycle. ] [ Designated as safety issue: No ]
- Eastern Cooperative Oncology Group (ECOG) performance status. [ Time Frame: Cycle 1: Week 1, then week 1 of each subsequent cycle. ] [ Designated as safety issue: No ]
- Calculated ejection fractions. [ Time Frame: Cycle 2: Week 1 and every subsequent cycle (once every 28 days). ] [ Designated as safety issue: No ]
- Study compliance and monitoring. [ Time Frame: Weeks: 0, 1, 2, 3 and 4. After Cycle 1 ( the first 28 days) subjects are seen only once every 4 weeks (28 days) unless clinically indicated. ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Endocrine levels (serum testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, luteinizing hormone and cortisol). [ Time Frame: Cycle 1: Weeks: 0, 1, 2, 3, 4 and week 1 of each subsequent Cycle. ] [ Designated as safety issue: No ]
- Prostate-specific antigen response. [ Time Frame: Cycle 1: Weeks 1 and 3, then week 1 of each subsequent cycle. ] [ Designated as safety issue: No ]
- Objective disease response by modified response evaluation criteria in solid tumors (RECIST) criteria and pharmacokinetic parameters. [ Time Frame: At Screening and every 12 weeks after study entry (after every 3 cycles of treatment). ] [ Designated as safety issue: No ]
Prostate cancer is the most common cancer diagnosed and the second most common cause of cancer death in men in North America. Current treatment strategies for hormone-sensitive prostate cancer includes targeting the reduction of circulating steroid hormones, or blocking their action in target tissues via androgen suppression either by surgical or medical castration (treatment with luteinizing hormone-releasing hormone). Unfortunately, surgical or medical forms of castration only remove the testicular source of androgen; they do not impact precursor molecules produced by the adrenal glands. These precursor molecules are subsequently metabolized to active androgens in the peripheral tissues, which then induce continued prostate tumor growth via androgen receptors. Subjects with locally advanced and metastatic disease have a poor prognosis. Hormonal therapy in the form of medical or surgical castration can induce significant long-term remissions. However, development of androgen-independent disease is inevitable and therapeutic options are limited. Prognosis is poor with a median survival of less than 12 months for symptomatic subjects.
An alternative therapeutic strategy for androgen deprivation is the use of antiandrogens. Antiandrogens, such as bicalutamide, flutamide, and nilutamide, inhibit the stimulatory effects of testosterone and dihydrotestosterone at the cellular androgen receptor level as competitive inhibitors. The most widely used antiandrogen, bicalutamide, has been compared with castration in clinical trials. In multicenter trials with long-term follow-up for survival, bicalutamide monotherapy was less effective than castration with respect to survival (a 6 week difference) in subjects with metastatic disease and not significantly different from castration with respect to either survival or time to progression in nonmetastatic, locally advanced prostate cancer. Side effects of bicalutamide and other antiandrogen treatments include hot flashes, breast pain, and gynecomastia.
Mitoxantrone in combination with prednisone has been shown to produce an improved palliative response rate and a longer duration of response but no improvement in overall survival compared with prednisone alone. Docetaxel a taxane, was approved for use in combination with prednisone for the treatment of metastatic androgen-independent prostate cancer in 2004 based on results of 2 randomized trials that reported a statistically significant median survival benefit of 2 to 3 months compared with mitoxantrone. High-dose ketoconazole, an antifungal agent, with 17m 20-lyase inhibition activity, has been used off-label in combination with hydrocortisone (to offset cortisol suppression as a side effect of ketoconazole), to reduce adrenally-derived androgens in androgen-independent prostate cancer, and is one treatment option for subjects with advanced prostate cancer progressing after androgen deprivation.
TAK-700, a nonsteroidal inhibitor of 17,20-lyase, is being developed as an endocrine therapy for relevant hormone-sensitive cancers like prostate cancer.
Subjects participating in this study will have been diagnosed with metastatic, androgen-independent prostate cancer for which second line therapy is indicated. Study visits will be scheduled at least weekly during initial treatment periods, and every 4 weeks thereafter until disease progression or an adverse event.