Study of the Effect of GTx-758 on Serum PSA and Testosterone in Men With Prostate Cancer

Phase II, Open Label Study of the Effect of GTx-758 as Secondary Hormonal Therapy on Serum PSA and Serum Free Testosterone Levels in Men With Metastatic Castration Resistant Prostate Cancer Maintained on Androgen Deprivation Therapy

Protocol G200712 is a Phase II, exploratory study to assess the effects of GTx-758 on serum prostate specific antigen (PSA) response ans serum PSA progression in men with Metastatic Castration Resistant Prostate Cancer (mCRPC) on Androgen Deprivation Therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, or orchidectomy. This study will also assess the venous thromboembolism (VTE) risk of lower doses of GTx-758.

Inclusion Criteria:

• Be over age 18 years
• Be able to Communicate effectively with the study personnel
• Have histologically confirmed prostate cancer
• Have castration resistant prostate cancer patients with radiographic evidence of metastatic disease (T any - N any - MI)
• ECOG performance status of 0 to 2
• Have been treated with ADT (chemical or surgical) for at least 6 months
• Have a castrate level of serum total testosterone (< 50ng/dL)
• Have a history of serum PSA response on ADT. A serum PSA response is an undetectable level of serum PSA (≤ 0.2/mL) or at least a 90% reduction in serum PSA from the serum PSA value prior to the initiation of treatment to < 10ng/mL
• Have a rising serum PSA on two successive assessments at least 2 weeks apart and serum PSA levels ≥ 2ng/mL or > 2 ng/mL and a 25% increase above the nadir from the ADT.
• Be continued on ADT throughout this study
• give written informed consent prior to any study specific procedures
• subjects must agree, if not already on anticoagulation therapy or aspirin, to take 81 mg aspirin daily throughout the duration of their participation in this study and for 30 days after completion of dosing with GTx-758.
• Subjects must agree to use acceptable methods of contraception:
• If their female partners are pregnant or lactating, acceptable methods of contraception from the time of the first administration of study medication until 3 months following administration of the last dose of study medication must be used. Acceptable methods are: condom used with spermicidal foam/gel/film/cream/suppository. If the subject has undergone surgical sterilization (vasectomy with documentation of azospermia), a condom with spermicidal foam/gel/film/cream/suppository should be used.
• If the male subject's partner could become pregnant, use acceptable methods of contraception from the time of the first administration of study medication until 3 months following administration of the last dose of study medication.Acceptable methods of contraception are as follows: condom with spermicidal foam/gel/film/cream/suppository [i.e., barrier method of contraception], surgical sterilization (vasectomy with documentation of azospermia) and a barrier method {condom used with spermicidal foam/gel/fil/cream/suppository}, the female partner uses oral contraceptives (combination estrogen/progesterone pills), injectable progesterone or subdermal implants and a barrier method {condom used with spermicidal foam/gel/film/cream/suppository}.
• If the female partner has undergone documented tubal ligation (female sterilization), a barrier method {condom used with spermicidal foam/gel/film/cream/suppository} should be used
• If the female partner has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS), a barrier method {condom with spermicidal foam/gel/film/cream/suppository} should also be used.

Exclusion Criteria:

• Known hypersensitivity or allergy to estrogen or estrogen like drugs

• Need for urgent chemotherapy, radiation therapy or surgical intervention for prostate cancer in the opinion of the investigator;

• Any disease or condition (medical or surgical) which might compromise the hematologic, cardiovascular, endocrine, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk

• Subjects with a personal history of abnormal blood clotting or thrombotic disease (venous or arterial thrombotic events such as history of stroke, deep vein thrombosis (DVT), and or pulmonary embolus (PE)).

• Any subjects, as determined by a central laboratory, with

  1. a modified activated protein C reaction ratio ≤ 2.5 and a Factor V Leiden gene mutation,
  2. an antithrombin level below the lower limit of the normal range,
  3. an antiphospholipid antibody level that is indeterminate, positive, or outside the normal range,
  4. or a prothrombin gene mutation

• Symptomatic congestive heart failure (NYHA Class III - IV), unstable angina pectoris, cardiac arrhythmia, or history of atrial fibrillation

• The presence of consistently abnormal laboratory values which are considered clinically significant. In addition, any subject with liver enzymes (ALT or AST) above 2 times the upper limit of normal, total bilirubin above 2 times the upper limit of normal, or serum creatinine above 1.5 times the upper limit of normal will NOT be admitted to the study.

• Received an investigational drug within a period of 90 days prior to the enrollment in the study.

• Received the study medication GTx-758 previously;

• Currently taking testosterone, testosterone like agents, 5a-reductase inhibitor (finasteride, dutasteride),or antiandrogens (bicalutamide, flutamide or nilutamide). Subjects taking a 5a-reductase inhibitor or one of these antiandrogens may be eligible if the subject undergoes a 6 week washout period after stopping therapy. The subject must have at least two rising serum PSA levels at least 2 weeks apart after therapy with these 5a-reductase inhibitor or these antiandrogens have been stopped (antiandrogen withdrawal)and complete the 6-week washout period to be eligible;

• Have previously taken or are currently taking diethylstilbestrol, other estrogens, abiraterone or ketoconazole or any other inhibitor of CYP17 (17a-hydroxylase/C17,20-lyase);

• Currently having radiation therapy to prostate for cancer control (radiation to bone to relieve pain is acceptable)

• Have previously taken or are currently taking enzalutamide;

• Have previously received cytotoxic chemotherapy for prostate cancer;

• Recent hospitalization (within 30 days of screening);

• Recent surgery (within 30 days of screening);

• Have taken body building or fertility supplements within 4 weeks of admission into the study;

• Have been previously diagnosed or treated for active cancer (other than prostate cancer or non-melanoma skin cancer)within the previous five years;

• Have a BMI > 35.